Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(=O)/C(=C/NCCN/C=C2/C=CC=CC/2=O)/C=1.[S:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C([O-])([O-])=O.[Cs+].[Cs+].[N+:32]([C:35]1[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCOCC1.C(Cl)(Cl)Cl.[Cu]I>[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([C:22]2[S:21][CH:25]=[CH:24][N:23]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: c1cscn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
As depicted in Scheme 24 below, anhydrous Co(OAc)2 (0.021 mmol, 5%) and SALEN (2,2′-(1,4-diiminobutane-1,4-diyl)diphenol, 0.041 mmol, 0.1 molequivalent) in 0.5 ml dry dioxane are placed in a flame-dried flask, and the mixture is stirred for 10 minutes at room temperature. A solution of thiazole (0.411 mmol) in 1 ml dry dioxane, anhydrous Cs2CO3 (0.493 mmol, 1.2 molequivalents) and CuI (0.822 mmol, 2 molequivalents) are thereafter added consecutively to the reaction mixture under argon. A solution of 4-nitrophenyl iodide (0.493 mmol, 1.2 molequivalents) in dry dioxane (0.5 ml) is then added dropwise and the resulting mixture is heated to 150° C. under argon, while monitoring the reaction progress by TLC. Once the reaction is completed (after about 10 hours), the resulting mixture is diluted with chloroform (20 ml) and filtered through a celite pad. The organic solvents are evaporated under reduced pressure and the crude product is purified by flash column chromatography, using a hexane:ethyl acetate mixture as eluent, to give pure 2-[4-nitrophenyl]thiazole.
Reaction SMILES: [Br-].[CH3:2][CH:3]([O:7][C:8]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4](=O)[CH3:5].[Na].[CH2:36](OCC)C.O>C(O)C>[I:34][C:31]1[CH:32]=[CH:33][C:8]2[O:7][C:3]([CH3:2])([CH3:36])[C:4]([CH3:5])=[CH:10][C:9]=2[CH:30]=1
Reactant: CC(=O)C(C)Oc1ccc(I)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1=Cc2cc(I)ccc2OC1(C)C
Yield: 85 %

Procedure:
To a suspension of 2-(1-methyl-2-oxo-propyloxy)-5-iodobenzyltriphenylphosphonium bromide (0.71 g, 0.00108 mol) in absolute ethanol (3 ml) was added dropwise at room temperature a solution of sodium (0.025 g) in absolute ethanol (1 ml). After twelve hours at room temperature, diethyl ether and water were added. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel, eluting with a mixture of dichloromethane/heptane (50/50) to give 0.29 g (85%) of 6-iodo-2,2,3-trimethyl-1(2H)-benzopyran, as an oil, 1NMR (CDCl3): δ1.4 (s, 6H), 1.8 (s, 3H), 6.0 (s, 1H), 6.55 (d, 1H), 7.2 (d, 1H), 7.35 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:23][S:24]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:11]3[CH:22]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(OS(C)(=O)=O)cc4)c3c2)o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A suspension of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (351 mg, 1.20 mmol), methanesulfonyl chloride (0.111 mL, 1.44 mmol) and potassium carbonate (332 mg, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 hr and at 60° C. overnight. The reaction mixture was diluted with ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) and recrystallized from hexane/ethyl acetate to give the title compound (107 mg, yield 24%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:11]=3)[N:7]=[C:6]([C:38](O)=[O:39])[CH:5]=2)[CH2:3][CH2:2]1.C[N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:26])[CH3:27])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=4)(=[O:29])=[O:30])[CH:11]=3)[N:7]=[C:6]([C:38]([NH2:42])=[O:39])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(=O)O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(N)=O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxylic acid (50 mg) was treated with HATU (51.1 mg, 0.134 mmol) followed by DMF (3 mL) and Hunig's base (0.1 mL). The reaction was stirred for 30 min at RT then treated with NH4OH (0.1 mL) and stirred for 30 min. The reaction was quenched with H2O and extracted with EtOAc (50 mL) and washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated. The crude residue was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.CN(C=O)C.Br[CH2:17][C:18]([CH:20]=[CH2:21])=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH2:19][C:18](=[CH2:17])[CH:20]=[CH2:21])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=CC(=C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(=C)COc1cc(Cl)ccc1C=O
Temperature: 70 °C
Yield: 84.6 %

Procedure:
To a solution of 4.1 g (0.026 mol) of 4-chloro-2-hydroxybenzaldehyde and 27 mL of DMF was added 5 g (0.034 mol) of 2-bromomethyl-1,3-butadiene and 7.2 g (0.052 mol) of potassium carbonate. The resulting mixture was heated at 70° C. for 4 h and then cooled to room temperature and poured into a mixture of 100 mL of water and 100 mL of methylene chloride. The aqueous layer was extracted with two 100 mL portions of methylene chloride and the combined organic layers were washed twice with 100 mL of water, twice with 100 mL of saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to give 4.9 g of an oil. Purification by flash chromatography using 250 g of silica gel and eluting with 10:1 hexanes-EtOAc gave 2.6 g of the desired product. 200 MHz 1H NMR (CDCl3): δ4.82 (s, 2H), 5.18-5.42 (m, 4H), 6.45 (dd, 1H), 7.01 (s, 1H), 7.05 (d, 1H), 7.79 (d, 1H), 10.48 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Yield: 51 %

Procedure:
Add to 1.2 g 3-(5-cyano-2-nitrophenyl)-2-oxopropionic acid ethyl ester 2 (m=0) in EtOH (40 mL), 10% Pd/C (0.40 g) and stir under a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. Filter the mixture and concentrate the filtrate to afford 1.1 g of crude product. Purify by chromatography on SiO2 eluting with CH2Cl2. Concentrate the desired fractions and vacuum dry the residue over night (40° C.) to provide the title compound (0.5 g) as white crystals, Rf=0.9 (silica gel, 10% MeOH/CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)=[CH:21][CH:20]=1)#[N:2].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(OCC)(=O)C.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2]
Reactant: Nc1ccccn1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccn4)cc3)c2cc1C#N
Temperature: 85 °C
Yield: 82.9 %

Procedure:
Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (104 mg, 0.228 mmol) was dissolved in dimethylsulfoxide (1 ml), and then 2-aminopyridine (43 mg, 0.457 mmol) was added and the mixture was heated at 85° C. for 3 hours while stirring. After cooling, ethyl acetate and water were added for distribution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent and concentrating under reduced pressure, ethyl acetate-hexane was added to the residue and the precipitated crystals were filtered out and dried under reduced pressure to obtain the title compound (86 mg, 0.189 mmol, 82.7%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:26]([NH2:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:26]([NH:28][C:18]([C:17]1[C:16]([F:24])=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[C:22]([F:23])[CH:21]=1)=[O:19])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(C(=O)O)cc2F)CC1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid (0.021 g, 0.061 mmol) and ethylamine hydrochloride (7.50 mg, 0.092 mmol) were suspended in DMF (Volume: 0.7 mL) and treated with DIPEA (0.054 mL, 0.307 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.047 g, 0.123 mmol). The reaction mixture was stirred at room temperature for 15 min and diluted with water. The precipitate was filtered, washed with water and dried in vacuum to afford tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (20.1 mg, 0.054 mmol, 89% yield). ESI-MS: m/z 370 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:14])([F:1])[F:15])[CH:5]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(SC(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(SC(F)(F)F)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(trifluoromethylthio)phenylacetic acid (5.00 g, 21.17 mmol) in methanol (50 mL) was treated slowly with concentrated sulfuric acid (10 drops). The resulting reaction mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford crude (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester (5.28 g, 99%) as a pale yellow oil which was used without further purification: EI-HRMS m/e calcd for C10H9F3O2S (M+) 250.0275, found 250.0274.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]
Reactant: Oc1cccc(Cl)c1
Reactant: CON=C(Cl)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.2 %

Procedure:
3-Chlorophenol (3.09 g, 0.024 mol), N,N-dimethylforamide (20 ml) and potassium carbonate (4.15 g, 0.03 mol) were added to 2-chloromethyl-α-methoxyiminobenzyl chloride (4.36 g, 0.02 mol), and the mixture was stirred at room temperature for 4 days. After completion of the reaction, ether (250 ml) was added, and the mixture was washed with brine (200 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (5.66 g, 91.2%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][C:4]#[N:5].[N+:7]([CH3:10])([O-:9])=[O:8].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][C:2]([CH3:6])([CH2:10][N+:7]([O-:9])=[O:8])[CH2:3][C:4]#[N:5]
Reactant: C=C(C)CC#N
Reactant: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CC#N)C[N+](=O)[O-]
Temperature: 103 °C
Yield: 93.6 %

Procedure:
In a one liter glass reactor equipped with a thermometer, a cooling apparatus and a stirrer, 3-methyl-3-butenenitrile (37.0 g, 0.456 mol) and nitromethane (557.0 g, 9.125 mol) were charged. Then, 1,8-diazabicyclo[5.4.0]-7-undecene (13.9 g, 0.091 mol) was dropwise added over a period of 5 minutes at room temperature while stirring. After the dropwise addition, the mixture was heated and refluxed at 103° C. for 13.5 hours. After cooling the mixture to room temperature, unreacted nitromethane was evaporated off under reduced pressure. To the residue, dichloromethane (300 g) and 5% sulfuric acid (300 g) were added and stirred. Thereafter, the mixture was phase separated to obtain a dichloromethane layer. To the aqueous layer, dichloromethane (300 g) was added and the mixture was phase separated to obtain a dichloromethane layer. Two dichloromethane layers were combined and washed with water (300 g). After drying the dichloromethane solution over anhydrous sodium sulfate, dichloromethane was evaporated off under reduced pressure to obtain brown crystal 3,3-dimethyl-4-nitrobutanenitrile (60.7 g), a purity of which was 92.0%. Its yield was 86.1% based on 3-methyl-3-butenenitrile.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]([F:26])([F:39])[F:40])(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(trifluoromethoxy)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: COC(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with methyl 4-formylbenzoate was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give methyl 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[CH3:27][NH2:28].Cl>O.O1CCOCC1>[CH3:27][NH:28][C:13]([C:6]1[NH:7][C:8]2[C:3]([C:4](=[N:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:5]=1)=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[O:15]
Reactant: CN
Reactant: COC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 18 h

Procedure:
Combine 5,7-dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.0 g, 2.4 mmol) and 40% methylamine in water (25 mL) and dioxane (50 mL). Stopper and stir for 18 hours. Evaporate in vacuo to give a yellow oil. Dissolve the oil in water (15 mL) and add 1M hydrochloric acid solution (15 mL). Stir for 15 minutes and then filter to obtain a solid. Rinse the solid with 1M hydrochloric acid solution and water. Recrystallize from acetonitrile/water to give the title compound as a solid: mp; 196°-197° C. Elem. Anal. calculated for C17H13Cl2N3O3S.H2O: C, 47.68; H, 3.53; N, 9.81. Found: C, 47.55; H, 3.42; N, 9.78.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:45][C:46]([CH3:51])([CH3:50])[CH2:47][CH:48]=[O:49]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:48]([OH:49])[CH2:47][C:46]([CH3:51])([CH3:50])[CH3:45])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CC(C)(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.5 g, 13 mmol) in dry tetrahydrofuran (150 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (12.5 mL, 20 mmol) to a 0° C. solution of diisopropylamine (3.06 mL, 21 mmol) in dry tetrahydrofuran (10 mL)] dropwise. The mixture was stirred at −78° C. for 15 min and then treated with 3,3-dimethyl-butyraldehyde (3.1 mL, 24 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,3-dimethyl-butan-1-ol as a colorless oil (3.1 g, 63%): LC/MS m/e calcd for C19H22N2O3S [M+H]+ 359.46, observed 359.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:20][CH:21]=[N:22][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:19]2[S:20][CH:21]=[N:22][CH:23]=2)[CH:8]=1)[NH2:5]
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Reactant: Brc1cncs1
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
Product: Nc1cc(F)cc(-c2cncs2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
The product of Step 1 (2.66 g, 11.2 mmol), 2-bromo-1,4-thiazole (1.00 ml, 11.2 mmol), Pd2(dba)3 (0.514 g, 0.561 mmol), X-phos (0.535 g, 1.122 mmol), and cesium carbonate (7.31 g, 22.4 mmol) were added to a dry flask. The flask was degassed with argon, then dioxane (25 ml) and water (2.5 ml) were added. The reaction mixture was degassed with argon for five minutes, and then heated to 95° C. After 16 hours, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated. The residue was purified by flash chromatography (EtOAc/hexane gradient) to afford 3-fluoro-5-(1,3-thiazol-5-yl)aniline (2.27 g, 9.49 mmol, 85% yield). MS APCI: [M+H]+ m/z 195.1. 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H); 8.18 (s, 1H); 6.66-6.62 (m, 1H); 6.61-6.59 (m, 1H); 6.29-6.26 (m, 1H); 5.58 (s, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7](=[O:22])[CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=3)[C:4]=2[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:6][C:5]=3[C:7](=[O:22])[CH:8]2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C1COCCN1
Reactant: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1C(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 0.3 %

Procedure:
A mixture of methyl 2-bromo-4-(3,4-dichlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (0.25 g, 0.59 mmol), morpholine (0.26 g, 2.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (26.9 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.0 mg, 0.06 mmol) and cesium carbonate (0.58 g, 1.76 mmol) in 1,4-dioxane (5.96 mL) was heated at 80° C. under argon for 3 h. And the temperature was raised to 100° C. and maintained overnight. The mixture was dryloaded on silica gel and purified by column chromatography (12 g cartridge, gradient hexanes to 60% EtOAc in hexanes) and then preparative HPLC to afford the product as a white solid (0.8 mg, 0.3%). LCMS: (FA) ES+ 426, 428, 430. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 6.99 (dd, J=8.0, 2.1 Hz, 1H), 5.77 (s, 1H), 4.73 (d, J=3.2 Hz, 1H), 3.86-3.76 (m, 7H), 3.67 (d, J=3.2 Hz, 1H), 3.35-3.26 (m, 4H).