Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[C:6]1[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]1=[O:15].[CH:19]1([Mg]Br)[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:5]([C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([OH:1])[CH:3]=2)[CH:6]2[C:7](=[O:15])[O:8][C:9]([CH3:14])([CH3:13])[O:10][C:11]2=[O:12])[CH2:21][CH2:20]1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 5-(3-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 66.6S (2.00 g, 8.06 mmol) in THF (25 mL) was added cyclopropylmagnesium bromide (available from Aldrich) (0.5M, 96.7 mL, 48.3 mmol) via cannula at 0° C. The resulting heterogeneous mixture was warmed to room temperature, stirred for 30 minutes, and quenched with 1 N aqueous HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (10-35% EtOAc/hexane) to afford 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 66.6T (2.04 g, 87% yield) as a yellow oil.
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[N:11]=1.BrCC(C1C=CC=CC=1[N+]([O-])=O)=O.[CH2:35]([O:37][C:38](=[O:47])[CH2:39]CCCCC(=O)N)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:47])[CH2:39][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[N:11]=1)[CH3:36]
Reactant: CCOC(=O)CCCCCC(N)=O
Reactant: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Agent: O=C(CBr)c1ccccc1[N+](=O)[O-]
Product: CCOC(=O)CCCCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Yield: 26 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester; reaction of 2-bromo-2′-nitroacetophenone (8.9 g, 36.5 mmol) with 6-carbamoyl-hexanoic acid ethyl ester (9.1 g, 48.7 mmol) gives 6-[4-(2-nitro-phenyl)-oxazol-2-yl]-hexanoic acid ethyl ester (3.19 g, 26%). MS (ES): (M+1)+ 333.2, 334.4 m/z.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=O)[S:15][CH:16]=1>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[S:15][CH:16]=1
Reactant: Cc1csc(C=O)c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1csc(C=C2C(=O)Nc3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 151.2 mg of the 4-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 147.3 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.CN(C)[CH:12]=[C:13]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:14](OCC)=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:14](=[O:15])[C:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: NNc1cc(Cl)ncn1
Solvent: CC(=O)O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 30.0 g (207.5 mmol) of the compound from Example 7A and 50.3 g (228.3 mmol) of the compound from Example 3A are stirred in 1000 ml of glacial acetic acid for 16 h. For work-up, the solvent is removed on a rotary evaporator, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution until neutral, and the organic phase is concentrated under reduced pressure. The residue is dissolved in 1000 ml of ethanol, 42.8 ml (41.1 g, 228.3 mmol) of 30% strength methanolic sodium methoxide solution are added and the mixture is stirred at RT for 2 h. The reaction mixture is then adjusted to pH 5 using 1 N hydrochloric acid and stirred for 16 h. The precipitate is filtered off, the filter residue is washed with water and ethanol and the product is dried under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>CCOCC>[CH2:19]([O:18][CH2:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12)[CH3:20]
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOCc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and lithium aluminum hydride in ether is heated at reflux temperature for 8 hours. To the mixture is added (dropwise) ethanol and water. The ethereal layer is separated, then ethanol and anhydrous hydrochloric acid is added to it. The resulting mixture is refluxed for 8 hours and the solvent is removed. The residue is extracted with dichloromethane. The dichloromethane extract is passed through a column of hydrous magnesium silicate. The eluent is concentrated and diluted with hexane to give the product of the example.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]#[C:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1>C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[NH:3][N:2]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(C#Cc1cccs1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Clc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Hydrazine hydrate (228 mg, 4.6 mM) and pyridinium p-toluenesulfonate (50 mg) were added to a solution of 1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one (750 mg, 3.0 mM) in ethanol (30 ml), and this mixture was heated under reflux for 2 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (50 ml). This solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 634 mg of 3-(4-chlorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 217° C., in an 80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylamine hydrochloride (13.5 g, 190 mmol) followed by the addition of a sodium hydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried (magnesium sulfate) to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%) as a white solid. 1H NMR (DMSO-d6): δ11.56 (s, 1H), 8.44 (d, 1H), 7.80 (m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); 19F NMR (DMSO-d6): δ −113.44; MS m/z 265 (M+1).
Reaction SMILES: CO[Na].[CH3:4][O:5][C:6]([CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:9]1)=[O:7].CCOC(C)=O>CO>[CH3:4][O:5][C:6]([C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:9]1)=[O:7]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: CO[Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 47.3 %

Procedure:
MeONa (2.27 g, 42 mmol) was added to a sol. of compounds D5 (22.6 g, 42 mmol) in MeOH (200 mL). The mixture was stirred at 70° C. for 6 h, and MeONa (2.27 g, 42 mmol) was added again. The mixture was stirred at 70° C. for 2 days, and was allowed to cool to rt. EtOAc was added, and the resulting mixture was washed with aq. 1M HCl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95→10:90) yielded the title compound (10.7 g, 47%). LC-MS: tR=1.19 min, ES+=538.39.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=1)#[N:2]
Reactant: Cc1ccc(CCN)cc1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: Cc1ccc(CCN=C(NC#N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2-(p-tolyl)ethylamine (0.47 g, 3.5 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.76 g, 2.9 mmol, yield: 93%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.S(Cl)(Cl)=O.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[NH2:30]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH:30][C:24]2[C:23]3[C:27](=[CH:28][CH:29]=[C:21]([CH2:20][C:19]4[CH:31]=[C:32]([F:34])[CH:33]=[C:17]([F:16])[CH:18]=4)[CH:22]=3)[NH:26][N:25]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1Cl
Yield: 34.6 %

Procedure:
2,6-dichloropyridine-3-carboxylic acid (480 mg, 2.5 mmol) and thionyl chloride (0.28 mL, 3.75 mmol) were heated in toluene dry (120 mL) and a few drops of dry DMF at 90° C. for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (15 mL) at 0° C. under nitrogen atmosphere. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (518 mg, 2 mmol) in dry pyridine (7 mL) was added to the cooled reaction mixture. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with aqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using DCM/EtOH 100:4 as the eluant, affording 300 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=1)(=[O:41])=[O:40])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Yield: 56.7 %

Procedure:
In a manner analogous to that described in Example 21, from 223 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 95 mg of toluene-4-sulphonyl chloride and 65 mg of diisopropylethylamine there were obtained 170 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(p-toluenesulphonyl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid (from ethyl acetate/n-hexane): MS: m/e 603 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:6]([F:15])[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].[CH3:19][Li]>CCOCC.O>[F:15][C:6]1[C:5]([F:16])=[C:4]([F:17])[C:3]([F:18])=[C:2]([CH3:19])[C:7]=1[C:8]1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=1
Reactant: [Li]C
Reactant: CC1(C)COC(c2c(F)c(F)c(F)c(F)c2F)=N1
Solvent: O
Solvent: CCOCC
Product: Cc1c(F)c(F)c(F)c(F)c1C1=NC(C)(C)CO1
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 21.2 g (80.0 mmol) of 2-(pentafluorophenyl)-4,4-dimethyl-2-oxazoline (Bull. Chem. Soc. Jpn., 57, 225 (1984)) in 300 mL of dry ether was cooled to -20° C. under argon and treated with 60 mL of 1.6M methyl lithium (96.0 mmol). The solution was stirred at -20° C. for 2 hours, then stirred at room temperature overnight. The mixture was diluted with water, and the organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil.
Reaction SMILES: N1C(C)=CC=CC=1C.C(Cl)Cl.[OH:12][C:13]([CH3:26])([CH3:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].FC(F)(F)S(O[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])(=O)=O>C(OCC)(=O)C>[Si:33]([O:12][C:13]([CH3:26])([CH3:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(CC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
2,6-Lutidine (3.6g) was added to an anhydrous methylene chloride solution of benzyl 3-hydroxy-3-methylbutyrate (3.5g) obtained in the step 1, and stirred with cooling with ice. t-butyldimethylsilyl trifluoromethanesulfonate (3.9mL) was gradually added dropwise thereto, and stirred for 1hour with cooling on ice and then for 2hours at room temperature. The reaction liquid was diluted with ethyl acetate, then washed with water, aqueous saturated ammonium chloride solution and aqueous saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. 4.5g of the residue was purified through silica gel column chromatography to give benzyl 3-(t-butyldimethylsilyloxy)-3-methylbutyrate (2.62g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:18]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:39]([F:42])([F:41])[F:40])[C:35]([NH2:38])=[N:36][CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:23][O:22][CH:20]1[CH2:21][N:18]([C:4]2[N:3]=[C:2]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:17][O:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:5]=2)[CH2:19]1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COC1CN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC1CN(c2cc(C3CCN(C4COC4)CC3)cc(-c3cnc(N)c(C(F)(F)F)c3)n2)C1
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (80 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (140 mg, 0.48 mmol) and cesium carbonate (160 mg, 0.48 mmol) in dioxane/H2O (5:1, 4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.024 mmol) under nitrogen. The mixture was irradiated by microwave at 110° C. for 30 min. The reaction mixture was filtered, the filtrate was concentrated and purified by Prep-HPLC to afford 6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amine (68.3 mg 61.5%, yield). LCMS (ESI) [MH]+=464, 1HNMR (400 MHz, CDCl3), δ8.745(s,1H), δ8.363(s,1H), δ8.232(s,1H), δ8.832(s,1H), δ6.109(s,1H), δ5.642(s,2H), δ4.74- 4.67(m,4H), δ 4.39-4.22 (m, 3H), δ 3.94-3.90 (m, 2H), δ 3.63-3.56(m, 1H), δ 3.346(s, 3H), δ 2.980(d, J=10.8 Hz, 2H), δ 2.55-2.46 (m,1H), δ 2.06-1.99 (m, 1H), δ 1.93-1.87(m, 4H). LCMS:464.0(M+1).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[C:14]2[NH:15][C:16]3[CH:17]=[C:18]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][C:21]=3[C:22]=2[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([C:11]2[CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[C:14]3[NH:15][C:16]4[CH:17]=[C:18]([C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH:19]=[CH:20][C:21]=4[C:22]=3[N:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)OC(C)C)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)OC(C)C)ccc12
Temperature: 80 °C
Yield: 70.3 %

Procedure:
A flask containing a mixture of phenylboronic acid (0.935 g, 7.67 mmol), 7-isopropyl 4-methyl 2-bromo-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (1.00 g, 2.56 mmol), powdered potassium phosphate tribasic (2.387 g, 11.25 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (0.244 g, 0.511 mmol), and Pd(OAc)2 (0.057 g, 0.256 mmol) was flushed with nitrogen. THF (8 mL) was added and the mixture was heated at 80° C. for 3 hr. The mixture was diluted with EtOAc, washed with water, dried with sodium sulfate, and the solvents removed. Silica gel chromatography (step gradient elution with hexane containing 50% to 100% DCM) afforded 7-isopropyl 4-methyl 2-phenyl-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (0.7 g, 1.8 mmol, 68% yield). MS (ESI) m/z 388.99 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.68 (1H, s), 8.52 (1H, d, J=8.24 Hz), 8.39 (1H, s), 8.30 (1H, s), 8.21 (2H, d, J=7.32 Hz), 8.08 (1H, d, J=8.24 Hz), 7.56 (2H, t, J=7.63 Hz), 7.41-7.51 (1H, m), 5.36 (1H, dt, J=12.51, 6.26 Hz), 4.14 (3H, s), 1.46 (6H, d, J=6.41 Hz).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19].C([O-])=O.[NH4+]>O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC#N.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:17]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:18]=1[NH2:19]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(F)cccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(F)cccc1-c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of Na2CO3 (1.116 g, 10.53 mmol) in water (15 ml) was added poly(ethylene glycol) 2000 (17 g, 5.26 mmol) followed by palladium(II) acetate (0.024 g, 0.105 mmol). The suspension was heated to 50° C. Once the mixture became clear, phenylboronic acid (0.963 g, 7.89 mmol) followed by 2-bromo-6-fluoroaniline (1 g, 5.26 mmol) were added and heated at 120° C. for 30 min. The mixture was cooled, diluted with EtOAc, washed with water, dried and concentrated. The crude material was purified by ISCO (24 g REDISEP® silica column, gradient elution, 0-15% ethyl acetate in hexanes) to give Preparation 5A (800 mg, 81%): LCMS: HPLC: RT=2.016 min (MeCN/H2O with HCOONH4, Ascentis Express C8 2.7 μm 5×2.1 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=188 [M+H]+; 1H NMR (CDCl3) δ 7.43-7.48 (m, 4H), 7.35-7.40 (m, 1H), 6.97-7.02 (m, 1H), 6.92 (dt, J=7.6, 1.2 Hz, 1H), 6.71-6.77 (m, 1H), 3.82 (br s, 2H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:17])[CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH:12]=[CH:13][CH:14]=1
Reactant: C=C(C)C(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl methacrylate (12.65 mL, 119 mmol) was added to a solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (30 g, 113 mmol, Example 1, Step A) in tetrahydrofuran (283 mL). Potassium tert-butoxide (1.27 g, 11.3 mmol) was then added and the reaction was stirred at room temperature for 2 days. The solvent was removed under a vacuum and replaced with 300 mL of ethyl acetate. The organic phase was washed with brine (50 mL), water (3×50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under a vacuum to afford methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate as an approximately 1:1 mixture of diastereomers.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CO.CCO.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1>[CH]Cl.O>[ClH:32].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Agent: [CH]Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)cc2)nc(N)n1

Procedure:
To solution of amine E5 (267 mg, 0.720 mmol) in ˜1:1:1 MeOH:EtOH:H2O were sequentially added 4-chloroquinoline (1.06 g, 6.48 mmol) and 3 drops of cHCl, and the resulting mixture was refluxed for ˜24 h. After this time, solvent was removed under reduced pressure, and the resulting residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH/EtOAc, and then further purified by preparative HPLC, to afford Cpd. E as an amorphous yellow solid (16 mg, 4%). 1H NMR [(CD3)2SO]: 1.91 [s, 3H, ArCH3], 6.11 [s, 1H, ArH], 7.02 [d, J=6.77 Hz, 1H, ArH], 7.65 [d, J=8.55 Hz, 2H, ArH], 7.71 [br s, 2H, ArNH2], 7.84 [m, 4H, ArH], 8.04 [m, 2H, ArH], 8.15 [d, J=8.55 Hz, 2H, ArH], 8.63 [d, J=6.77 Hz, 1H, ArH], 8.70 [d, J=8.50 Hz, 1H, ArH], 10.38 [s, 2H, ArNHAr & ArH], 10.77 [br s, 1H, ArNHAr], 13.10 [v v br s, 2H, ArC(O)NHAr & quinoline-N+H]. LCMS (APCI+): 463 (100%). HPLC: 95.7%.