Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:8]([NH:9][C:10](=[O:46])/[C:11](=[N:25]\[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:12]2[N:13]=[C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[S:15][CH:16]=2)[C:7](=[O:47])[NH:6]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[NH2:1][CH2:4][C@@H:5]1[C@H:8]([NH:9][C:10](=[O:46])/[C:11](=[N:25]\[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:12]2[N:13]=[C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[S:15][CH:16]=2)[C:7](=[O:47])[NH:6]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Reaction time: 12 h
Yield: 55.9 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(azidomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (689 mg, 1.04 mmol) in THF (10 mL) and MeOH (1.3 mL) was added Ph3P (301 mg, 1.15 mmol). After 12 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (369 mg, 56%). LCMS: Rt=0.88 min, m/z=635.1 (M+1), Method 2m_acidic.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:25]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][Si](C(C)(C)C)(C)C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:25]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1csc(-c2ccc3cc(O[Si](C)(C)C(C)(C)C)c(C45CC6CC(CC(C6)C4)C5)cc3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.29 g (15.2 mmol) of ethyl 2-[7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-naphthyl]-4-thiophenecarboxylate and 60 ml of THF were introduced into a round-bottomed flask. A solution of 15.2 ml (16.6 mmol) of tetrabutylammonium fluoride in THF (1.1N) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane, filtered and dried. 6.12 g (93%) of ethyl 2-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-4-thiophenecarboxylate of melting point 199°-200° C. were recovered.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:25]1[N:13]2[CH:14]=[N:15][C:16]3[CH:17]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])[CH:9]=[CH:10][C:11]=3[C:12]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
a mixture of dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (11.7 g) in diphenyl ether (58 ml) was stirred at 250° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were collected by filtration, washed with hexane, and dried. The crystals were dissolved in a mixture of chloroform and ethanol under heating. The solution was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure until crystallization began. After the solution was cooled to ambient temperature, the resulting crystals were collected by filtration to give methyl 4-oxo-9-pivalamido-4H-pirimido[1,2-C]quinazoline-3-carboxylate (5.1 g). Concentration of the mother liquor gave additional crystals of the same compound (3.4 g).
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[K+]>O1CCOCC1>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCCC(C(C)=O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCC(C(C)=O)C(=O)O
Temperature: 0 °C

Procedure:
3.08 g (17.9 mmol) of methyl 2-acetylhexanoate (Example 14A) is dissolved in 10 ml of dioxane and cooled to 0° C. 7.00 ml of a 3.5 M potassium hydroxide solution are added with cooling. After a reaction time of 5 h, the batch is concentrated, treated with 20 ml of ethyl acetate and 20 ml of water and extracted with shaking. The water phase is recovered, cooled to 0° C. and slowly treated with 1 N hydrochloric acid until a pH of 1 is reached. The mixture is then extracted with dichloromethane. The dichloromethane phase is dried and directly reacted further without concentrating.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:17]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[C:20]1[CH:21]=[CH:16][N:17]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:19]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccc2cc[nH]c12
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CNS(=O)(=O)c1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 1H-indole-7-sulfonic acid methylamide and (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting groups with TBAF. Yield: 70 mg (5%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[CH:16]=[C:15]([Cl:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1>>[Cl:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:16]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Product: COc1ccc2c(Cl)cc(-n3cccn3)nc2c1
Temperature: 115 °C
Yield: 56.1 %

Procedure:
Solid pyrazole (3.2 g, 47.36 mmol) was heated to 80° C. Then 2,4-Dichloro-7-methoxyquinoline (3.6 g, 15.78 mmol) was added. The reaction mass was heated to 115° C. for 3 hr. The reaction mass was cooled to RT and was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 56%) as white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=[O:19])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)(=[O:7])=[O:6]>CC(C)=O>[CH3:1][N:2]([CH3:3])[S:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=[O:19])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)(=[O:7])=[O:6]
Reactant: CNC
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
500 cm3 of acetone and a solution of 99 g of dimethylamine in 250 cm3 of acetone were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 0° C. and then 139 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced. The mixture was agitated at ambient temperature, the acetone distilled off and the residue dissolved in 1 liter of water. The solution was rendered alkaline, filtered and treated with 70 cm3 of hydrochloric acid. The precipitate was dried off, washed and dried. 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 220°-221° C.; yield: 89%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:47])[CH2:43][CH2:44][CH2:45][CH3:46]>C1COCC1>[CH2:42]([NH:47][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31])[CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCN
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of n-pentylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 512.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.Cl.O>C1COCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CC(CN)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-propionitrile (5.0 g, 30.2 mmol) in THF (80 mL) was added borane-tetrahydrofuran complex solution (45 mL, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. Ethanol (10 mL) was then added to the reaction mixture; after stirring at room temperature for 20 min, a solution of HCl in ether (2 M, 12.5 mL) was added. After stirring for another 1 hour, water was added to induce the precipitation of the product. The white solid was collected by filtration and dried in vacuo to give the title compound (3.6 g, 70%). MS (for free amine): 170.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].[N-:13]=[N+:14]=[N-:15].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:15][N:14]=[N:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(I)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Product: Cc1nnnn1-c1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5 g, 18.24 mmol) in acetoritrile (100 mL) was cooled to 0° C. and then treated with sodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treated with trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (100 mL) and water (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%) as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C8H6FIN4 (M+) 303.9621, found 303.9615.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[CH3:13][N:12]([CH3:14])[S:11]([C:10]1[C:2]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid (3.08 g), phenol (2 g), sodium hydrogen carbonate (3.4 g), and water (20 ml) was heated at 90°C for 8 hours. Then water (40 ml) was added and, after cooling, the 5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid was precipitated by acidification with 4N hydrochloric acid. After isolation by filtration and several recrystallizations from ethanol, the said compound was obtained with a melting point of 224°-226°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:22]=1[CH2:23]Cl.Cl>O.C(#N)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:22]=1[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)c(CNc2cccc(S(=O)(=O)O)c2)c(C)c1
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A mixture of 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid, 83.0 g (0.61 mole) of sodium acetate trihydrate, 33.7 g (0.20 mole) of 2,4,6-trimethylbenzyl chloride, 225 ml of water and 150 ml of acetonitrile was refluxed for 4 hrs, then acidified by the dropwise addition of 40 ml of conc. HCl over 30 minutes during which time approximately 100 ml of acetonitrile was distilled off. The resulting mixture was vacuum filtered while hot (80° C.) and a grayish-white powder obtained which was then slurried in 300 ml of hot (65° C.) water for 20 minutes and vacuum filtered. The slurrying process was repeated with water and then with 300 ml of boiling methanol for 20 minutes. Vacuum filtration followed by drying in vacuo at about 60° C. afforded 24.85 g (40.7% yield) of purified 3-(((2,4,6-trimethylphenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cl)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cl)c2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, 113.2 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (23.1 g, 50%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 (M+H)+: 409.73, observed: 407.9 & 409.9.
Reaction SMILES: [Cl-].C([Al+]CC)C.[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17](OCC)=[O:18])=[C:15]([CH:22]([NH:30][C:31]2[CH:36]=[C:35]([Cl:37])[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:14]([CH:40]([CH3:42])[CH3:41])[C:13]=1[Br:43])=[O:11])[CH3:8]>>[CH2:7]([O:9][C:10]([C:12]1[C:16]2[C:17](=[O:18])[N:30]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=3)[CH:22]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:15]=2[N:14]([CH:40]([CH3:42])[CH3:41])[C:13]=1[Br:43])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)n(C(C)C)c1Br
Agent: CC[Al+]CC
Agent: [Cl-]
Product: CCOC(=O)c1c2c(n(C(C)C)c1Br)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but diethylaluminium chloride (1.8M in toluene) was used instead of trimethylaluminium chloride, and 2-bromo-5-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3,4-dicarboxylic acid diethyl ester (Step BM1) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a beige solid. tR: 1.16 min (HPLC 3); ESI-MS: tR=1.11 min, [M+H]+ 566/568/570 (LC-MS 1); TLC: Rf=0.14 (EtOAc).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1OC
Temperature: 100 °C
Reaction time: 0.15 h
Yield: 13.9 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (100 mg, 0.3 mmol), 3,4-dimethoxyphenylboronic acid (82 mg, 0.45 mmol), Pd2(dba)3 (0.018 g, 0.03 mmol), X-phos (0.029 g, 0.06 mmol) and Na2CO3 (0.096 g, 0.9 mmol) in dioxane (3 mL) and water (3 mL) was heated to 100° C. for 15 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was 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 afford 6-(3,4-dimethoxyphenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (18 mg, 14%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.19 (s, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.50-7.48 (m, 1H), 7.11 (d, 1H, J=8.4 Hz), 6.66 (d, 1H, J=7.2 Hz), 6.12 (d, 1H, J=7.8 Hz), 4.22 (brs, 1H), 3.85 (s, 6H), 3.56-3.37 (m, 3H), 2.07-1.97 (m, 2H), 1.74-1.70 (m, 1H), 1.11 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 431, tR=1.769 min, HPLC: 98.38% at 214 nm, 99.04% at 254 nm, tR=7.213 min.
Reaction SMILES: [O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:3]=1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(O)(C(F)(F)F)=O>ClCCl>[O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: CC(C)(C)OC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reaction time: 6 h

Procedure:
14 g of the compound obtained in Step A dissolved in 100 ml of dichloromethane are placed under argon, 10 ml of TFA are added, and then stirring is carried out for 6 hours at ambient temperature.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN
Product: CNc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine and methyl amine by a procedure similar to example 14. 1H NMR (CDCl3): 7.42-7.42 (m, 1H), 7.34 (ddd, J=8.1, 6.9, 4.0, 1H), 7.04 (m, 2H), 6.94 (m, 1H), 6.63-6.71 (m, 3H), 5.13 (s, broad, 1H), 3.49 (s, 3H), 3.10 (d, J=4.8, 3H), 2.97 (s, 6H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=5)=[CH:27][C:26]=4[N+:41]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=5)=[CH:27][C:26]=4[NH2:41])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3cncc(Br)c3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)Nc2cncc(Br)c2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
The product of Example 231C (146.5 mg, 0.2195 mmol), ammonium chloride (77 mg, 1.438 mmol), and iron powder (75.4 mg, 1.35 mmol) in a mixture of water (3 mL), ethanol (6 mL) and tetrahydrofuran (6 mL) was heated at 80° C. under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification by silica gel chromatography eluting with 4% methanol/methylene chloride afforded the title compound as a yellow solid (103 mg, 74%).