Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[NH:21][C:20](=[O:26])[CH:19]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:24][N:23]1[C:18]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)=[CH:19][C:20](=[O:26])[NH:21][C:22]1=[O:25]
Reactant: Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(N2CCN(CCCOc3ccccc3)CC2)cc(=O)[nH]c1=O
Reaction time: 12 h
Yield: 68.1 %

Procedure:
1.3 g of 1-(3-phenyloxypropyl)piperazine and 0.5 g of 6-chloro-1-methyl-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of isopropanol, and 2.7 ml of triethylamine was then added. Next, the solution was heated under reflux with stirring for 12 hours and then allowed to stand for cooling, and the solvent was distilled off. The resultant residue was dissolved in 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain an oily product. This oily product was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 0.73 g of 1-methyl-6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:28][CH2:27]1)=[O:25])=O)(C)(C)C.Cl>C(O)C>[ClH:23].[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH:9]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=4[CH3:39])[CH2:30][CH2:31]3)=[O:25])[CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(Cl)cc4)CCN3C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(Cl)cc4)CCN3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-chloro-benzenesulfonyl)-2-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.64 g) in ethanol (16.4 mL) was added a saturated solution of HCl in ethanol (16.4 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h and concentrated to give [4-(4-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone hydrochloride, MS: 477.0 ([M+H, 1Cl]+).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH2:11][C@H:12]2[CH2:16][C@H:15]([O:17]S(C)(=O)=O)[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:34]=[C:33](O)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]([O:17][C@H:15]2[CH2:14][O:13][C@@H:12]([CH2:11][O:10][C:8](=[O:9])[C:7]3[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:16]2)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37]
Reactant: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution of ((2R,4S)-4-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl 4-nitrobenzoate (296m, 300 mg, 0.869 mmol), 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296 g, 222 mg, 0.956 mmol), and cesium carbonate (566 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was heated to 100° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 128 mg, 31% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.33 (m, 4H), 7.03 (s, 1H), 6.09 (br. s., 1H), 4.99 (td, J=4.28, 1.96 Hz, 1H), 4.56-4.62 (m, 2H), 4.42-4.52 (m, 1H), 4.27 (d, J=10.64 Hz, 1H), 4.02 (dd, J=10.58, 4.34 Hz, 1H), 3.48 (td, J=6.36, 3.91 Hz, 2H), 2.99-3.09 (m, 2H), 2.56 (ddd, J=14.24, 8.19, 6.42 Hz, 1H), 2.18 (dd, J=14.12, 5.07 Hz, 1H). MS: 481 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(F)cc1
Temperature: 50 °C
Yield: 95.4 %

Procedure:
To a solution of 4-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 721 mg of the product 388.
Reaction SMILES: C(OC(=O)CCC[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](I)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])C.[N:46]1[CH:51]=[C:50](B(O)O)[CH:49]=[N:48][CH:47]=1>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([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:51]3[CH:50]=[CH:49][N:48]=[CH:47][N:46]=3)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH3:10])[CH3:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cncnc1
Product: CCOC(=O)CCc1c(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(-c3ccncn3)c2)cccc1OC(CC)C(=O)OCC
Yield: 151.3 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-iodo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (47 mg, 0.06 mmol) and pyrimidin-5-ylboronic acid (32 mg, 0.26 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyrimidin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy-butyric acid ethyl ester (31 mg, 71%) as a light yellow oil: ES(+)-HRMS m/e calculated for C40H46N2O8 (M+H)+ 683.3327, found 683.3327.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([N:12]1[C:16]([CH:17]=O)=[CH:15][C:14]([N:19]([CH3:28])[S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N+]=[N-].[Cl-].[NH4+]>C(O)C>[CH2:5]([N:12]1[C:16]2[CH:17]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH:29][C:15]=2[C:14]([N:19]([CH3:28])[S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[CH:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CN(c1cc(C=O)n(Cc2ccccc2)c1)S(=O)(=O)c1cccs1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]1)c(N(C)S(=O)(=O)c1cccs1)cn2Cc1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution (150 mL) of sodium ethoxide (7.8 g) in ethanol was added dropwise a mixture of N-(1-benzyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (10.3 g) and ethyl azidoacetate (15 g) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated. The obtained residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, volume ratio). The obtained yellow oil was dissolved in toluene (50 mL), and the mixture was stirred at 110° C. for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:1, volume ratio) and concentrated to give ethyl 4-benzyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylate (13 mg, yield 0.1%) as colorless crystals. melting point 120° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C:19](=[O:20])[N:18]2[C@@H:13]1[CH2:14][CH2:15][O:16][C:17]2([CH3:22])[CH3:21])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]1[C:19](=[O:20])[N:18]2[C@@H:13]1[CH2:14][CH2:15][O:16][C:17]2([CH3:22])[CH3:21]
Reactant: CC1(C)OCC[C@@H]2[C@@H](NC(=O)OCc3ccccc3)C(=O)N21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OCC[C@@H]2[C@@H](N)C(=O)N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
A mixture of (6R,7R)-7-benzyloxycarbonylamino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (748 mg) and 10% palladium charcoal (180 mg) in ethyl acetate (15 ml) was stirred under a hydrogen atmosphere for 1.5 hours at ambient temperature. The mixture was filtered and the filtrate was evaporated in vacuo to give (6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (382 mg) as a crystalline solid.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:50]=[CH:49][C:33]([CH2:34][CH2:35][N:36]([CH3:48])[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#[N:47])[CH:41]=2)=[O:38])=[C:32]([CH2:51][CH3:52])[CH:31]=1>>[C:46]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:35][CH2:34][C:33]2[CH:49]=[CH:50][C:30]([B:25]([OH:27])[OH:26])=[CH:31][C:32]=2[CH2:51][CH3:52])[CH3:48])[CH:45]=[CH:44][CH:43]=1)#[N:47]
Reactant: CCc1cc(Br)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCc1cc(B(O)O)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Yield: 40 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 36D (500 mg, 1.3 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 36E (183 mg, 40%) as a tan foam. MS (ESI) m/z 352.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:27]=[CH:26][C:9]([CH2:10][CH:11]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:18])[C:12]([O:14]CC)=[O:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]1[CH:27]=[CH:26][C:9]([CH2:10][CH:11]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:18])[C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)Oc1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (2RS,3RS)-2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate (7.12 g, 18.2 mmol) in methanol (60 ml) was added 2N aqueous sodium hydroxide solution (18.2 ml, 36.4 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (4.70 g, 82%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:3]1[C:4]([OH:5])=[CH:6][CH:7]=[CH:8][C:1]=1[OH:2])(=[O:11])[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1c(O)cccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of resorcinol in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of toluene was added to the reaction mixture and the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired mono acetyl resorcinol was obtained by evaporating the residue under vacuum. (Yield: 149.7 g(98%). mp: oil, 1H-NMR(200 MHz, CDCl3, ppm) 2.29(s, 3H), 6.53-6.67 (m, 4H), 7.18 (t. 1H)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:18])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])C.[Li+].[OH-].C1COCC1.CO>O>[CH3:18][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1
Reactant: CCOC(=O)c1cnc(-c2ccccn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)O
Yield: 95.7 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid ethyl ester (26.7 mmol) and LiOH (53.4 mmol) in a 1:1:1 solution of THF, MeOH and water (200 mL) is stir at rt overnight. The THF/MeOH is evaporated, and the aqueous solution is treated with 10% aqueous HCl to adjust the pH to between 1.5 and 2.5. The solid is filtered off, washed with water and dried in vacuo to yield 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5.50 g, 96%) as a solid. MS: 233 (M+H); 1H 1H NMR (300 MHz, CD3OD): δ=2.93(s, 3H), 7.59 (m, 1H), 8.05 (t, 1H), 8.62 (d, 1H), 8.76 (d, 1H), 9.28 (s, 1H).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:32]=[CH:33][N:34]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](O)=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>O1CCOCC1.ClCCl>[C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:32]=[CH:33][N:34]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:38])=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C1CCN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C1CCN(c2cccc(Nc3cc(-c4cccc(C(N)=O)c4)nn4ccnc34)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A mixture of 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (25 mg, 0.106 mmol), 0.5 M ammonium in dioxane solution (2 mL), EDCI (43 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), Et3N (23 mg, 0.22 mmol) and dichloromethane (2 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (6 mg, 24%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.79 (s, 1H), 8.91 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 8.16-8.02 (m, 3H), 7.79 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.52-7.47 (m, 2H), 6.72 (d, 1H, J=7.8 Hz), 6.11 (d, 1H, J=8.4 Hz), 3.72-3.66 (m, 1H), 3.52-3.40 (m, 2H), 3.12 (t, 1H, J=10.0 Hz), 2.13-1.94 (m, 2H), 1.78-1.74 (m, 1H), 0.86 (s, 9H). LC-MS: [M+H]+, 456, tR=1.72 min, HPLC: 99.11% at 214 nm, 99.64% at 254 nm, tR=4.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].O>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH:25][C:27](=[O:30])[CH2:28][CH3:29])[C:19](=[CH:23][CH:24]=3)[C:20]([O:22][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)OC(C)(C)C

Procedure:
840 mg (1.86 mmol) of Compound 17 was dissolved in 8 ml of 1,4-dioxane, 240 μl (2.79 mmol) of propionyl chloride was added dropwise, then the resultant mixture was stirred overnight at 60° C. An excess of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer thus obtained was washed, dried, and concentrated to obtain a crude product of t-butyl 4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilate. The obtained crude product was stirred at room temperature in 3 ml of trifluoroacetic acid for 1 hour, then the reaction solution was concentrated in vacuo to obtain a crude product. This was washed by diethyl ether to obtain 400 mg (yield 48%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 1.10 (3H, t), 2.45 (2H, dd), 7.11 (1H, s), 7.24 (1H, d), 7.85 (1H, d), 7.88 (1H, d), 8.17 (1H, d), 9.18 (1H, s), 11.07 (1H, s), 11.63 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:25][C:23]1([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21][B:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:24]1
Reactant: Nc1ccccc1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2c(CNc3ccccc3)ccc3ccccc23)OC1(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 12.0 g (129 mmol) of aniline, 30.0 g (86.5 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 13.1 g (94.9 mmol) of K2CO3 in 500 cm3 of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 1000 cm3 of water. The product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. An excess of aniline was distilled off using Kugelrohr apparatus. Yield 25.3 g (82%). Anal. calc. for C23H26BNO2: C, 76.89; H, 7.29; N, 3.90. Found: C, 77.02; H, 7.45; N, 3.70. 1H NMR (CDCl3): δ 8.19 (m, 1H, 8-H in naphthalene), 7.83 (d, J=8.8 Hz, 1H, 4-H in naphthalene), 7.80 (m, 1H, 5-H in naphthalene), 7.49 (d, J=8.8 Hz, 1H, 3-H in naphthalene), 7.40-7.51 (m, 2H, 6, 7-H in naphthalene), 7.19 (m, 2H, 2, 6-H in Ph), 6.75 (m, 1H, 4-H in Ph), 6.69 (m, 2H, 3, 5-H in Ph), 4.51 (s, 2H, CH2N), 4.07 (br.s, 1H, NH), 1.38 (s, 12H, Me in tetramethyldioxaborolane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[C:17]([CH3:25])=[CH:18][N:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2.O.ClCCl>ClCCCl>[CH3:14][O:15][C:16]1[C:17]([CH3:25])=[C:18]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[N:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)cn2ccccc12
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COc1c(C)c(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
690 mg (3.1 mmol) of 4-nitrobenzenesulphonyl chloride in solution in 4 ml of 1,2-dichloroethane are added to 500 mg (3.1 mmol) of 1-methoxy-2-methylindolizine dissolved in 8 ml of 1,2-dichloroethane, and the medium is stirred at room temperature for 20 hours. The reaction medium is poured over water and dichloromethane. The organic phase is separated after settling out, washed with water, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C1=O
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
1.28 g of 5,5-dimethylimidazolidine-2,4-dione was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (150 mL) was added to the reaction solution, and washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded white crystals. The resulting fraction was recrystallized from IPE to obtain 232 mg of white crystals.
Reaction SMILES: [OH-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:10]1[CH:15]=[C:14]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[N:19]=[C:18]([CH3:28])[CH:17]=2)[CH:13]=[CH:12][N:11]=1.[CH2:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[CH2:29]([O:36][C:10]1[CH:15]=[C:14]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[N:19]=[C:18]([CH3:28])[CH:17]=2)[CH:13]=[CH:12][N:11]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(OCc3ccccc3)c2)c1

Procedure:
To a suspension of potassium hydroxide (0.67 g, 0.012 mol) and potassium carbonate (0.41 g, 0.003 mol) in 30 mL of toluene was added 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (0.85 g, 0.003 mol). Then benzyl alcohol (0.49 g, 0.0045 mol) was charged into the reaction mixture, followed by the addition of tris[2-(2-methoxyethoxy)ethyl]amine (0.1 g, 0.0003 mol) and the mixture was heated at reflux overnight (about eighteen hours). Toluene was removed under vacuum and the residue was partitioned between water and ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:23]=1
Reactant: O=Cc1cccc(-c2ccccc2F)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3F)c2)CC1

Procedure:
164 mg of the target compound (0.44 mmol, 87.1%) was obtained using 1-(2-methoxyphenyl)piperazine (192 mg, 1.00 mmol), 2′-fluorobiphenyl-3-carbaldehyde (100 mg, 0.50 mmol) and NaBH(OAc)3 (322 mg, 1.50 mmol) according to the synthesis method of Compound 1.