Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]>CN(C=O)C>[N:1]1([CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[O:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc21)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzimidazole (0.785 g, 0.7 mmol) was taken in dry DMF (15 ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration gave material that on purification by flash chromatography (CHCl3/MeOH) afforded pure product: 1H NMR (300 MHz, CDCl3): δ 8.10-7.65 (m, 4H), 7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.79-3.66 (m, 4H), 3.14 (br, 4H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1.O1CCOCC1>C(OCC)(=O)C>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:19])=[O:18]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CC(C)(C)CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
Neopentyl alcohol (0.75 g, 8.50 mmol) was added to a solution of commercially available 2-methyl-5-nitro-benzenesulfonyl chloride (1.00 g, 4.20 mmol), pyridine (1.72 mL, 21.2 mmol and anhydrous dioxane (40 mL). A water cooled condenser was attached and the material was heated to reflux. After stirring for two days the mixture was cooled to room temperature and diluted with ethyl acetate (350 mL). The organic layer was washed with water, then 1 N HCl solution, and finally brine. After drying with MgSO4 the solution was concentrated to afford 690 mg of the title compound as a yellow solid.(55%): 1HNMR (DMSO-6) δ8.57 (d, J=2 Hz, 1H), 8.51 (dd, J=8 Hz, 2 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 3.78 (s, 2H), 2.70 (s, 3H), 0.88 (s, 9H); MS (EI): [M+] 287; Anal. Calc. for C12H17NO5S: C, 50.16; H, 5.96; N, 4.88. Found: C, 49.83; H, 5.69; N, 4.90.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>O1CCOCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:7]2[C:3]([C:2]([F:1])([F:10])[F:11])([CH3:9])[CH2:4][CH2:5][C:6]2=[O:8])=[O:28])=[CH:21][CH:22]=1
Reactant: CC1(C(F)(F)F)CCC(=O)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2C(=O)CCC2(C)C(F)(F)F)cc1

Procedure:
5.0 g (0.03 mol) of 5-(trifluoromethyl)-5-methylpyrrolidin-2-one in 10 ml of dioxane are stirred with 3.3 g of triethylamine and 6.8 g (0.04 mol) of anisoyl chloride for 16 h at 110°-120° C. The solid which precipitates is filtered off with suction and the salt is washed with a little dioxane. The dioxane solution is stirred into 50 ml of water and the organic phase is separated off with the addition of a little methylene chloride. After stripping off the solvent, the residue is a brownish solid which is recrystallized from ligroin.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]=[C:11]([CH:19](OC(=O)C)[C:20]([Cl:23])([Cl:22])[Cl:21])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13].[O-]C1C=CC=CC=1>O1CCCC1.CCOCC.O>[CH2:10]=[C:11]([CH:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]([Cl:21])([Cl:23])[Cl:22])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13]
Reactant: Oc1ccccc1
Reactant: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C(=O)OCCCC)C(Oc1ccccc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Phenol (2.0 g) in 15 ml of tetrahydrofuran (THF) was slowly added to sodium hydride (1.0 g, 60% in oil) suspended in 5 ml THF at 0° C. Fifteen minutes later, 3.0 g of butyl 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate (crude, GC: 86%) in 10 ml THF was slowly dropped into the phenoxide solution. The reaction was stirred at 0° C. for 3 hours and then permitted to warm to room temperature. The reaction was worked up by addition of 50 ml of water and 50 ml of ether. The organic layer was separated and the solvents were removed by vacuum. The resulting yellow oil was transferred to an alumina column and the product was eluted out with hexanes. A slightly yellow oil was obtained after removal of the hexanes, 3.1 g. The product was confirmed by NMR spectroscopy to be butyl 2-methylene-3-phenoxy-4,4,4-trichlorobutyrate.
Reaction SMILES: [C:1]1(CCl)[C:2](CCl)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:11]([O-:14])(=O)[CH3:12].[Na+].C(N(CC)CC)C.[Cl-].[Na+].[OH2:25]>ClC1C=CC=CC=1>[C:12]1([CH2:11][OH:14])[C:6]([CH2:5][OH:25])=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: ClCc1ccccc1CCl
Reactant: O
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: OCc1ccccc1CO
Temperature: 100 °C
Reaction time: 10 h
Yield: 94 %

Procedure:
Into a four-neck flask provided with a reflux condenser, thermometer, dropping funnnel, and stirrer, were charged 40 parts of o-xylylene dichloride of 99.8% purity, 40 parts of anhydrous sodium acetate, and 20 parts of monochlorobenzene. Into the flask was added with stirring at 100° C., 0.8 part of triethylamine. Esterification was allowed to proceed at 97° to 101° C. for 10 hours. To the reaction mixture was added 100 parts of warm water to dissolve the by-product sodium chloride. The mixture was left standing to allow it to settle in monochlorobenzene layer and aqueous layer. To the monochlorobenzene layer which had been freed from the catalyst amine by removing with 2.6 parts of 30-% sulfuric acid, were added 19.4 parts of sodium hydroxide and 170 parts of water. Saponification was allowed to proceed at 94° C. for 2 hours. After saponification, the reaction mixture was neutralized with 3N hydrochloric acid and left standing at 85° C. to allow the mixture to settle in two layers. Without having been freed from impurities, the aqueous layer containing o-xylylene glycol was extracted three times with ethyl acetate in a manner similar to that in Example 1. The ethyl acetate extracts were combined, distilled to recover ethyl acetate, and dried in vacuo to obtain 29.6 parts of o-xylylene glycol (melting point, 60.7° - 62° C.) in a yield of 94.0%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].[CH2:10](O)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:19](I)[CH3:20]>O>[CH2:19]([N:6]([CH2:10][CH3:11])[C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:20]
Reactant: CCO
Reactant: CCI
Reactant: CCc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cccc(N(CC)CC)c1
Temperature: 45 °C
Yield: 96 %

Procedure:
To a 100 cm3 round bottom flask was added 3-ethylaniline (5.0 g, 41.3 mmol), ethanol (7.5 cm3), sodium carbonate (5.9 g, 55.7 mmol). Ethyl iodide (17.38 g, 111.4 mmol) was added dropwise. The mixture was then heated at 45° C. for 12 hours before cooling to room temperature and adding water (50 cm3). The mixture was extracted into diethyl ether (3×50 cm3) the extracts were dried over magnesium sulphate, filtered, and concentrated to give the title compound (7.03 g, 96%) as a light yellow oil. δH (250 MHz; CDCl3): 7.20 (1H, dd, 9, 7.25, ArH), 6.60 (3H, m, ArH), 3.43 (4H, q, 7, NCH2), 2.69 (2H, q, 7.25, CH2), 1.32 (3H, t, 7.5, CH3), 1.23 (6H, t, 7, CH3); δC (62.9 MHz; CDCl3): 12.7 (CH3), 15.8 (CH3), 29.5 (CH2), 44.4 (NCH3), 109.4 (ArC), 111.4 (ArC), 115.1 (ArC), 129.2 (ArC), 145.4 (ArC), 147.9 (ArC).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)(=[O:36])=[O:35])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Alternatively, to a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno-[2,3-b]pyridin-4-amine (460 mg, 1.317 mmol) (Description 17) in DMF (10 mL) was added sodium tert-butoxide (316 mg, 3.29 mmol) and 3-chlorobenzenesulfonyl chloride (0.371 mL, 2.63 mmol). The reaction mixture was stirred at RT under nitrogen for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and NaHCO3 (50 mL). The organic layer was then separated and the aqueous layer re-extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over Na2SO4 and the solvent concentrated in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (447 mg).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][NH2:16])=[O:14])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29](O)=O)[CH2:25][CH2:24]1>P(Cl)(Cl)(Cl)=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[O:14][C:29]([CH:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:28][CH2:27]3)=[N:16][N:15]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: COCCCN1CCC(C(=O)O)CC1
Reactant: CC(C)n1nc(C(=O)NN)c2ccccc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COCCCN1CCC(c2nnc(-c3nn(C(C)C)c4ccccc34)o2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To the mixture of 1-isopropyl-1H-indazole-3-carboxylic acid hydrazide (15.0 grams, 68.8 mmol) and 1-(3-Methoxy propyl)-piperidine-4-carboxylic acid hydrochloride (20.9 grams, 88.2 mmol, obtained in preparation 7) cooled at 0° C. was added phosphoryl chloride (130 mL). The reaction temperature was gradually raised to 100° C. and stirred was 2 hours. Upon completion of the reaction, it was cooled to 0° C. and triturated with hexanes (3×250 mL). The crude product was basified with aqueous sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-isopropyl-3-{5-[1-(3-methoxy propyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole (15.78 grams)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]4)=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12]([O:33][CH3:34])=[CH:13][CH:14]=3)[C:9]2=O)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:33][CH3:34])[CH:11]=3)[CH:16]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-6-methoxy-3-{4-[(2-piperidyl)ethoxy]benzyl}isoindolin-1-one (0.50 g, 1.05 mmol) in tetrahydrofuran (10 mL) under nitrogen was added a 1.5 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (2 mL, 3 mmol). After heating at reflux for 5 hours, the reaction was cooled to room temperature, 6 N HCl solution (6 mL) was added, and the reaction was stirred for 1 hour at room temperature. The mixture was basified with a saturated sodium bicarbonate solution and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 20-30% ethyl acetate/hexane) to provide the title compound (0.297 g, 61% yield): 1H NMR (CDCl3) 7.05 (t, 2H), 6.91 (d, 1H), 6.78 (dd, 1H), 6.61-6.72 (m, 7H), 5.24 (m, 1H), 4.30-4.41 (m, 3H), 4.15 (dd, 1H), 3.80 (s, 3H), 3.17 (t, 2H), 2.98-3.10 (m, 4H), 2.91 (m, 2H), 1.81 (m, 4H), 1.56 (m, 2H); ES−MS (m/z) 461 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.C1C[O:32]CC1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][OH:32])=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Lithium aluminum hydride (61 mL of a 1.0 M solution in THF) is added to a solution of the title A compound, 5-methyl-2-phenyl-4-(2-p-tolyloxy-ethyl)-oxazole (8.22 g, 24.36 mmol) in THF (200 mL) at 0° C. The mixture is stirred at 0° C. for 5 h, then at RT overnight. The reaction mixture is then cooled in an ice-water bath and quenched with saturated aqueous sodium bicarbonate and concentrated under vacuum to remove some of the THF. The residue is extracted with EtOAc, and the resulting organic phase is washed with brine, dried with magnesium sulfate, and concentrated under vacuum to give {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-methanol as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=2[CH:21]=1>>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4cccc(CC#N)c4)n3)cc21

Procedure:
{3-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-acetonitrile was prepared from [3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (from Example 358a) in an analogous manner to Example 1d. (120° C., 20 min) Title compound was isolated as a white foam: 99 mg (69%) HPLC purity 90%, LCMS: 447.25 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.39-7.30 (m, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=8.0 Hz, 2H), 3.77 (s, 2H), 3.90-3.50 (bm, 2H), 2.71-2.60 (m, 2H), 2.34-2.23 (m, 2H), 2.05-2.12 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)=[CH:7][N:6]=3)=[CH:17][N:16]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)NCc3ccc(-c4ccnc(F)c4)nc3)nc2)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a tube was added 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 (38 mg, 0.10 mmol), 3-(methylsulfonyl)phenylboronic acid 43-1 (33 mg, 0.20 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), toluene (0.4 mL), ethanol (0.1 mL) and 2M Na2CO3 (0.15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the tube sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified with reverse phase HPLC to give N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)-5-(3-(methylsulfonyl)phenyl)picolinamide 43 as a white powder. MS m/z 463.10 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.63 (t, 1H, J=6.0 Hz), 9.06 (d, 1H, J=1.6 Hz), 8.75 (d, 1H, J=1.6 Hz), 8.42 (dd, J1=8.4 Hz, J2=2.0 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.31 (m, 1H), 8.20-8.15 (m, 3H), 8.03-8.01 (m, 2H), 7.94 (dd, 1H, J1=8.2 Hz, J2=2.0 Hz), 7.85-7.80 (m, 2H), 4.62 (d, 2H, J=6.4 Hz), 3.30 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[NH:18][C:19]4[C:20]([N:25]=3)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[O:26]1[CH2:27][CH:28]=[C:29]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([C:17]4[NH:18][C:19]5[C:20]([N:25]=4)=[N:21][CH:22]=[CH:23][CH:24]=5)=[O:16])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:30][CH2:31]1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ncccc2[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ncccc2[nH]1
Temperature: 120 °C

Procedure:
To a glass microwave vial was added (4-(3-bromopyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone (1.1099 g, 2.81 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.180 g, 5.62 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.158 g, 0.225 mmol), and sodium carbonate (0.893 g, 8.43 mmol) in DMF (7.02 mL) and water (2.340 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 120° C. for 20 min. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone. MS (ESI, pos. ion) m/z: 398.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:11]([CH3:13])[CH3:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CC(C)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 102.6 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.889 g, 9.1 mmol) was dissolved in isopropyl acetate (20 ml) and acetone (0.81 ml, 11 mmol), trifluoroacetic acid (1.40 ml, 18 mmol), and sodium triacetoxyborohydride (2.34 g, 11 mmol) were added. The reaction was stirred under nitrogen at room temperature for almost 4.5 hours and then quenched with 10% sodium hydroxide in water (˜20 ml) to raise the pH to about 9. The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to afford 5-bromo-2-chloro-N-isopropylpyridin-3-amine (2.33 g, 89% purity, 100% yield). MS (ESI pos. ion) m/z: 249 (MH+, 79Br), 251 (MH+, 81Br). Calculated exact mass for C8H10BrClN2 248 (79Br), 250 (81Br).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([NH2:12])=[C:4]([NH2:13])[CH:3]=1.[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:12][C:14](=[O:20])[C:15](=[O:16])[NH:13]2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(N)c(N)cc1C
Reactant: CCOC(=O)C(=O)OCC
Product: COC(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A mixture of 3.98 g of methyl 4,5-diamino-2-methyl benzoate and 40 mL of diethyl oxalate was stirred at 145° C. for 3 hours. After cooling to room temperature, the solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 4.75 g of methyl 7-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:61][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To N-(toluene-4-sulfonyl)-L-alanine (2.0 mmoles) in DMF (10 mL) was added BOP (2.1 mmoles) and N-methylmorpholine (4.0 mmoles) and the reaction stirred at room temperature for 45 minutes. L-Phenylalanine benzyl ester (2.0 mmoles) was added and the reaction stirred for 16 hours at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3×50 mL) The combined organic layers were successively washed with 0.2 N HCl (2×50 mL), sat. NaHCO3 (50 mL), and sat. NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a colorless oil (387 mg, 40%). The crude product was purified by silica gel chromatography (50% EtOAc /Hexane, Rf=0.61). The title compound was crystalized from CHCl3/Hexane to yield a white solid, mp=109-110° C.