Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]=O)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:43]1[CH2:46][CH:45]([OH:47])[CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:43]4[CH2:46][CH:45]([OH:47])[CH2:44]4)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC=O)c4ccc(OC(F)F)cc34)nc12
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (27 mg, 46.0 mmol) in dichloroethane (4.76 mL) was added azetidin-3-ol hydrochloride (6.55 mg, 59.8 μmol.30). The mixture was stirred at 25° C. for 15 min, then sodium triacetoxyborohydride (14.6 mg, 69.0 μmol0) was added and stirring was continued for 18 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with dichloromethane (5×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give traces of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide and obtained mainly N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxypropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (17 mg, 28.9 μmol, 62.7%) as an off-white solid. MS (M+H)+=589; 1H NMR (CDCl3) δ: 9.21 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.06 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.37 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.4 Hz, 1H), 5.75 (s, 2H), 4.70 (t, J=6.6 Hz, 2H), 3.74 (t, J=5.7 Hz, 2H), 3.55-3.67 (m, 2H), 2.29 (quin, J=6.0 Hz, 2H), 1.64 (s, 9H), 0.91-1.05 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[O-]CC.[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[C:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1)#[N:7]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.3 g (35.3 mmol) of 1H-imidazole-4-carbonitrile [Matthews et al., J. Org. Chem. 1986, 51, 3228-3231] are initially charged in 13.2 ml (11.5 g, 35.3 mmol) of 21% strength sodium ethoxide solution in ethanol, and 4.3 ml (6.5 g, 38.9 mmol) of ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For work-up, the precipitated solid is filtered off, the filter residue is washed with ethanol and the filtrate is concentrated under reduced pressure. Diisopropyl ether is added to the residue, the mixture is filtered again, the filtrate is once more concentrated on a rotary evaporator and the residue is dried under reduced pressure. Yield: 3.8 g (60% of theory)
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][F:27])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C.O>CO.C(OCC)(=O)C>[F:27][CH2:26][CH2:25][O:24][CH2:23][C@@H:7]1[CH2:6][C@H:5]([SH:4])[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(=O)S[C@H]1C[C@@H](COCCF)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1COCCF
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.70 g) in methanol (35 ml) was dropwise added a 28% solution (1.2 ml) of sodium methoxide in methanol at -10°~-5° C. in a nitrogen stream, followed by stirring at the same temperature for 1 hour. To the mixture was added acetic acid (0.4 ml) at -10°~-5° C. The mixture was concentrated under reduced pressure to give a residue. The residue was poured into a mixture of water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with chloroform to give (2S,4S)-2-(2-fluoroethyloxymethyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.91 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C@@H:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:32]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:62][CH:63]=[O:64])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:55]([O:54][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:62][CH:63]=[O:64])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C@@H:38]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:32]=2)=[CH:22][CH:21]=1)([C:58]([CH3:61])([CH3:59])[CH3:60])([CH3:57])[CH3:56]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NC=O)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
N-{2-(benzyloxy)-5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]phenyl}formamide (Preparation 29, 400 mg, 0.45 mmol), ammonium formate (570 mg, 9.0 mmol) and 20% palladium hydroxide on carbon (60 mg) were mixed in methanol (8 ml) and stirred at 70° C. for 1 hour under nitrogen. Further ammonium formate (500 mg, 7.9 mmol) and 20% palladium hydroxide on carbon (50 mg) were then added and heating continued at 70° C. for further 1 hour. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. The residue was dissolved in methanol (8 ml) and ammonium formate (500 mg, 7.9 mmol) and 20% palladium hydroxide on carbon (50 mg) were added and stirred at 70° C. for 1 hour under nitrogen. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. The residue was dissolved in ethyl actate (25 ml) and saturated aqueous sodium hydrogen carbonate (25 ml). Organics were separated and washed with brine (15 ml), dried (magnesium sulphate) and solvent was removed in vacuo to furnish the title compound as a yellow solid, 280 mg.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](N(OC)C)=[O:13].[CH3:18][Mg]Br.CCOCC>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[CH3:18]
Reactant: CON(C)C(=O)c1ccc2ccccc2c1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-bromo-N-methoxy-N-methyl-2-naphthamide (0.708 g, 0.00241 mol) in tetrahydrofuran (10 mL) was added 3.00 M of methylmagnesium bromide in ether (8.19 mL, 0.0246 mol). The reaction was stirred at room temperature for 2 h, quenched with water at 0° C., then acidified with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was used directly in next step (488 mg, 81%). LCMS calculated for C12H10BrO(M+H)+: m/z=249.0.; found: 249.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22]OS(C)(=O)=O)=[CH:15][C:14]=1[C:31]([F:34])([F:33])[F:32])#[N:12].Cl.C>O.C(O)(C)C>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22][S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[C:31]([F:32])([F:34])[F:33])#[N:12]
Reactant: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, to a solution of 25.6 g (0.20 mol) of 4-fluorthiophenol in 500 ml of isopropanol 8.4 g (0.20 mol) of sodium hydroxide in 400 ml of water was added. The mixture was stirred at 25° C. for 2 h, then 58.6 g (16 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2-hydroxy-3-(methanesulfonyloxy)-2-methyl-propionamide in 500 ml of isopropanol was added. Then the mixture was stirred at 25° C. for 5 h, then the pH was adjusted to neutral with concentrated hydrochloric acid and treated with charcoal at reflux temperature. Most of the isopropanol was evaporated in vacuum and 250 ml of 2% aqueous sodium hydroxide solution was added to the residue under vigorous stirring, then the crystalline mixture was left for 1 h, then filtered and washed with water. The dried crystals were recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:23][OH:24].B.N1C=CC=CC=1.Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Agent: B
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the oxime from Step 3 (2.0 g, 5.9 mmol) in ethanol (35 mL) at 0° C. there was added pyridine-borane (1.1 g, 11.8 mmol) and 12N aqueous HCl (1.48 mL, 17.75 mmol). The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature. Most of the ethanol was evaporated, the residue diluted with water and ethyl acetate (the product as hydrochloride salt remains in the organic phase) and basified with 1N aqueous NaOH. The product obtained from the organic phase was triturated with hexane and filtered to afford the title compound as a yellow solid, mp: 126° C. dec.
Reaction SMILES: Cl.N#N.C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]([CH3:31])([CH3:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)(C)(C)C>C(Cl)Cl>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])([CH3:30])[CH3:31])=[CH:27][CH:26]=1)#[N:29]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)COc1ccc(C#N)cc1
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)NC(C)(C)COc1ccc(C#N)cc1
Yield: 93.6 %

Procedure:
Hydrogen chloride gas was introduced into a solution containing 3.7 g of N2 -tert-butoxycarbonyl-N1 -[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-valinamide dissolved in 50 ml of methylene chloride for 3 hours at room temperature. After the completion of the reaction, the methylene chloride was removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue. The organic layer in the residue was extracted with methylene chloride, washed with water, and then dried over anhydrous magnesium sulfate. The solvent in the organic layer was removed under reduced pressure, thus yielding 2.4 g of the desired product (yield: 87%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18](O)[CH:17]=[C:16]([CH3:21])[N:15]=2)=[N:6]1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:18]1[CH:17]=[C:16]([CH3:21])[N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Temperature: 100 °C

Procedure:
300 mg (0.90 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-methyl-4-pyrimidinol (example I, step 6) are suspended in 2 ml of phosphoryl chloride and stirred at 100° C. After the reaction is complete, a concentrated aqueous sodium carbonate solution is added, and the mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulfate and filtered, and the solvent is removed in vacuo. 256 mg (77% of theory) of the product are obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(Cn2c(CCl)nc3cnc4ccccc4c32)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc(CCl)n(CC3(O)CCCCC3)c2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloroperoxybenzoic acid (8.37 g of 70% pure material, 34 mmol) was added to a suspension of 1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (8.0 g, 24 mmol) in chloroform (100 mL), and the reaction was stirred at room temperature for four hours. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for 15 minutes. A precipitate formed and was isolated by filtration to provide 1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[S:18][CH:19]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(Br)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42, using tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 2,4-dibromothiazole (0.124 g, 39%); MS: 377.3 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.N1C=CN2C=C(C=O)C=CC=12.[F:28][C:29]1[C:38]([CH:39]=O)=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2>>[F:28][C:29]1[C:38]([CH2:39][C:2]2[N:6]3[N:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2
Reactant: O=Cc1ccc2ncccc2c1F
Reactant: Cn1cc(-c2ccc3ncc(Br)n3n2)cn1
Agent: O=Cc1ccc2nccn2c1
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)cn1

Procedure:
(rac)-(5-Fluoro-quinolin-6-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol was obtained analogously to Stage 9.1 by replacing 3-bromo-6-chloro-imidazo[1,2-b]pyridazine with 3-bromo-6-(1-methyl-1h-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Stage 8.1) and imidazo[1,2-a]pyridine-6-carbaldehyde with 5-fluoro-quinoline-6-carbaldehyde (Intermediate A) (tR 0.90 min (conditions 1), (MH+=375).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([Sn:14](Cl)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>O1CCCC1>[CH2:1]([Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzylmagnesium chloride (2.0M in tetrahydrofuran, 1.32 mmol) in 5 mL of tetrahydrofuran at -78° C. under argon was added tributyltin chloride (0.36, 1.27 mmol). After 15 min, the reaction mixture was allowed to warm to room temperature. After 3 hours, solvent was removed, and the residue was purified by flash chromatography, eluting with dichloromethane/hexanes, to give 0.45 g of a clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]>>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: Fc1cccc(Cl)c1CBr
Product: O=c1[nH]c2ncccc2c2cc(NCc3c(F)cccc3Cl)ccc12
Yield: 5.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (149 mg, 0.70 mmol) and 2-(bromo-methyl)-1-chloro-3-fluorobenzene (189 mg, 0.85 mmol) to provide 471 (14 mg, 6% yield) as a white powder. LC-MS (M+H=355, obsd.=355). 1H NMR (400 MHz, DMSO-D6) δ 11.53 (s, 1H), 8.64 (m, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.50 (s, 2H), 7.43 (s, 2H), 7.30 (s, 1H), 6.97 (s, 1H), 4.55 (s, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: COc1ccc(OC)c(NCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(NCCCCCCCCCCCCCCCCO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
[16-(t-Butyldimethylsilanyloxy)hexadecyl]-(2,5-dimethoxyphenyl)amine (144.2 mg) was dissolved in tetrahydrofuran, and then tetrabutylammonium fluoride (1 M solution in THF) (3.4 ml) was added to this solution. The reaction mixture was stirred for one day at room temperature. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with diethyl ether. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off at reduced pressure. Purification of the residue by silica gel flash chromatography (heptane:ethyl acetate=6:4) gave 16-(2,5-dimethoxyphenylamino)hexadecan-1-ol as white crystals at an 81% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8](I)[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1.[CH2:25]([Sn])[CH:26]=[CH2:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH2:27][CH:26]=[CH2:25])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Reactant: C=CC[Sn]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCc1cc(C(=O)OC)c(NC(=O)Cc2cc(C)cc(C)c2)cc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-iodo-benzoic acid methyl ester (2.39 g in 12 mL N,N-dimethylformamide) and 0.183 g bis(triphenylphosphine)palladium(II) chloride was added 2.02 mL allyltin and the mixture heated to 100° C. on an oil bath. After 2 hours, the mixture was cooled, partitioned between ethyl acetate and water and the organic layer washed further with brine. Concentration of the dried (magnesium sulfate) organics and purification by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (1.4 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[C@@H:20]([C@@H:21]([OH:35])[C@@H:22]([NH:31][C:32](=[O:34])[CH3:33])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:16]1[CH3:42])=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:40][C:38]([CH3:39])([CH3:41])[CH2:37][O:36][C@H:17]1[C@H:16]([CH3:42])[NH:15][C@@H:20]([C@@H:21]([OH:35])[C@@H:22]([NH:31][C:32](=[O:34])[CH3:33])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[CH2:19][O:18]1
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1
Reaction time: 0.67 h

Procedure:
Add trifluoroacetic acid (3 mL) to (2R,3S,5R)-5-[(1S,2S)-2-acetylamino-1-hydroxy-3-(3-hydroxy-phenyl)-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (84 mg, 0.17 mmol). Stir 40 minutes and evaporate to give N-[(1S,2S)-2-[(3R,5S,6R)-6-(2,2-dimethyl-propoxy)-5-methyl-morpholin-3-yl]-2-hydroxy-1-(3-hydroxy-benzyl)-ethyl]-acetamide trifluoroacetate (115 mg). Add diisopropylethyl-amine (0.074 mL, 0.425 mmol) dropwise to an ice cold solution of N-[(1S,2S)-2-[(3R,5S,6R)-6-(2,2-dimethyl-propoxy)-5-methyl-morpholin-3-yl]-2-hydroxy-1-(3-hydroxy-benzyl)-ethyl]-acetamide (115 mg) and benzyl chloroformate (0.029 mL, 0.20 mmol) in tetrahydrofuran (4 mL). Stir 30 minutes and add an additional portion of diisopropylethylamine (0.074 mL) and benzyl chloroformate (0.025 mL). Stir 50 minutes and warm to ambient temperature, stir 10 minutes and dilute with saturated aqueous sodium chloride followed by ethyl acetate and 1N aqueous hydrochloric acid. Separate layers and wash organic phase with saturated aqueous sodium chloride, dry with magnesium sulfate. Purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (69 mg) as a white foam. MS(ESI): m/z=529 [M+H]+.