Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Yield: 88.9 %

Procedure:
A mixture of 4-trifluoromethylbenzyl bromide (5.68 g, 23.8 mmol) and triethyl phosphite (10.4 g, 63 mmol) was heated at reflux under nitrogen for 5 hours. The excess triethyl phosphite was removed by distillation and the crude product was purified by distillation at 95° C. (0.07 mm Hg.) to give 6.27 g, 89% of the product as an oil. D.C.I.M.S.[MH+, 297].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]([OH:26])=O)=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][NH2:40])[CH2:34][CH2:33]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][NH:40][C:24]([C:19]2[C:18]3[C:22](=[CH:23][C:15]([C:12]4[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:27]=[CH:28][CH:29]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:4]=5)=[CH:14][CH:13]=4)=[CH:16][CH:17]=3)[NH:21][N:20]=2)=[O:26])[CH2:34][CH2:33]1
Reactant: NCCN1CCOCC1
Reactant: O=C(Nc1ccc(-c2ccc3c(C(=O)O)n[nH]c3c2)cc1)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc3c(C(=O)NCCN4CCOCC4)n[nH]c3c2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
To a stirred solution of 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylic acid (6 mg, 14 μmol), morpholinoethyl amine (3 μl, 17 μmol), HOBt (3 mg, 17 μmol), and triethylamine (4 μl, 28 μmol) in N,N-dimethylformamide (0.3 Ml), was added EDCI (4 mg, 21 μmol). After the mixture was stirred at 70° C. for 12 h, the mixture was cooled to room temperature, and ethyl acetate and saturated sodium bicarbonate solution were added. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate/hexane to give N-(2-morpholinoethyl)-6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide (4 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].N([O-])=O.[Na+].Cl>O.O1CCCC1>[CH:13]1[CH:12]=[C:11]([N:16]2[NH:7][N:6]=[N:5][C:17]2=[O:18])[C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 0 °C
Yield: 72 %

Procedure:
Anhydrous aluminum chloride (1.5 g) was added to tetrahydrofuran (30 ml) with ice bath cooling, followed by a fifteen minute-stirring, addition of sodium azide (1.95 g) and 2-chlorophenylisocyanate (1.53 g) thereto and a sixteen hour-refluxing under heating in that order. After cooling, the reaction mixture was added with stirring to a mixture of sodium nitrite (2 g), water (200 ml) and ice (100 g) and the resulting mixture was acidified with 10% hydrochloric acid (until a potassium iodide starch paper became discolored), followed by extraction with ethyl acetate. The thus obtained ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: hexane: ethyl acetate = 2:1) to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (1.41 g) having a m.p. in the range of from 124.5° to 125.5° C. in a yield of 72% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15](CC)[CH2:16][C:17]3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:43][CH2:42][C@@H:41]2[C@H:36]([O:37][CH2:38][CH2:39][N:40]2C(OC(C)(C)C)=O)[CH2:35]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:3]([N:34]2[CH2:43][CH2:42][C@@H:41]3[C@H:36]([O:37][CH2:38][CH2:39][NH:40]3)[CH2:35]2)=[CH:4][C:5]([C:32]#[N:33])=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]2[N:10]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC(C)(C)C)c2Cl)nn2c(C#N)cnc12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
(+/−)-(4aR,8aR)-tert-butyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (75 mg, 0.104 mmol) was taken up in DCE (2 mL), anisole (0.05 mL, 0.458 mmol) and TFA (0.5 mL, 6.49 mmol). The mixture stirred 2 h at 25° C. and solvents removed. 50 ml 2N NH3/MeOH was added and stirred for 30 mins. The white precipitate was collected by filtration and washed with 20 ml cold MeOH, then ether and dried under air-suction for 2 hrs to give (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][CH:9]2[CH2:1][O:2][CH2:3][CH:4]2[CH2:5]1
Reactant: ClCCCBr
Reactant: C1CC2COCC2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCC2COCC2C1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A mixture of octahydrofuro[3,4-c]pyridine (300 mg, 2.40 mmol, 1 eq), 1-bromo-3-chloropropane (760 mg, 4.80 mmol, 2 eq) and K2CO3 (736 mg, 9.60 mmol, 4 eq) in acetone (30 mL) was heated to reflux overnight, cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (223 mg, 46.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 248.05 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[CH2:2].[CH2:15]([O:17][SiH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH3:16].C1(C(O)=O)CCCCC1.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][Si:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(-c2ccccc2)cc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: O=C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(-c2ccccc2)cc1)(OCC)OCC
Temperature: 50 °C
Yield: 32 %

Procedure:
361 mg Of 4-vinylbiphenyl and 394 mg of triethoxysilane were placed in a glass reaction tube and 0.0009 ml of cyclohexanoic acid was added. Then, 0.009 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.0044 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of 4-vinylbiphenyl was 36% and para-phenylphenethyltriethoxysilane was produced at a yield of 32%. The yield of α-(4-biphenylyl) triethoxysilane was 3%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)ccc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(O)ccc1O

Procedure:
To a solution of 2-nitrobenzene-1,4-diol (3.00 g, 19.34 mmol) in ethanol (100 mL) was added 10% palladium on carbon (0.600 g, 0.564 mmol). After shaking under 40 psi of hydrogen for 2 hours, the mixture was filtered and the filtrated was concentrated under reduced pressure to provide the product as solid.
Reaction SMILES: F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>C(#N)C.CCOC(C)=O.O>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 95 °C

Procedure:
1-Butyl-3-methylimidazolium tetrafluoroborate (1.75 g, 7.74 mmol) was added to a stirred solution of 1-fluoro-2-methyl-4-nitrobenzene (12 g, 77.35 mmol) and 1-acetylpiperazine (39.7 g, 309.4 mmol) in acetonitrile (3 ml). The reaction mixture was then heating at 95° C. overnight. The reaction mixture was allowed to cool down to room temperature. The solution was diluted with EtOAc and water. The precipitate formed was filtered off to give a solid corresponding to the required product. The organics were washed with water (4 times), brine, dried and evaporation of solvent to give a solid. Both solids were combined and after trituration with isohexane/ether and filtration, the title compound was obtained as a yellow solid which was dried in vac oven overnight at 50° C. (19.61 g, 96%). NMR (400 MHz) 2.06 (s, 3H), 2.38 (s, 3H), 2.99 (dt, 4H), 3.61 (m, 4H), 7.14 (d, 1H), 8.04 (dd, 1H), 8.07 (d, 1H); m/z 264.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.[Cl-].[Mn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: [Mn+2]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (20.8 g, 56.5 mmol) in methanol (500 ml) was added manganese (II) chloride (14.2 g, 113 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added sodium borohydride (4.28 g, 113 mmol) under ice-cooling, and the mixture was stirred for 20 min. The reaction solution was poured into 1N hydrochloric acid (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.1 g, 53%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:45])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([NH:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)=[O:17])[S:15][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC4CCNC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of 290 (40 mg, 0.084 mmol) and 2-phenylacetyl isothiocyanate (22 mg, 0.126 mmol) in THF (2 mL) was stirred for 30 min. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (eluent EtOAc), to afford a solid material, which was dissolved in a mixture of TFA/DCM (0.5 mL/0.5 mL) and stirred at room temperature for 2 h. Solvents were removed under reduced pressure and the residue was purified by preparative HPLC (Aqusil C18, gradient eluent, 60-95% MeOH in water, 45 min) to afford the title compound 291 (8 mg, 80% yield) as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 9.27(d, 1H), 8.57(d, 1H), 8.37(s, 1H), 8.30(s, 1H), 8.01(d, 1H), 7.53(m, 2H), 7.33-7.31(m, 4H), 7.29-7.25(m, 1H), 6.74(d, 1H), 4.46(m, 1H), 3.82(s, 2H), 3.11-3.03(m, 2H), 2.18-2.09(m, 2H), 1.93-1.89(m, 2H). MS (m/z): 550.2(M+H) (found).
Reaction SMILES: [OH-].[Li+].[CH2:3]1[CH:14]2[CH:6]([NH:7][C:8]3[C:9]([C:15]([NH:17][C@@H:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[O:16])=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4]1>C1COCC1>[CH2:3]1[CH:14]2[CH:6]([NH:7][C:8]3[C:9]([C:15]([NH:17][C@@H:18]([CH3:24])[C:19]([OH:21])=[O:20])=[O:16])=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4]1
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cccc2c1NC1CCCC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 1 M aqueous lithium hydroxide solution (13 mmol, 13 mL) was added to a solution of ethyl (2S)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (6.1 mmol, 1.9 g) in THF (50 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and diluted with 0.1 N HCI and ethyl acetate. The phases were separated and the organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a yellow oil (1.6 g, 6.1 mmol, quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:11]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:8]=2)[N:6]=[CH:10][CH:9]=1
Reactant: C=CC(C)=O
Reactant: Cc1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccc2nccc(C)c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 4-methylaniline (1 g. 9.3 mmol.) in acetic acid (10 ml), activated silferc (1.5 g. ferric chloride 9.3 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.72 g, 10 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.27 g. 9.3 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH:18]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2].Br>C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH2:18])=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2]
Reactant: CCOC(=O)NC1CCc2ccc(CCNC(=O)OCc3ccccc3)cc2C1Cc1cccc(Cl)c1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCN)cc2C1Cc1cccc(Cl)c1
Yield: 105.5 %

Procedure:
To [7-(2-benzyloxycarbonylamino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamic acid ethyl ester (500 mg, 0.960 mmol) was added at room temperature 8 ml of 33% HBr in acetic acid. After 2 h the mixture was diluted with CH2Cl2, washed twice with NaHCO3, dried and filtered. The solvent was evaporated to obtain the product as a yellow oil (392 mg), which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:20]([C:19]1[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1c(O)ccc2c1CC(CO)O2
Reaction time: 48 h
Yield: 87.2 %

Procedure:
5-Benzyloxy-4-tert-butyl-2-formylbenzofuran (5.0 g, 16 mmol) was dissolved in a 25:1 mixed solution (260 ml) of ethyl acetate and acetic acid. After adding 10% Pd on carbon (5.0 g), the solution was stirred under a hydrogen atmosphere for 48 h. After filtering off the Pd on carbon, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was subjected to silica gel chromatography and eluted with a solvent system consisting of a 4:1 mixture of hexane and ethyl acetate to afford 4-tert-butyl-5-hydroxy-2-hydroxymethyl-2,3-dihydrobenzofuran [3.1 g (yield, 87%)] as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O-])(=O)C.[Pb+2].C([O-])(=O)C.F[B-](F)(F)F.[CH3:17][C:18]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[Se+:22]=1)([CH3:20])[CH3:19].[Cl:32][C:33]1[C:34](=[O:40])[C:35]([Cl:39])([Cl:38])[C:36]=1Cl>ClCCl.C(N(CC)CC)C>[CH3:20][C:18]([C:21]1[Se:22][C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][C:25](=[CH:27][C:36]2[C:35]([Cl:39])([Cl:38])[C:34](=[O:40])[C:33]=2[Cl:32])[CH:26]=1)([CH3:17])[CH3:19]
Reactant: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Reactant: O=C1C(Cl)=C(Cl)C1(Cl)Cl
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Yield: 60 %

Procedure:
A 500 mL three-necked round-bottom flask was equipped with a magnetic stirrer, a dropping funnel with a pressure-equalizing side arm, a condenser with a dry nitrogen gas inlet tube and an outlet attached to a succession of scrubbers containing 10% aqueous sodium hydroxide and 10% aqueous lead acetate. Into this flask were placed 2,6-bis(1,1-dimethylethyl)-4-methyl-selenopyrylium tetrafluoro-borate (3.0 g, 8.4 mmole, prepared as in Example 1 above, 2,3,4,4-tetrachloro-cyclobut-2-en-1-one (1.7 g, 8.4 mmole) and dichloromethane (150 mL). Stirring was begun and a solution of triethylamine (2.3 mL, 16 mmole) in dichloromethane (50 mL) was added dropwise over a period of 1.5 hours under nitrogen. After the addition of the triethylamine had been completed, the reaction mixture was stirred at room temperature for an additional 1.5 hours, then filtered through a sintered glass funnel containing silica gel (40 g). The silica gel was washed several times with small portions of dichloromethane until the washings were pale orange. The filtrate and washings were combined and evaporated to dryness on a rotary evaporator on a water bath kept at approximately 40° C. The residual green mass was triturated with hexane (60 mL) until maroon crystals formed; these crystals were removed by suction filtration and dried in vacuo at approximately 30° C. to yield 3-[2,6-bis(1,1-dimethylethyl)-(4H-selenopyran-4-ylidene)methyl]-2,4,4-trichlorocyclo-but-2-en-1-one (2.2 g, 60% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1.CC(C)([O-])C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C([O-])(O)=O.[Na+].CCOC(C)=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]>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:34][CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:3][C:4]=2[CH3:25])=[CH:9][C:10]([C:21]([OH:24])([CH3:23])[CH3:22])=[N:11]1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(Br)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Product: Cc1cc(NCCN2CCOCC2)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Temperature: 160 °C
Yield: 38 %

Procedure:
A mixture of 2-(5-(4-bromo-2-methylphenyl)-1-(2,6-dichlorophenyl)-1H-pyrazol-3-yl)propan-2-ol ((160 mg, 0.36 mmol), 2-morpholinoethanamine (75 mL, 0.57 mmol), sodium tert-butoxide (54 mg, 0.57 mmol), biphenyl-2-yldi-tert-butylphosphine (13.1 mg, 44 μmol), and Pd2(dba)3 (19.8 mg, 22 μmol) was placed in a microwave reaction vial and heated at 160° C. for 15 minutes. After cooling, the reaction was diluted with saturated aqueous NaHCO3, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a dark oil. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCN/H2O with 0.05% TFA. The product peak from the HPLC was basified by addition of saturated aqueous NaHCO3, and concentrated under reduced pressure to remove most of the solvents. The basic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(1-(2,6-dichlorophenyl)-5-(2-methyl-4-(2-morpholinoethylamino)phenyl)-1H-pyrazol-3-yl)propan-2-ol (67 mg, 38% yield) as a white foam. 1H NMR (400 MHz CDCl3): δ 7.34-7.29 (2H, m), 7.20 (1H, m), 6.84 (1H, d), 6.46 (1H, d), 6.32 (1H, s), 6.23 (1H, m), 4.32 (1H, s), 3.74-3.66 (4H, m), 3.15-3.07 (2H, m), 2.66 (1H, s), 2.63-2.55 (2H, t), 2.48-2.40 (4H, m), 2.33 (3H, s), 1.67 (6H, s). MS(ES): 489 [M+H]+.
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.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=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.[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.[Pd]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
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: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccncc3)nn3ccnc23)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.15 mmol), pyridin-4-ylboronic acid (0.022 g, 0.18 mmol), Pd(dba)2 (0.02 g, 0.035 mmol), X-Phos (0.02 g, 0.042 mmol) and Na2CO3 (0.032 g, 0.3 mmol) in dioxane/H2O (20 mL/2 mL) was stirred at 95° C. for 18 h under N2 atmosphere. The solvent was removed in vacuo and the residue purified by chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-amine (0.025 g, 44%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.75-8.70 (m, 3H), 8.15 (brs, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J=5.7 Hz), 7.62 (s, 1H), 7.41 (t, 1H, J=7.9 Hz), 6.22 (d, 1H, J=7.5 Hz), 6.05 (d, 1H, J=8.4 Hz), 4.26-4.22 (m, 1H), 3.68-3.63 (m, 1H), 3.49-3.46 (m, 1H), 2.16-2.04 (m, 3H), 1.77 (brs, 1H), 1.24 (t, 3H, J=6.3 Hz). LC/MS: 372 [M+H]+, 370 [M−H]−, tR=1.68 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.57 min.