Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].O.[OH-].[Cs+]>CN(C=O)C>[Si:34]([O:33][CH2:32][CH2:31][N:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol) in DMF (5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg, 0.16 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves (2 g). The reaction mixture was stirred for 3 hours and then concentrated. Purification by silica gel chromatography (DCM/MeOH 10:1) gave the desired product (16 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:21])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:21])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(Br)c2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: Cc1cc(Br)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)N2
Temperature: 25 °C
Yield: 81.8 %

Procedure:
Ethyl 8-bromo-6-methyl-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (1.8 g , 4.95 mmol) was suspended in methanol-tetrahydrofuran-water (20 mL, 7:2:1). Lithium hydroxide (414 mg, 9.88 mmol) was added and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N aqueous hydrochloric acid added until pH=1. The organic solvent was removed in vauco to afford a suspension of a crude yellow solid. Diethyl ether (50 mL) was added, and the solution was washed with water (2×50 mL), saturated ammonium sulfate (2×50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 8-bromo-6-methyl-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (1.3 g, 4.05 mmol) as a yellow solid (82% yield). 1H NMR (300 MHz, CDCL3) 7.78 (s, 1H), 7.82 (s, 1H), 6.59 (s, 1H), 5.20 (m, 2H), 5.13 (bs, 1H), 2.34 (s, 1H). HRMS m/z 334.9763; (M+, C12H9BrF3NO2 calcd 334.9769).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[S:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([C@@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:38][CH2:39]1)=[S:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (579 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. The solution was stirred for 5 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g) using dichloromethanelmethanol/25% aqueous ammonia 100:10:1 as eluent to give 201 mg of (2R)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido) ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.[Ru](=O)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][CH2:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([NH2:15])[CH2:16][CH2:17]2)[CH2:3]1
Reactant: Cc1cccc(CCCc2ccc(N)cc2)c1
Agent: O=[Ru]=O
Solvent: C1COCCO1
Product: C[C@H]1CCC[C@H](CCC[C@H]2CC[C@@H](N)CC2)C1
Temperature: 140 °C

Procedure:
0.5 g of ruthenium dioxide is added to a solution of 63 g (0.28 mole) of 4-[3-(3-methylphenyl)-propyl]aniline in 100 ml of dioxane, and hydrogenation is carried out in a 300 ml stirred autoclave at 140° C. and under an H2 pressure of 300 bar until the pressure remains constant (about 3 hours). The discharged mixture is filtered under suction over kieselguhr, the filtrate is evaporated down under reduced pressure and the residue is subjected to fractional distillation to give 47 g (71% of theory) of a colorless oil of boiling point 100°-116° C./0.2 mm, consisting of about 30% of the cis isomer and 70% of the trans isomer (compound no. 64).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C@@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (125 mg, 0.34 mmol), (R)-2-amino-3,3-dimethyl-1-pyrrolidin-1-yl-butan-1-one hydrochloride (155 mg, 0.70 mmol), EDC (148 mg, 0.77 mmol) and HOBt (104 mg, 0.772 mmol). DMF (4.0 mL) was added followed by i-Pr2NEt (0.19 mL, 1.07 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was taken up in EtOAc and 10% citric acid and the organic layer washed with 10% citric acid, sat. NaHCO3, sat LiCl and brine, dried over MgSO4, and concentrated to give 162 mg (90%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a viscous brown oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:23])[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])C>C1COCC1.CO.O>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:6]([OH:23])=[O:5])=[O:10])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
LiOH (1.111 g, 26.47 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (5 g, 17.65 mmol) in THF:MeOH:H2O (3:1:1, 95 mL), and the resulting mixture was stirred at room temperature overnight. The MeOH and THF were evaporated, and the residue was diluted with water (2 mL), acidified with citric acid solution and extracted with EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo to obtain afford 3.892 g (86.3% yield) of [(biphenyl-4-carbonyl)-amino]-acetic acid. LCMS purity: 96.4%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16]>CS(C)=O.O>[CH2:3]([O:6][C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16])[CH2:4][CH3:5]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydroxide with 200 mL of dimethylsulfoxide, 13.0 g of 1-propanol (2.0 eq.) was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a solution containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, and the obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-propoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:17][CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=1)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]([CH2:17][CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCC(c1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N(CCC(c1ccc(O)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A 1.03 g portion of the thus obtained N-ethoxycarbonyl-N-[3-(4 -methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide was dissolved in 25 ml of ethanol. After adding 1 ml of 6N hydrochloric acid, the solution was stirred at 60° C. for 1.5 hours. The resulting reaction mixture was concentrated under a reduced pressure, mixed with methylene chloride and then adjusted to alkalinity with saturated sodium hydrogencarbonate aqueous solution to separate organic layer. After extraction with chloroform, the extract was washed with saturated sodium chloride aqueous solution and dried using anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under a reduced pressure to obtain 0.80 g of N-ethoxycarbonyl-N-[3-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Li+].[Br-].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1c(Cl)cc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
To a mixture of 6-chloro-uracil (3.0 g, 20.47 mmol, 1 equiv.) and LiBr (1.78 g, 20.5 mmol, 1.0 equiv.) in NMP (70 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 0.82 g, 20.5 mmol, 1.0 equiv.). The reaction mixture was stirred at 0° C. for 10 min, and 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g, 22.5 mmol, 1.1 equiv.) was slowly added via an addition funnel. The reaction mixture was stirred overnight at room temperature and then diluted with EtOAc (150 mL). The mixture was washed with a saturated aqueous NH4Cl solution (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure to provide 3.2 g (57%) of the title compound as a white solid. LC/MS: m/z (ES+) 299 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ ppm 9.00-8.80 (br-s, 1H), 5.95 (s, 1H), 5.45 (s, 2H)), 3.63 (t, J=7.0 Hz, 2H), 1.48 (t, J=7.0 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=C[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Cool a solution of 5-methylthiophene-2-carbaldehyde (1 g, 7.9 mmol, 1 eq) and nitromethane (484 mg, 7.9 mmol, 1 eq) in methanol (3 mL) to 10° C. Add sodium hydroxide (332 mg, 8.3 mmol, 1.05 eq) as an aqueous solution (1.5 mL) to the reaction mixture. Stir reaction for 15 minutes and add ice water. Add this mixture to an aqueous HCl solution (1.67 mL concentrated HCl in 2.4 mL water) and stir overnight. Extract product with ethyl acetate, separate organics, dry with magnesium sulfate, and concentrate on rotovap to give 2-methyl-5-(2-nitrovinyl)thiophene (966 mg, 72% yield) as a crude solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(O)C>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Yield: 74.1 %

Procedure:
4-Chloro-7-trifluoromethylquinoline (0.043 moles, 10.0 g), 4-aminothiophenol (0.043 moles, 5.3 g) and 4-dimethylaminopyridine (0.04 moles, 4.9 g) were stirred in 250 ml ethanol for 3 days. The reaction mixture was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 25% ethyl acetate/hexane to yield 4-(4-aminophenylthio)-7-trifluoromethylquinoline 10.2 g, 74%. Mass Spec (FD) 320. Calculated for C16H11F3 N2S: C, 59.99; H, 3.46; N. 8.74. Found: C, 60.08; H, 3.49; N, 8.77.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:9]([CH:13]1[C:18](=[O:19])[CH2:17][CH:16]([C:20]2([CH3:40])[CH:25]=[C:24]([CH3:26])[CH2:23][C:22]([CH:28]3[CH2:33][C:32](=[O:34])[CH:31]([C:35](=[O:38])[CH2:36][CH3:37])[C:30](=[O:39])[CH2:29]3)([CH3:27])[CH2:21]2)[CH2:15][C:14]1=[O:41])(=[O:12])[CH2:10][CH3:11].Cl>ClCCl>[C:1]([C:24]1([CH3:26])[CH2:23][C:22]([CH:28]2[CH2:29][C:30](=[O:39])[CH:31]([C:35](=[O:38])[CH2:36][CH3:37])[C:32](=[O:34])[CH2:33]2)([CH3:27])[CH2:21][C:20]([CH:16]2[CH2:15][C:14](=[O:41])[CH:13]([C:9](=[O:12])[CH2:10][CH3:11])[C:18](=[O:19])[CH2:17]2)([CH3:40])[CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1C(=O)CC(C2(C)C=C(C)CC(C)(C3CC(=O)C(C(=O)CC)C(=O)C3)C2)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)C1C(=O)CC(C2(C)CC(C)(C(C)=O)CC(C)(C3CC(=O)C(C(=O)CC)C(=O)C3)C2)CC1=O
Reaction time: 15 h
Yield: 65 %

Procedure:
Acetyl chloride (0.3 ml) was added to a cooled, stirred suspension of aluminium chloride (1.5 g) and 1,3-bis (2-propionylcyclohexane-1,3-dione-5-yl) mesitylene (1.0 g) in dichloromethane (30 ml). Stirring was continued as the solution was allowed to come to room temperature and then for a further 15 hours. The solution was poured into dilute hydrochloric acid and the organic layer was separated, dried (Mg SO4) and evaporated to give 5-acetyl-1,3-bis(2-propionyl-cyclohexane-1,3-dione-5-yl)mesitylene (0.7 g, 65%) as a semi-crystalline foam.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([CH2:13][CH2:14][C:5]2=[N:4][N:3]=1)=[CH:11][C:10](B1OC(C)(C)C(C)(C)O1)=[CH:9][CH:8]=3.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:1][C:2]1[N:6]2[C:7]3[C:12]([CH2:13][CH2:14][C:5]2=[N:4][N:3]=1)=[CH:11][C:10]([C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)=[CH:9][CH:8]=3
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cncc(C(F)(F)F)c3)cc1CC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (75-2; 0.5 g, 0.00112 mol) and 3-bromo-5-(trifluoromethyl)pyridine (0.381 g, 0.00168 mol) in the mixture of 1,4-dioxan (10 mL) was added aqueous sodium carbonate (2M) (1.68 mL, 0.003376 mol). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.0459 g, 0.003376 mol) was added and allowed to stir at 80° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts were concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.97 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.91-7.89 (d, J 8.4 Hz, 1H), 7.78-7.76 (d, J=8 Hz, 1H), 3.04 (s, 4H), 2.70 (s, 3H). MS (M+1): 331.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH:22]([N:25]1[C:29]([CH3:30])=[CH:28][C:27]([CH2:31]O)=[C:26]1[CH3:33])([CH3:24])[CH3:23].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:33][C:26]1[N:25]([CH:22]([CH3:24])[CH3:23])[C:29]([CH3:30])=[CH:28][C:27]=1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1cc(CO)c(C)n1C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c(C)n1C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
To a stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.84 g, 3.0 mmol) and (1-isopropyl-2,5-dimethyl-1H-pyrrol-3-yl)methanol (0.50 g, 3.0 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise tributylphosphine (0.90 g, 1.5 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.78 g, 4.5 mmol) was added. The solution was stirred at ambient temperature for 16 h then quenched with saturated ammonium chloride (50 mL). The aqueous solution was extracted with ethyl acetate (200 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 1′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 24%) as a colorless solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.02-6.95 (m, 2H), 6.49 (s, 1H), 6.09 (s, 1H), 5.85-5.82 (m, 2H), 5.77 (br s, 1H), 4.77 (ABq, 2H), 4.69 (ABq, 2H), 4.37 (sep, J=7.0 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 1.43 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ194.7, 177.2, 155.9, 148.7, 142.9, 142.2, 132.5, 128.7, 127.0, 125.5, 123.6, 122.9, 119.9, 113.0, 109.6, 107.6, 103.2, 101.4, 93.5, 80.5, 58.2, 47.3, 37.0, 22.2, 14.1, 11.5; MS (ES+) m/z 431.20 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][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.[K+].[K+]>O1CCOCC1.O.CO.Cl.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]>[ClH:1].[C:22]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A mixture of 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (157 mg, 0.5 mmol), phenylboronic acid (92 mg, 0.75 mmol), Pd2(dba)3 (29 mg, 0.05 mmol), X-phos (96 mg, 0.2 mmol) and K2CO3 (208 mg, 1.5 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product (135 mg) which was further 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 a light yellow solid. The mixture was dissolved in methanol then three drops of concentrated HCl were added and the mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product 6-phenyl-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (65 mg, 37%) as a HCl salt. 1H NMR (300 MHz, CD3OD): δ 9.40 (s, 1H), 8.48 (d, 1H, J=2.1 Hz), 8.21 (d, 1H, J=2.4 Hz), 8.12-8.06 (m, 3H), 7.61-7.56 (m, 4 h), 7.48 (d, 1H, J=8.4 Hz). LC-MS: 356, [M+H]+, tR=1.822 min, HPLC: 100% at 214 nm, 99.96% at 254 nm, tR=7.247 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:4]=2[CH:3]=1.CNC1CCCCC1NC.[I-:31].[Na+].O1CCOCC1>O.[Cu]I>[I:31][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Ic1ccc2c3ccccc3n(-c3ccccn3)c2c1
Yield: 83.1 %

Procedure:
A 100 ml three neck round bottom flask was charged with 2-bromo-9-(pyridin-2-yl)-9H-carbazole (10.15 g, 31.4 mmol), copper(I) iodide (1.196 g, 6.28 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (1.981 ml, 12.56 mmol), sodium iodide (18.83 g, 126 mmol), and Dioxane (60 ml.). The reaction mixture was then heated to reflux for 18 hours. The reaction mixture was diluted with deionized water and extracted with ethyl acetate. The organic portion was combined and subjected to column chromatography (SiO2, 50%/DCM in heptane) to yield 2-iodo-9-(pyridin-2-yl)-9H-carbazole (9.66 g, 83%).