Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:14])[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:17]([O:13][CH:10]1[CH2:11][O:12][C:7]([CH3:14])([CH3:6])[O:8][CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OCC(O)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(OCc2ccccc2)CO1
Yield: 54.2 %

Procedure:
To a N,N-dimethylformamide (200 ml) solution of the 2,2-dimethyl-1,3-dioxan-5-ol (7.1 g, 0.054 mol) obtained in the step (9a), sodium hydride, in oil (2.81 g, 0.064 mol as the content was regarded as 55%) was added at 0° C. and stirred. After benzyl bromide (12.9 ml, 0.108 mol) and tetrabutylammonium iodide (220 mg, 0.001 mol) were added at the same temperature to the mixture, the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate three times. Organic layers were combined, washed five times with water and once with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. After NH silica gel was added, the resultant mixture was concentrated and purified by silica gel column chromatography (elution solvent: heptane, heptane/ethyl acetate=9/1, 4/1, ethyl acetate) to obtain the title compound (6.5 g, 54.5%) as a colorless oil.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>O1CCOCC1.O>[C:1]([NH:6][C:10](=[O:11])[O:12][CH2:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=C(C)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
In 100 g of dioxane, 10 g of methacrylamide and 14.4 g of sodium hydroxide were dissolved and the solution was stirred for 30 minutes at 25°-27° C. Then, 16.6 g of ethyl chloroformate was dissolved in 30 g of dioxane and the solution was added dropwise to the reaction mixture in 3 hours while keeping the reaction temperature of 25° to 30° C. After stirring the solution for 20 minutes, water was added thereto and the solution was neutralized with conc. hydrochloric acid. The solution was extracted with chloroform and the extractant was evaporated in vacuo. The crude product was subjected to NMR assay and 17.2 g of ethyl N-methacryloylcarbamate was isolated.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([OH:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])(=[O:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:4][CH2:5][CH2:6][C:7](=[O:20])[CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(O)CN1C(=O)c2ccccc2C1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of N-(4-acetoxy-2-hydroxybutyl)phthalimide (10.2 g, 36.8 mmol) in CH2Cl2 (185 mL) at 0° C. was treated with molecular seives (18.4 g), N-methylmorpholine oxide (6.46 g, 55.2 mmol), and tetrapropylammonium perruthenate (1.29 g, 3.7 mmol). The mixture was allowed to warm to room temperature over 20 minutes and immediately filtered through silica (using 500 g SiO2 in a coarse glass flitted funnel). The silica was washed with excess diethyl ether (2 L) and concentrated under reduced pressure to afford the desired N-(4-acetoxy-2-oxobutyl)phthalimide (9.22 g, 92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[C:22]([O:24][CH3:25])=[O:23]>C(C(C)=O)C>[CH2:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[C:22]([O:24][CH3:25])=[O:23])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cccc(C(=O)OC)c1C(=O)OC

Procedure:
The starting material can be prepared as follows: 225 g of potassium carbonate and 98 g of allyl bromide are added to a solution of 170.0 g of dimethyl 3-hydroxy-phthalate in 400 ml of methyl ethyl ketone. The mixture is heated to the reflux temperature for 18 hours, whilst stirring, and then filtered, the filter residue is washed with methyl ethyl ketone and the filtrate, combined with the wash liquid, is evaporated under reduced pressure. The residual oily crude product is distilled under reduced pressure; dimethyl 3-allyloxyphthalate is obtained as the main fraction; boiling point 126°-130°/0.015 mm Hg.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:34][O:35][CH3:36])[C:10]([NH:12][CH:13]2[C:32](=[O:33])[N:15]3[C:16]([C:20]([O:22][CH:23]([CH2:28][O:29][CH2:30][CH3:31])[CH2:24][O:25][CH2:26][CH3:27])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:34][O:35][CH3:36])[C:10]([NH:12][CH:13]2[C:32](=[O:33])[N:15]3[C:16]([C:20]([O:22][CH:23]([CH2:28][O:29][CH2:30][CH3:31])[CH2:24][O:25][CH2:26][CH3:27])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOCC(COCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOCC(COCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a stirred solution of 2-ethoxy-1-ethoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.85 g) in methanol (57 ml) was slowly added conc. hydrochloric acid (1.13 ml) at room temperature, and stirred at room temperature for 3 hours. The resultant mixture was poured into ice water (280 ml), adjusted to pH 7 to 8 with an aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate (150 ml). The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was subjected to column chromatography on silica gel with a mixture of chloroform and methaol (30:1). The eluate was concentrated under reduced pressure to give 2-ethoxy-1-ethoxymethylethyl 7-[2-(2-aminothiazol-4-yl]-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.77 g), mp. 95° to 97° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O.C([O-])(=O)C.[Zn+2:16].C([O-])(=O)C>O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[Zn:16]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC(C)C[C@H](N)C(=O)O
Solvent: O
Product: [Zn]
Temperature: 48.888888888888886 °C

Procedure:
Anhydrous L-leucine, 5.2472 g, 0.0400 mole, was dissolved in 30 ml of deionized water and heated to 120° F. Ultra-pure zinc acetate dihydrate, Zn(C2H3O2)2.2H2O, 4.3900 g, 0.0200 mole, was added in small increments over one hour, with stirring. The solution did not clear, so another 20 ml of water was added and the mixture was heated in a boiling water bath to 190° F. for an additional 21/2hours. Water was then added to a total volume of 75 ml, the mixture heated again to 190° F., and gravity filtered. The retained solid was dried at 150° F. for 12 hours, found to weigh 2.717 g, and was analyzed.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Yield: 50.4 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2 g, 7.20 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (1.65 g, 8.64 mmol) and N-ethyldiisopropyl-amine (1.5 mL, 8.64 mmol) is heated at 80° C. in 2-propanol (50 mL) for 8 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous phase is extracted twice with dichloromethane. The organic layers are washed with brine, dried over MgSO4, filtered and evaporated to furnish the title compound (1.41 g) as a grey solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.27 (3H, s), 2.54 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.80 (2H, d), 7.87 (1H, s), 8.72 (1H, s), 9.92 (1H, br s). LCMS: Rt 2.07 min (77.4%), m/z (APCI) 388 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1>C1COCC1>[S:27]1[C:23]([CH2:22][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:12])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: BrCc1cc2ccccc2s1
Reactant: O=C1CCCN1C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2cc3ccccc3s2)CCN1C1CCCCC1
Yield: 71.5 %

Procedure:
Place 1-cyclohexyl-pyrrolidin-2-one (500 mg) in THF (30 mL) and cool to −78° C. Slowly add lithium diisopropylamide (LDA) (2M, 1.5 eq) and stir for 15 minutes. Add 2-bromomethyl-benzo[b]thiophene [J. Med. Chem. (1992) 1176-1183] (815 mg, 3.59 mmol) and stir for 3 hours. Quench with ammonium chloride and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to give 670 mg, 71% of the title compound as a white powder. MS (APCI-pos mode) m/z (rel intensity) 314 (100).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][NH:28][CH3:29]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](=[O:25])(=[O:24])[N:28]([CH3:29])[CH3:27]
Reactant: Nc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CNC
Product: CN(C)S(=O)(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C

Procedure:
A mixture of 5-amino-4-chlorosulphonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.2 g) and dimethylamine (17.6 ml of a 40% aqueous solution) was heated on a steambath for 1 hour, cooled, and poured onto crushed ice (50 g) to give a brown solid. This solid was filtered, dried, and recrystallized from toluene to give 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(N,N-dimethylsulphamoyl)-3-trifluoromethylpyrazole (0.8 g) as light brown crystals, m.p. 177.6-178.6° C.
Reaction SMILES: [Br-:1].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41](O)[CH2:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(OCC)C>[Br:1][CH2:41][CH2:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCC#CCCO
Reactant: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCC#CCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Triphenylphosphonium dibromide (36.8 g, 87.2 mmol) was suspended in diethyl ether at -20° C. and a solution of 3-octyne-1-ol (10.0 g, 79.2 mmol) was added dropwise over a twenty minute period. The mixture was allowed to stir overnight. The mixture was poured into ice-water and solids precipitated which were collected by filtration. The organic layer was separated, washed with 1N aqueous sodium hydroxide, water and dried over magnesium sulfate. The organic layer was then filtered and concentrated in vacuo to give a residue which was taken up in hexanes, filtered to remove undissolved material and concentrated to give 1-bromo-3-octyne as an orange oil (14.2 g, 96%). 1H NMR (300 MHZ) spectral data were consistent with the desired bromide (plus a trace of triphenylphosphine), and the crude product was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.C(N(CC)CC)C.[CH2:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][CH3:44].O1CCOCC1.Cl>O1CCCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][S:45]([CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])[C:11]=3[N:10]=2)[CH2:25][CH2:24]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in tetrahydrofuran (1 ml), triethylamine (0.04 mmol) and propane-1-sulfonyl chloride (0.08 mmol) were added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour. The solvent was removed under reduced pressure, dichloromethane and 5N aqueous sodium hydroxide were added to the obtained residue, and after stirring, the organic layer was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain propane-1-sulfonic acid (2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-amide. The compound was identified by LC-MS.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.C(OCC)(=O)C.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>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:13]2[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])[CH:5]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCB(CC)c1cccnc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
A mixture of diethyl 3-pyridylborane (16.3 g, 0.11 mol), 3-bromoaniline (12.2 ml, 0.11 mol), potassium carbonate (45.8 g, 0.33 mol) and tetrakis(triphenylphosphine)palladium(0) (80 mg) in a mixture of water (40 ml) and dimethoxyethane (80 ml) is heated to 80° C. under a stream of nitrogen over night. After cooling the mixture is diluted with water and ethyl acetate and filtered through a fluted filterpaper. The layers are separated. The aqueous layer is extracted once with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is dissolved in ethanol. Water is added and the mixture is evaporated to dryness. This residue crystallizes upon trituration with ice-cold water. The crystals are collected, dried and washed with petroleum ether to afford pure 2p (16.3 g, 87%). Mp 75-76° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(N)CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(F)c2)cc1
Agent: NC1CCCC1
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)c2)cc1
Temperature: 25 °C
Yield: 136.1 %

Procedure:
A solution of N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (37 mg, 0.10 mmol) in cyclopentylamine (4 mL) was heated to 150° C. in a sealed tube for 12 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and the residue was taken up in ether and washed with water and then brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes:ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (31 mg, 72%) as a solid. 1H NMR (CDCl3): δ 8.01 (d, 1H), 7.64 (dd, 2H), 7.21 (t, 1H), 7.10–7.02 (m, 3H), 6.57 (d, 1H), 6.34 (s, 1H), 6.01 (d, 1H), 5.97 (d, 1H), 4.63 (broad, 1H), 4.02 (m, 1H), 3.79 (m, 1H), 2.16 (m, 2H), 1.96–1.42 (m, 14H); 19F NMR (CDCl3) δ −114.06; MS m/z 456 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH2:28][CH3:29])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH2:28][CH3:29])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCC(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc(Cl)cc1
Product: CCC(Nc1ccc(Cl)cc1)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
4-Chloroaniline is reacted with m-phenoxybenzyl 2-bromobutanoate using the process of Example 4 to yield m-phenoxybenzyl 2-(4-chlorophenylamino)butanoate, MS m/e 395 (M+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH2:27][C:28]3([NH:36]C(=O)OC(C)(C)C)[CH2:33][O:32]C(C)(C)[O:30][CH2:29]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH3:12])[CH2:2][CH3:3].C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:36][C:28]([CH2:27][N:22]1[C:23]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH3:12])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=4)[O:17][N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1)([CH2:33][OH:32])[CH2:29][OH:30]
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1CCC
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1CCC
Yield: 80 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 80% yield, as a creamy solid. 1H-NMR (DMSO-d6) 0.94-0.97 (m, 6H); 1.33 (s, 2H); 1.53-1.62 (m, 4H); 2.61-2.68 (m, 4H); 2.98 (s, 2H); 3.2-3.3 (m, 6H, +H2O); 3.54 (tr, 2H, J=9 Hz); 4.55 (m, 2H); 6.77 (d, 1H, J=6 Hz); 7.1-7.16 (m, 1H); 7.25 (d, 1H, J=6 Hz); 7.87-7.91 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)[CH2:23][C:22](=[O:34])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K63) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (23 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6]2)#[N:2]>CO.CCOC(C)=O.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6]2)#[N:2]
Reactant: CCOC(=O)/C=C/c1cc2cc(C#N)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCc1cc2cc(C#N)ccc2[nH]1
Yield: 99.2 %

Procedure:
Ethyl (2E)-3-(5-cyano-1H-indol-2-yl)-2-propenoate (D29) (200 mg) in methanol (40 mL) and EtOAc (20 mL) was hydrogenated using the H-cube (full mode) with a large 10% Pd—C catcart (flow rate: 2.5 mL/min). The solvent was evaporated to afford ethyl 3-(5-cyano-1H-indol-2-yl)propanoate (D30) (200 mg) as a white solid. MS (ES): C14H14N2O2 requires 242; found 243.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[C:4]=3[CH:3]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1cc2c(cn1)cnn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cc3c(cn2)cnn3C2CCCCO2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.80 g, 3.4 mmol) (Example 24, Step 1), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 4.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (200 mg, 0.3 mmol), and potassium phosphate (1400 mg, 6.7 mmol) in 1,4-dioxane (7 mL) and water (1 mL) in a reaction vial was degassed and sealed. It was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (660 mg). LCMS (M+H)+=340.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:24]([OH:33])=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[CH3:29]>>[CH3:22][C:23]1[C:24]([OH:33])=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[OH:21])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(B(O)O)c(O)c1C
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c(O)c1
Yield: 54 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenylboronic acid in 54% yield using method F; δH [2H6]-DMSO 13.40,(1H, b), 8.32,(2H, d), 8.24,(2H, m), 8.14-8.00,(3H, m), 7.86,(1H, d), 6.81,(3H, m), 2.33,(3H, s), 2.30,(3H, s), 2.19,(3H, s).