Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[CH3:26])[CH:2]([CH3:4])[CH3:3].[OH:34][CH2:35][C:36](O)=[O:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CCOCC.C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:35](=[O:34])[CH2:36][OH:37])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(C(=O)CO)CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 76.9 %

Procedure:
A methylene chloride (5 ml) solution of 5-{9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-8-piperazin-1-yl-9H-purin-2-yl}pyrimidin-2-amine (126 mg, 0.28 mmol), hydroxyacetic acid (25 mg, 0.33 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.33 mmol), and triethylamine (58 μl, 0.42 mmol) was stirred at room temperature for 2 days. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=96:4) to give a solid. Ether was added to the resulting solid and the solid was collected by filtration and dried to give the title compound (110 mg, 77%) as a powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].O1CCOCC1>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(F)ccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc(F)c2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O

Procedure:
To 320 mg of the compound prepared in (9) above were added 9 ml of dioxane and 15 ml of ethanol. The mixture was catalytically hydrogenated with 290 mg of 10% palladium-on-carbon. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 206 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11](=[O:17])[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:17])[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CN(C)CCC(=O)c1cc(N)cc2c1OCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCC(O)c1cc(N)cc2c1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
A solution of 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-3-dimethylaminopropan-1-one (D15) (2.5 g) in ethanol (200 ml) was treated with sodium borohydride (1.22 g) and stirred for 4 h at room temperature. The solvent was evaporated under reduced pressure, and the residue partitioned between water and dichloromethane. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound as an orange/red solid (2.12 g, 84%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[S:14][C:13]([N:15](C)[CH:16]=O)=[N:12][C:11]=2[CH3:19])[N:9]=1)[C:2]([NH2:4])=[NH:3].O.C(=O)([O-])[O-].[K+].[K+]>CO.Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[S:14][C:13]([NH:15][CH3:16])=[N:12][C:11]=2[CH3:19])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(N(C)C=O)sc1-c1csc(NC(=N)N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1nc(C)c(-c2csc(NC(=N)N)n2)s1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A solution of 5-(2-guanidinothiazol-4-yl)-2-(N-methylformamido)-4-methylthiazole (1.5 g) in a mixture of methanol (25 ml) and 10% hydrochloric acid was stirred for 2 hours under refluxing. After addition of water (100 ml), the reaction mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water (10 ml×2) and methanol (15 ml×2) successively and dried over phosphorus pentoxide under reduced pressure to give 5-(2-guanidinothiazol-4-yl)-4-methyl-2-methylaminothiazole (1.05 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:16](=S)=[S:17].Cl>C(O)C>[F:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]2[N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:16](=[S:17])[NH:1][CH2:2]2)=[CH:9][CH:8]=1
Reactant: S=C=S
Reactant: NCC(NCCCO)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: OCCCN1C(=S)NCC1c1ccc(F)cc1

Procedure:
Dissolve 5.3 g of the product of Step B in 50 ml of 80% aqueous ethanol, then add 2.02 g of carbon disulfide and reflux the mixture for one (1) hour. Cool the solution then treat with 0.2 ml of concentrated hydrochloric acid and reflux the mixture for sixteen (16) hours. Concentrate the reaction mixture in vacuo, extract with methylene chloride and dry the extract. Concentrate the extract to a residue and triturate with isopropyl ether to obtain the product of this step. Yield 5.2 g M.P. 104°-106° C. Recrystallize the product from ethanol petroleum ether to obtain the product as a colorless solid. M.P. 105°-106°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd].ClCCl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
A round bottom flask was charged with (S)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (1.3 g, 0.0050 mol),methanol (40 mL, 1 mol), dichloromethane (5 mL) and palladium on charcoal (0.2 g, 0.001 mol) were added and the mixture was stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered over celite and the solvent removed under reduced pressure to yield the pure product as an off white solid. MS m/z=232.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C[Al](C)C.C[O:15][C:16]([C:18]1[S:19][CH:20]=[C:21]([Br:24])[C:22]=1[CH3:23])=O>C(Cl)Cl>[Br:24][C:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])=[O:15])[S:19][CH:20]=1
Reactant: COC(=O)c1scc(Br)c1C
Reactant: Nc1c(F)cccc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1c(Br)csc1C(=O)Nc1c(F)cccc1F
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a 0° C. solution of 2,6-difluoroaniline (1.10 g, 8.58 mmol, 1.0 eq) in DCM (20 mL) was added drop wise trimethyl aluminium (2 M in toluene, 4.3 mL, 1.0 eq) followed by a solution of methyl-4-bromo-3-methylthiophene-2-carboxylate (2.0 g, 8.58 mmol, 1.0 eq). The reaction was allowed to come to room temperature and then stirred for 2 h at the same temperature. The reaction was quenched with water (10 mL) followed by the addition of DCM (20 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the residue was purified by flash column chromatography (silica gel, 30% ethyl acetate in hexane) to afford 1.0 g (35%) of the desired product as a brown solid. 1HNMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.28-7.21 (m, 1H), 7.15 (s, 1H, D2O exchangeable), 7.03-6.94 (m, 2H), 2.56 (s, 3H); ESI-MS (m/z) 332, 334 [(MH)+, Br79,81].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:12]([N:14](CC)CC)[CH3:13].C(Cl)(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[NH:14][C:12]([CH3:13])=[N:11]2)=[CH:9][CH:10]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 0.81 g 4-bromoanthranilic acid (J. Org. Chem. 1997, 62, 1240-1256), 39 mg 4-(dimethylamino)pyridine and 2.09 ml triethylamine in dry dimethylformamide is added dropwise 0.69 ml acetylchloride at 3° C. for 20 min. in an ice-water bath under argon. The reaction mixture is then heated at 90° C. for 3 h. and 1.08 g ammonium carbonate is added portionwise over 10 min., and the mixture is stirred at the same temperature for 1 h. After cooling, the mixture is poured onto 20 ml water and the precipitate is filtered, washed with water and dried in vacuo to give 0.46 g (51%) of crude 7-Bromo-2-methyl-3H-quinazolin-4-one as a light-brown solid. Mp.>191° C. (dec.). MS (EI): peaks at m/e: 240(M+, 100%), 223 (14%), 197(18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH2:26]([CH:28]=[CH:29][CH2:30][NH2:31])[CH3:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH2:28][CH:26]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CCC=CCN
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and ethylallylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 43 8-(Trifluoromethyl)-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>CCOC(C)=O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=2)=[CH:27][CH:26]=1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
4-[1-(4′-tert-Butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoic acid methyl ester (718 mg) is taken into MeOH (10 mL), followed by the addition of 5N NaOH (1 mL). The reaction is stirred for 4 h, diluted with EtOAc, washed with aqueous HCl and brine. The organic portion is dried over MgSO4, and concentrated to afford 510 mg of the titled compound, which is used directly in the next step.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CCO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of 2-mercaptobenzimidazole (2.0 g, 13 mmol) and N-(4-bromobutyl)phthalimide (3.8 g, 13 mmol) in EtOH (50 mL) was added solid K2CO3 (2.2 g, 16 mmol). The resulting mixture was heated to reflux for 18 h, then cooled to room temperature and saturated aqueous NaHCO3 (50 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3×50 mL) then the combined organic fractions were dried (MgSO4), and concentrated. Purification of the crude material thus obtained by flash chromatography (silica gel, hexane/EtOAc; 4:1) afforded 4.2 g of 2-[4-(1H-benzoimidazol-2-ylsulfanyl)-butyl]-isoindole-1,3-dione (90% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:5]([OH:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1.COC(=O)C(C1C=CC(F)=CC=1)C(O)C1C=CN=CC=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1
Reactant: COC(=O)C(c1ccc(F)cc1)C(O)c1ccnc(SC)n1
Agent: COC(=O)C(c1ccc(F)cc1)C(O)c1ccncc1
Product: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1

Procedure:
Using the procedure from Example 1b set forth above, substitute 2-(4-fluorophenyl)-3-hydroxy-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid methyl ester for 2-(4-fluorophenyl)-3-hydroxy-3-pyridin-4-yl-propionic acid methyl ester to produce the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3cnn4CC(C)(C)C(=O)O)no2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Ethyl 3-[4-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D105) (50 mg, 0.103 mmol) was dissolved in ethanol (10 ml). Sodium hydroxide (2N in H2O, 0.258 ml, 0.517 mmol) was added and the resulting mixture was stirred at 60° C. overnight then cooled to room temperature. Solvent was evaporated, then the residue was diluted with water. The aqueous phase was neutralised with a 2N HCl aqueous solution then extracted with EtOAc. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo to give the title compound (22 mg, 42%) as an off-white solid. MS (ES): C22H22ClN5O4 requires 455; found (MH+) 456.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)=O>C(N(CC)CC)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
3.60 g (0.025 mol) of Meldrum's acid and 3.8 g (0.025 mol) of p-nitrobenzaldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example l. The reaction mixture was heated to 105° C. during 1 hour and reacted at the same temperature for 1 hour. The product was isolated according to Example 1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 0 %

Procedure:
Using cyclohexyl[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.38 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.35 mg, 43%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]O)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:59]>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][Br:59])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 212.3 %

Procedure:
To a solution of compound 48 (578 mg, 0.81 mmol) in Et2O (14 mL) was added pyridine (0.007 mL, cat.) and phosphorus tribromide (0.038 mL, 0.40 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 20 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product 49 (654 mg) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([C@H:13]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:24])=[CH:5]2.C(N(C(C)C)CC)(C)C.Cl[Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])=[C:7]([C@H:13]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:24])=[CH:5]2
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O[Si](CC)(CC)CC
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (238 mg, 0.6 mmol) in anhydrous DCM (20 mL) at 0° C. was added diisopropylethylamine (0.21 mL, 1.2 mmol), followed by chlorotriethylsilane (0.12 mL, 0.72 mmol) and the resulting mixture stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with DCM and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired compound. 1H NMR (400 MHz, CDCl3): δ 7.82 (m, 2H), 7.42 (m, 1H), 7.08 (s, 1H), 5.98 (s, 1H), 4.19 (m, 2H), 2.43 (s, 3H), 1.21 (s, 9H), 0.98 (t, 9H), 0.83 (m, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)=[C:7]([O:19][CH3:20])[CH:6]=1.[Na+].[I-].C(N(C(C)C)CC)(C)C.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1>C1COCC1.CN(C=O)C>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([CH2:4][CH2:3][CH2:2][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)=[CH:6][C:7]=2[O:19][CH3:20])[N:11]=1
Reactant: COc1cc(CCCCl)ccc1Oc1cccc(F)n1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CCCn2cncn2)ccc1Oc1cccc(F)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of 2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine (0.14 mmol) in a THF/DMF mixture (340 μL/170 μL), under argon, was added NaI (0.14 mmol; 21 mg). The mixture was stirred 30 minutes at 50° C., before addition of diisopropylethylamine (0.28 mmol, 36 mg) and 1,2,4-triazol (0.28 mmol; 19 mg). The reaction mixture was allowed to stir overnight at 50° C. After concentration, the reaction was hydrolysed with saturated NH4Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (15 mg; 33%) was obtained as a yellow oil after purification on preparative TLC (dichloromethane/methanol: 9/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[CH3:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30][CH2:29]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:32]2[C:33]3[C:28](=[CH:27][C:26]([CH3:25])=[CH:35][CH:34]=3)[CH2:29][CH2:30][CH2:31]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(C)ccc43)CC2C)cc1OC
Yield: 16.7 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (500 mg, 1.53 mmol) prepared in Reference Example 1 and 6-methyl-1,2,3,4-tetrahydroquinoline (676 mg, 4.59 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (117 mg, yield: 18%) as a white crystal. (cis:trans=1.6:1)