Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[CH3:17][NH:18][CH3:19]>O>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:18]([CH3:19])[CH3:17])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CNC
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Solvent: O
Product: CN(C)CC(O)COC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 10.0 g (0.044 mol) of 1-oxyl-2,2,6,6-tetramethyl-4-glycidyloxypiperidine and 10 mL of 40% (ca. 0.091 mol) of dimethylamine (w/w) is dissolved in 100 mL of water and then stirred for 16 hours at ambient temperature. Water is then removed by vacuum distillation to leave 10 g of the title compound as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Solvent: CCCCO
Product: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cn1
Temperature: 25 °C
Yield: 3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide (260 mg, 0.745 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (447 mg, 2.23 mmol) in n-BuOH (3 mL) was heated to 155° C. in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by reverse phase HPLC to give (R)-tert-butyl 1-(5-bromo-3-(6-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (12 mg, 3% yield).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CCc1ccccc1

Procedure:
2-Oxo-4-phenylbutyric acid (130 g) is added to a mixture of 650 ml of ethanol and 13 ml of concentrated sulfuric acid, and the whole mixture is refluxed for 5 hours. The reaction mixture is concentrated to approximately half the original volume, and then diluted with 500 ml of water. The resulting oil is collected and, the aqueous layer is extracted with ethyl acetate. The extract and the oil are combined and dried, and the solvent is distilled off under reduced pressure. The residue is distilled under reduced pressure to give 113 g of ethyl 2-oxo-4-phenylbutyrate as a colorless oil boiling at 135°-141° C./3 mmHg.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:35][C:36]1[S:37][C:38](Br)=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12>C1(C)C=CC=CC=1>[Br:35][C:36]1[S:37][C:38]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)sc(Br)c2C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2c(Br)sc(-c3ccccc3)c2C1
Yield: 34.4 %

Procedure:
0.91 g (7.5 mmol) of phenylboronic acid, 0.209 g (0.38 mmol) of (dibenzylideneacetone)-palladium(O), 0,397 g (1.5 mmol) of triphenylphosphine and 7.5 ml (15 mmol) of a 2M sodium carbonate solution are added to a solution of 3.2 g (8.3 mmol) of 1,3-dibromo-5-(1,1-dimethylethoxy)carbonyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 45 ml of toluene. The mixture is heated at reflux for 5.5 hours and then cooled. The organic phase is separated by settling, washed with water, dried over magnesium sulphate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the 5/95 ethyl acetate/hexane eluent mixture. There is obtained 0.98 g of a white solid. Yield 34%. Melting point: 139°-140° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CCCP(=O)=O>C1COCC1>[CH2:11]([N:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6]/[C:7]/1=[N:15]\[C:19](=[O:20])[C:18]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:17]=1[F:16])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCn1ccc(C(C)(C)C)cc1=N
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCn1ccc(C(C)(C)C)c/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Yield: 44.2 %

Procedure:
A mixture of Example 92A (315 mg, 1.3 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (324 mg, 1.56 mmol), Et3N (543 μL, 3.89 mmol) and propylphosphonic anhydride (927 μL, 1.56 mmol) in THF (15 mL) was stirred at room temperature for 12 hours. The reaction mixture mixture was quenched with NaHCO3 and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 10-100% EtOAc/hexanes gradient) to afford 228 mg (44%) of the title compound. MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2].[S:45]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:47]3[CH:48]=[CH:49][S:45][CH:46]=3)[CH:25]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCc3ccccc3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 62.9 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-benzyloxy-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (260 mg, 0.39 mmol), 3-thiophenylboronic acid (99 mg, 0.78 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (253 mg, 0.78 mmol) to obtain 4-[3-[6-(3-benzyloxy-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (165 mg, 67%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C40H48O7S (M+Na)+ 695.3013. found 695.3008.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].C[C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)=O.[H-].[Na+].CC(C)(C)C(=O)CC(=O)C>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])/[CH:11]=[CH:17]/[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=2)=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C(=O)CC(C)=O)ccc1O
Reactant: COc1cc(C(C)=O)ccc1O
Agent: CC(=O)CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)CC(=O)c2ccc(O)c(OC)c2)ccc1O
Yield: 39 %

Procedure:
By a similar procedure as described in Example 1 using 1-(4-hydroxy-3-methoxyphenyl)-butane-1,3-dione (prepared by reaction of 4-hydroxy-3-methoxyacetophenone with ethyl acetate in the presence of sodium hydride) in place of 5,5-dimethylhexane-2,4-dione, (E)-1,5-bis-(4-hydroxy-3-methoxyphenyl)-pent-4-ene-1,3-dione (920 mg, 39%) was obtained as yellow needles: mp 170-172° C.; LRMS m/z 342 (M+); 1H NMR (500 MHz, CDCl3) δ 3.95 (3H, s, OCH3), 3.98 (3H, s, OCH3), 5.85 (1H, brs, OH), 6.04 (1H, brs, OH), 6.26 (1H, s, H-2), 6.48 (1H, d, J=15.7 Hz, H-4), 6.94 (1H, d, J=7.2 Hz, H-5″), 6.97 (1H, d, J=8.3 Hz, H-5′), 7.05 (1H, brs, H-2″), 7.12 (1H, brd, J=8.3 Hz, H-6″), 7.51 (1H, brd, J=7.2 Hz, H-6′), 7.56 (1H, brs, H-2′), 7.60 (1H, J=15.7 Hz, H-5), 16.2 (1H, brs, OH) ppm; TLC Rf=0.5 (silica, dichloromethane); HPLC Rt 14 min 99.6% purity.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1C2C(=CC=CC=2)C=C[C:28]=1[S:37]CC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:37][CH2:28][CH3:27])#[CH:2]
Reactant: CCSc1ccc2ccccc2c1Br
Reactant: C#Cc1c(C)ccc2ccccc12
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(SCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-ethylthionaphthalene was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by 1-bromo-2-ethylthionaphthalene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.C1COCC1.CN(C)C=O.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cc1I
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
3-Iodo-4-methylbenzoic acid (1.0 g, 3.96 mmol) in dry CH2Cl2:THF 1:1 (200 mL) was treated with oxalyl chloride (1 mL, 11.9 mmol) and several drops of N,N-dimethylformamide. The mixture was heated at 65° C. for 30 minutes, allowed to cool to ambient temperature, and concentrated under reduced pressure to provide a light yellow solid. The obtained solid was dissolved in THF (200 mL) and treated with a 1M solution of lithium tri-tert-butoxyaluminohydride in THF (4.1 mL, 4.1 mmol) via syringe at −78° C. After 30 minutes at −78° C., a saturated solution of Rochelle's salt was added and the mixture was allowed to warm to ambient temperature. The organic layer was washed in succession with 1N HCl, saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography using hexanes:ethyl acetate (4:1) as the eluent to provide the title compound as a white solid (300 mg, 18%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: Cc1ccccc1
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 112.6 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g) was obtained by concentrating under a reduced pressure (yield: 97.3%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:21]=[C:22]=[O:23])[CH:18]([CH3:20])[CH3:19].C(OCC)C.C1CCCCC1>O1CCCC1>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([NH:11][NH:12][C:22]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CN=C=O
Reactant: NNC(=O)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)CNC(=O)NNC(=O)c1ccccc1-c1ccccc1
Reaction time: 8 h

Procedure:
1.00 g (4.71 mmol) of 2-phenylbenzoic acid hydrazide are placed in 10 ml tetrahydrofuran at room temperature. 0.51 g (5.15 mmol) of isobutyl isocyanate, dissolved in 2 ml tetrahydrofuran, are rapidly added dropwise with stirring. The mixture is firstly stirred further at room temperature and then allowed to stand overnight. Addition of an equal volume of diethyl ether and 10 ml of cyclohexane results in separation of a small quantity of a solid, which is filtered off and discarded. Concentration of the filtrate yields 1.53 g (ca. 100% of theory) of a slightly THF-moist product, which is used further as such.
Reaction SMILES: [NH2:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].CN1CCOCC1.[Cl-].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30]>C(#N)C>[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29]([NH:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])=[O:30]
Reactant: COC(=O)CC(=O)O
Reactant: NC1(c2ccccc2)C(=O)NC(=O)NC1=O
Agent: [Cl-]
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)CC(=O)NC1(c2ccccc2)C(=O)NC(=O)NC1=O
Yield: 68 %

Procedure:
2 g 5-amino-5-phenyl-2,4,6-trioxopyrimidine is dissolved in 20 ml acetonitrile and admixed with 1.5 ml N-methyl-morpholine. 1.03 ml malonic acid monomethyl ester chloride is added dropwise while stirring and cooling on ice and the suspension is stirred for 2 hours at room temperature. The precipitate is suction filtered, washed with acetonitrile, water and again with acetonitrile and dried. 1.97 g (68%) of the title compound is obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([CH3:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C.C(#N)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([CH3:27])=[N:14]2)=[CH:21][CH:22]=1
Reactant: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-4,8-dimethyl-7,8-dihydropyrazino-[1′,2′:1,5]pyrrolo-[2,3-d]pyridazine-1,9(2H,6H)-dione (17 mg, 38 μmol) and Pearlman's catalyst (6.0 mg, 20% Pd(OH)2 on carbon) in ethanol (20 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 30 minutes. The reaction mixture was diluted with acetonitrile and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue triturated with a mixture of methanol and diethyl ether. A solid precipitate was obtained by filtration to provide the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[F:22].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[N:37]=[CH:36][CH:35]=[N:34]3)O1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(OCC)(=O)C.O.O1CCOCC1>[C:18]([NH:17][S:14]([C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[N:37]=[CH:36][CH:35]=[N:34]4)=[C:3]([F:22])[CH:4]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:16])=[O:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(Br)c(F)c1
Reactant: CC1(C)OB(c2ccc3nccnc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc3nccnc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
4′-Bromo-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (30 mg, 0.078 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (12 mg, 0.085 mmol) were added to a 5 mL sealable vial equipped with a stir bar. Dioxane (0.2 mL) and 2 M Na2CO3 (0.2 mL) were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 min then Pd(dppf)Cl2.CH2Cl2 (3 mg, 0.004 mmol) was added, and the mixture heated for 15 hours at 80° Celsius under an argon atmosphere. The reaction was diluted with 2 mL of ethyl acetate and 2 mL of water and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C24H22FN3O2S, 435.14; m/z found, 436.4 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.93-8.91 (d, J=1.8, 1H), 8.91-8.89 (d, J=1.8, 1H), 8.37-8.34 (m, 1H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 8.09-8.04 (m, 1H), 7.71-7.66 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.52 (m, 1H), 7.51-7.44 (dd, J=7.9, 1.8, 1H), 7.44-7.40 (dd, J=11.3, 1.7, 1H), 7.40-7.36 (dd, J=7.5, 1.4, 1H), 3.74 (s, 1H), 1.10 (s, 9H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:33][CH2:32][CH2:31][CH2:30][C:25]54OCC[O:26]5)[O:18][N:17]=3)=[CH:11][C:10]=2[CH3:40])[CH2:4][O:3]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[C:10]([CH3:40])=[CH:11][C:12]([C:16]2[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:33][CH2:32][CH2:31][CH2:30][C:25]3=[O:26])[O:18][N:17]=2)=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1cc(-c2noc(CCCC3(c4ccccc4)CCCCC34OCCO4)n2)cc(C)c1OC[C@@H]1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2noc(CCCC3(c4ccccc4)CCCCC3=O)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of 3-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylphenyl)-5-(3-(6-phenyl-1,4-dioxaspiro[4.5]decan-6-yl)propyl)-1,2,4-oxadiazole (57 mg, 0.101 mmol) in acetic acid (1 mL) was added 1N HCl (0.2 mL, 0.200 mmol), and the mixture was stirred at 0° C. for 1.5 hrs. The mixture was poured into saturated Na2CO3 and the product was extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (24 g silica gel) eluting with 1:1 followed by 7:3 EtOAc-hexane, to afford 2-(3-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)propyl)-2-phenylcyclohexanone as a solid (34.4 mg). LC/MS: m/e 479.1 (M+H)+. 1H NMR (400 MHz, CCl3D) δ ppm 7.67 (2H, s), 7.31-7.38 (2H, m), 7.24 (1H, t, J=7.25 Hz), 7.14 (2H, d, J=7.47 Hz), 4.06-4.15 (2H, m), 3.75-3.90 (5H, m), 2.70-2.81 (3H, m), 2.26-2.38 (8H, m), 1.84-1.97 (2H, m), 1.59-1.78 (6H, m), 1.37-1.52 (1H, m).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[N:14]=1)(=[O:4])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:15]2[N:14]=[C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=2)[CH2:25]1
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)ncc1C(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1Nc1nc(N[C@H]2CCCNC2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(4-(2-acrylamidophenylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)piperidine-1-carboxylate (3 g) in DCM (30 ml) was added trifluoroacetic acid (5 ml) at 0° C. for 10 min and stirred at rt for 2 h. TLC showed completion of starting material. (TLC system: 15% methanol in dichloromethane, Rf=0.2). The reaction mixture was concentrated, and the crude was co-distilled with DCM (3×20 mL) and washed with diethyl ether (2×10 mL) to obtain (S)—N-(2-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) pyrimidin-4-ylamino)phenyl)acrylamide as an off white solid. (3 g, 97%). MS: m/z=407.1 (ES+, M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH3:33])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (85 mg, 0.198 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (55 m mg, 0.398 mmol, 2 eq) and methyl iodide (2M in t-butylmethyl ether, 0.100 mL, 1 eq). The reaction vial was capped, purged with nitrogen gas, and stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progress by 70%. An additional 0.050 mL of 2M solution of methyl iodide was added and the reaction mixture was stirred at 80° C. for 6 h. Analysis by LC/MS displayed the reaction had progress by 95%. The reaction mixture was cooled to room temperature and then poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 23-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (37 mg, 42%). MS(ES)+ m/e 443.2 [M+H]+.