Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].C(O)(=O)C>C1(C)C=CC=CC=1>[O:16]=[C:15]([CH3:17])[C:14](=[CH:5][C:4]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)ccc1OC)C(C)=O
Yield: 76.7 %

Procedure:
A stirred solution of 25.0 grams (0.15 mole) of 2,5-dimethoxybenzaldehyde, 22.0 grams (0.17 mole) of ethyl acetoacetate, 2 mL of pipeddine, and 3 mL of glacial acetic acid in about 250 mL of toluene is placed in a reaction vessel equipped with a Dean-Stark trap, and heated at reflux for about 12 hours. After this time, the reaction mixture is cooled and washed in turn with water, a cold solution of aqueous 10% hydrochloric acid, aqueous 5% sodium bicarbonate, and aqueous 1% acetic acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using methylene chloride The column chromatography does not provide product purification as expected. The fractions are recombined and concentrated under reduced pressure to a residual oil. The oil is distilled under vacuum, yielding 32 grams of impure ethyl 3-oxo-2-(2,5-dimethoxyphenylmethylidene)butanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.Cl.[CH3:28][NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:30])[CH3:28])[CH2:18]2
Reactant: CNC
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN(C)C)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.5 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.20 g), dimethylamine hydrochloride (411 mg) and potassium carbonate (1.74 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (620 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:16]([CH2:17][CH2:18][CH2:19][C:20]2[CH2:21][C:22](=O)[CH:23]=[CH:24][CH:25]=2)=[C:15]([OH:27])[C:9]2[N:10]=[C:11]([CH3:14])[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+].[OH2:32]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:16]([CH2:17][CH2:18][CH:19]([OH:32])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:15]([OH:27])[C:9]2[N:10]=[C:11]([CH3:14])[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c(O)c1CCCC1=CC=CC(=O)C1
Reactant: O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(nc(C)n2C)c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 4.6 g (12.5 mmol) 7-hydroxy-2,3-dimethyl-6-(3-oxo-phenylpropyl)-3H-benzimidazole-5-carboxylic acid ethyl ester in ethanol (200 ml) was treated with 570 mg (15.0 mmol) sodium borohydride and the reaction was stirred at room temperature for 3 h. A saturated ammonium chloride solution was added and the reaction was poured into water (200 ml). The precipitate was filtered off and dried in vacuo at 40° C. to afford 4.4 g (95%) of the title compound as a white solid. m.p. 193°-195° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CCCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (60 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, n-butyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-n-butoxycarbonyl-quinoline (compound 9, 142 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:27]1[O:32][C:30](=[O:31])[NH:29][C@H:28]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1.O1CCCC1.S(=O)(=O)(O)[O-].[Na+]>[CH2:33]([C@H:28]1[CH2:27][O:32][C:30](=[O:31])[N:29]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Yield: 42 %

Procedure:
To a solution of (2-(4-bromo-2-fluorophenyl)acetic acid) (3 g, 13 mmol) and triethylamine (2.5 mL, 14 mmol) in toluene (50 mL) at 0° C. was added trimethylacetyl chloride (6.1 mL, 65 mmol) dropwise. After 10 mins the reaction mixture was cooled to −78° C. In a separate flask, to a solution of (S-(+)-4-benzyl-2-oxazolidinone (2.5 g, 14 mmol) in tetrahydrofuran (50 mL) at −78° C. was added LiHMDS (1 M in hexane, 17 mL, 17 mmol)) until yellowish color persisted. After 10 mins the resulting solution was transferred through a cannula into the suspension of mixed anhydride prepared as described above. The reaction mixture was allowed to reach rt over the period of 4 h, then diluted with saturated aqueous sodium bisulfate (ca. 20 mL), and extracted with ethyl acetate (ca. 100 mL). The extract was washed with brine (2×50 mL), dried over sodium sulfate, and evaporated under vacuum. Flash chromatography of the residue followed by trituration (hexanes) afforded the desired product (2.1 g, 42%) as white solid. ESI MS m/z 393 [C18H15BrFNO3+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxycarbonylmethyl-azetidine-1-carboxylic acid tert-butyl ester (2.3 g, 0.095 mol) in 30 mL THF/MeOH/water (3:2:1) was added (0.477 g, 11.35 mmol) of LiOH*H2O at 0° C. The reaction mixture was stirred for 3 h at 25° C. Methanol and THF were removed in vacuo, and the reaction mixture was diluted with 50 mL water, and extracted with ethyl acetate. The aqueous layer was acidified with 2N HCl, extracted with ethyl acetate, and the organic layer was dried over Na2SO4, and concentrated to give 2-(1-(tert-butoxycarbonyl)-azetidin-3-yl)acetic acid. 1H-NMR (400 MHz, CDCl3), δ ppm 4.12-4.07 (m, 2H), 3.66-3.60 (m, 2H), 2.91-2.84 (m, 1H), 2.68-2.66 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.[F-].[Cs+].C(O)(C(F)(F)F)=O>[Cu]I.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.CO.O.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:7]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (50 mg, 0.18 mmol), 2-(tributylstannyl)pyridine (65 mg, 0.18 mmol), CuI (8 mg, 0.04 mmol), CsF (81 mg, 0.53 mmol), and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was capped and then placed under N2 atmosphere. To the vial was added DMF (1 mL). The vial was placed in a 80° C. heating block with stirring for 1 h. The mixture was allowed to cool to room temperature. The vial was opened and to the reaction was added 2-(tributylstannyl)pyridine (65 mg, 0.18 mmol) and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was placed under N2 atmosphere and then returned to the 80° C. heating block with stirring for 1 h. The mixture was cooled to room temperature and then adsorbed onto diatomaceous earth (Celite®). The resulting powder was subjected to C18 chromatography (water:MeOH w/0.1% TFA) to afford 4-chloro-6-(4-isopropoxyphenyl)-2,2′-bipyridine as an amber solid. This material was carried forward into step 2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:44]=[CH:43][C:11]([CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:42])=[C:24]([C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]3)[CH3:21])=[O:19])=[O:15])=[CH:10][C:9]=1[CH3:45])=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:42][C:23]1[C:22]([N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:11]2[CH:43]=[CH:44][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[C:9]([CH3:45])[CH:10]=2)=[CH:40][CH:39]=[C:38]([Cl:41])[C:24]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCCBr)c(C)c4)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCCC5=O)c(C)c4)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 8-[3-[N-[4-(4-bromobutyramido)-3-methylcinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (110 mg) in N,N-dimethylformamide was added potassium carbonate (64 mg) and the mixture was stirred for 2 hours at 50° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-[3-methyl-4-(2-oxopyrrolidin-1-yl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (72 mg) as an amorphous powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[CH2:17][O:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[O:38][C:39]([CH:42]3[CH2:45][CH2:44][CH2:43]3)=[N:40][N:41]=2)=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>O.CO>[CH:42]1([C:39]2[O:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([C:9]4[CH:14]=[CH:13][C:12]([C:15]56[CH2:20][CH2:19][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:21][CH2:22]5)[CH2:17][O:16]6)=[CH:11][CH:10]=4)=[CH:31][CH:32]=3)=[N:41][N:40]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: Brc1ccc(Nc2nnc(C3CCC3)o2)cc1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)OC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Temperature: 80 °C
Yield: 162.4 %

Procedure:
A vial was charged with methyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (20 mg, 0.052 mmol), N-(4-bromophenyl)-5-cyclobutyl-1,3,4-oxadiazol-2-amine (30.5 mg, 0.104 mmol), PdCl2(dppf)-CH2Cl2adduct (6.34 mg, 7.77 μmol), potassium phosphate (21.98 mg, 0.104 mmol), dimethoxyethane (0.6 ml), methanol (0.2 ml), and water (0.1 ml) at room temperature. The vial was sealed, flushed with nitrogen for three times and heated at 80° C. for 16 hours. The mixture was purified by flash chromatography (heptanes/acetone 1/1, washed with acetone/ethanol 1/1) to afford methyl 2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (40 mg, 40% purity, 65% yield) as white solid. LC/MS, ESI-MS(+1) m/z 474.19, RT 1.41 (Condition E).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO>[NH2:30][CH:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 33.5 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (2.5 g), ammonium acetate (5.4 g) and sodium cyanoborohydride (0.96 g) in methanol (50 ml) was refluxed for 5 hours. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried, and evaporated. The residue (2.6 g) was purified by column chromatography on silica gel (70 g) eluting with a mixture of chloroform and methanol (9:1) to give a white powder of 4'-(1-aminoethyl)-2'-(2,4-difluorophenylthio)methanesulfonanilide (0.84 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[C:7](\[NH:11][C:12]([CH:14]1[CH2:16][C:15]1([CH3:18])[CH3:17])=[O:13])/[C:8]([OH:10])=[O:9].[SH:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>O>[C:22]([C:21]1[C:20]([S:19][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[C:7](\[NH:11][C:12]([CH:14]2[CH2:16][C:15]2([CH3:18])[CH3:17])=[O:13])/[C:8]([OH:10])=[O:9])=[N:28][CH:27]=[CH:26][CH:25]=1)([OH:24])=[O:23]
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCBr)C(=O)O
Reactant: O=C(O)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCSc1ncccc1C(=O)O)C(=O)O

Procedure:
A solution of 600.0 mg (1.89 mmole) of (+) Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, 267.0 mg (1.72 mmole) of 2-mercaptonicotinic acid and 400.6 mg (3.78 mmole) of Na2CO3 in 3.0 ml of H2O was stirred under N2 at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].BrC1C=C2C(C(Cl)=NNC2=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][C:11]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=3)=[CH:2][CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: O=c1[nH]nc(Cl)c2ccc(Br)cc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2ccc(NCc3cccc(F)c3)cc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one and 7-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-fluorobenzylamine (0.08 mL, 0.70 mmol), Pd-2(dba)3 (43 mg, 0.047 mmol), rac-BINAP (118 mg, 0.190 mmol) and NaOt-Bu (139 mg, 1.45 mmol) in DMA (8 mL) was heated at 80° C. for 40 min. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-7-(3-fluoro-benzylamino)-2H-phthalazin-1-one (32 mg) as a white solid, 1H (600 MHz, CDCl3) δ: 4.44 (s, 2H), 6.92 (m, 1H), 7.00 (d, 1H), 7.05 (dd, 1H), 7.08 (d, 1H), 7.26 (m, 1H), 7.37 (d, 1H), 7.71 (d, 1H), 10.40 (s, 1H) ppm. m/z (M+1) 303.97; 4-chloro-6-(3-fluoro-benzylamino)-2H-phthalazin-1-one (23 mg) as an off white solid, 1H (600 MHz, CDCl3) δ: 4.35 (s, 2H), 6.78 (d, 1H), 6.86 (m, 1H), 6.94 (dd, 1H), 6.97 (bd, 1H), 7.05 (d, 1H), 7.21 (m, 1H), 8.00 (d, 1H), 11.00 (s, 1H) ppm. m/z (M+1) 303.97.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[CH:31]1[CH:36]=[CH:35][C:34]([C@H:37]([NH2:41])[C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:41][C@@H:37]([C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][CH:35]=3)[C:38]([O:40][C:3]([CH3:22])([CH3:4])[CH3:2])=[O:39])=[CH:12][CH:13]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:30]
Reactant: CS(=O)(=O)OCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Reactant: N[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H](NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)c1ccccc1

Procedure:
From Intermediate 4J and L-Phenylglycine tbutyl ester. LC/MS: m/z 542 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 10.30 (1H, br s), 7.51-7.45 (3H, m), 7.38 (2H, d, J=6.9 Hz), 7.27-7.04 (9H, m), 5.82 (1H, d, J=9.6 Hz), 4.20 (1H, s), 2.86-2.75 (4H, m), 2.04 (1H, br s), 1.31 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH:36]=[N:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (30% yield). LCMS: 515.20 (M+1)+; HPLC: 98.36% (@ 254 nm), (Rt; 4.876); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 9.01 (s, 1H), 8.85 (t, 1H), 8.36 (d, 1H, J=8.8 Hz), 8.31 (s, 1H), 8.07 (s, 1H), 6.97 (d, 1H, J=8.4 Hz), 5.89 (s, 1H), 5.32-5.25 (m, 1H), 4.40 (d, 2H, J=4.4 Hz), 3.61 (t, 4H), 2.41 (t, 4H), 2.22 (s, 6H), 2.12 (s, 3H), 1.53 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[O:37][NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:26]1([CH2:25][N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:38][O:37][CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][O:31]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:21]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(CC2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(CC2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (77 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) in DMF (4.5 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=10-1) to give tert-butyl [(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (181 mg, 69%) as an amorphous powder.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[O:35][CH2:34][CH2:33][O:32][C:29]=3[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]5[O:35][CH2:34][CH2:33][O:32][C:29]=5[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc5c(cc34)OCCO5)c2)no1
Temperature: 60 °C

Procedure:
According to the procedure described in Example 50, a mixture of the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.105 g, 0.36 mmol), 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline described in Example 14A (0.111 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (7 mL) was heated at 60° C. for 2 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio]phenyl)urea as solid.