Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[S:14][C:15]=1[C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]1([C:11]2[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=3[S:14][C:15]=2[C:16](=[O:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1sc2ccccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)c1sc2ccccc2c1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of trans-dichlorobis(triphenyl-phosphine)palladium (ii) (0.138 g, 0.196 mmol), phenylboronic acid (0.717 g, 5.88 mmol), 1-(3-bromobenzo[b]thiophen-2-yl)ethanone (0.50 g, 1.960 mmol) and 2.0 N aqueous sodium carbonate (2.94 mL, 5.88 mmol) in Toluene (10 mL) was purged with nitrogen and heated to 110° C. overnight. After 16 h, the reaction mixture was partitioned between EtOAc and water. The organic layer was stirred over MgSO4, filtered and concentrated under reduced pressure to give a red oil. The product was purified by column chromatography on a silica gel column using 20 to 40% gradient of EtOAc in hexane as eluent to give 1-(3-phenylbenzo[b]thiophen-2-yl)ethanone a colorless oil: 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H) 7.30-7.35 (m, 1H) 7.38-7.42 (m, 2H) 7.42-7.49 (m, 2H) 7.52-7.58 (m, 3H) 7.87 (d, J=8.2 Hz, 1H); LC-MS (ESI)] m/z 253.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=2)[CH:15]=[CH:14][C:13]=1[CH3:28])=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)[CH:17]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-{2-methyl-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (2.5 g, 6.0 mmol), calcium chloride (1.75 g, 15 mmol) and reduced iron (4.03 g, 72 mmol) in ethanol (300 mL)/water (30 mL) was stirred with heating at 80° C. for 2 days. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethanol. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (300 mL×2), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.31 g, 99%) as a pale-yellow amorphous substance.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cccc(C)n3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (157 mg), cesium carbonate (229 mg), and 4-(N,N-dimethylamino)-pyridine (86 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (17 mg, yield 18%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:18])[Cl:17])[CH2:12][F:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)(C)(C)C.O>[NH2:24][CH2:21][C:22]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:17])[Cl:18])[CH2:12][F:13])=[CH:6][CH:5]=2)[CH:23]=1
Reactant: C#CCN
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Solvent: CC(C)(C)O
Solvent: O
Product: NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
To the solution of ((N-[(1S,2R)-2-(4-Azido-phenyl)-1-fluoromethyl-2-hydroxy-ethyl]-2,2-dichloro-acetamide (150 mg, 0.465 mmol) in tert-butylalcohol: water (1:1, 3 mL) is added Na-ascorbate (12 mg, 0.060 mmol), CuSO4.5H2O (3 mg, 0.012 mmol), propargyl amine (26 mg, 0.472 mmol) resulting reaction mixture stirred at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 25-40% methanol in dichloromethane and washed with diethyl ether and dried under vacuum to afford the title compound (25 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 3.84 (s, 2H), 4.23-4.29 (m, 1H), 4.30-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.93 (bs, 1H), 6.07 (d, 1H, J=4.28 Hz), 6.49 (s, 1H), 7.54 (d, 2H, J=8.48 Hz), 7.81 (d, 2H, J=8.52 Hz), 8.57 (s, 1H), 8.61 (d, 1H, J=5.6 Hz). LC-MS (m/z): [M+H]=376.2.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=O)C1C=CC=CC=1.[N:29]1[C:38]2[C:33](=[N:34][C:35]([CH:39]=O)=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.N1CCCCC1>CC(O)C>[N:34]1[C:33]2[C:38](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:36][C:35]=1[CH:39]=[C:15]1[NH:11][C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[N:13][C:14]1=[O:16]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccccc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.4 mg, 0.18 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH and ether. The solid was then re-crystallized from AcOEt-MeOH to give 5-[1,5]naphthyridin-2-ylmethylene-2-(2-trifluoromethybenzylamino)-1,5-dihydro-imidazol-4-one as a light yellow crystalline material (11.6 mg, 16.2%). HR-ES (+) m/e calcd. for C20H14F3N5O: (M+H)+ 398.1223. Found: 398.1222.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH:7]=[O:8].C([O-])(=O)C.[K+]>CO.O1CCOCC1.[C].[Pd]>[Cl:22][C:11]1[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[CH:15][C:10]=1[CH2:9][N:5]1[C:6]([CH:7]=[O:8])=[CH:2][N:3]=[C:4]1[CH3:23]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Br)c2C=O)c(Cl)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCOc1ccc(Cn2c(C=O)cnc2C)c(Cl)c1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
4-Bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (4.00 g) was dissolved in a mixed solvent of methanol (20 ml) and 1,4-dioxane (20 ml), and palladium carbon (400 mg) and potassium acetate (1.08 g) were added. The reaction mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane/ethyl acetate=1/2. The objective fraction was concentrated under reduced pressure to give 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (3.10 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Agent: Br
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCN(Cc5ccccn5)CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione (30 mg, 0.066 mmol) in DMF was added 2-(bromomethyl)pyridine hydrogen bromide (26.0 mg, 0103 mmol). The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(pyridin-2-ylmethyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=544)
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:20]([O-])=O)[CH:12]=[CH:13][C:14]=3[OH:19])[C:9](=[O:23])[C:8]=2[C:7]([OH:24])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([NH2:20])[CH:12]=[CH:13][C:14]=3[OH:19])[C:9](=[O:23])[C:8]=2[C:7]([OH:24])=[CH:6][CH:5]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(O)c2c1C(=O)c1c(O)ccc(N)c1C2=O
Reaction time: 5 h
Yield: 98 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g (0.0151 mole) of 1,5-dinitro-4,8-dihydroxyanthraquinone, 100 g of a 4% aqueous solution of sodium hydroxide and 0.25 g of 5% palladium-carbon. The inside of the reactor was purged with hydrogen, and the 1,5-dinitro-4,8-dihydroxyanthraquinone was hydrogenated at 50° C. with stirring. In 5 hours, 0.0906 mole of hydrogen was absorbed, whereupon the reaction was stopped. The reaction mixture was filtered to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours, and then neutralized with 20% sulfuric acid to a pH of 2-3. The crystals precipitated were filtered, washed with water, and dried to afford 4.0 g of 1,5-diamino-4,8-dihydroxyanthraquinone in a yield of 97.8%.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Br[C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To a solution of 4-(adamantan-1-yl)phenol (0.8 g, 3.50 mmol) in N,N-dimethylformamide (8 mL) was added anhydrous potassium carbonate (1.45 g, 10.51 mmol) and methyl 2-bromo-2-methylpropanoate (1.15 g, 7.0 mmol), and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate as colorless oil (1.1 g, 94.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)C>[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:23][CH2:22]1
Reactant: c1ccc2c(c1)NCCS2
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCSc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (118 mg) and 3,4-dihydro-2H-1,4-benzothiazine (H. I. El-Subbagh et al., Arch. Pharm. Med. Chem., 1999, 332, pp. 19-24) (122 mg) in dimethylformamide (1 mL) was heated at 140° C. for 73 hours. The resulting mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by radial chromatography with a chromatotron (eluted with 0% to 1% ethyl acetate-hexanes) to give the title compound as a white solid (53.5 mg), m.p. 103° C.-104° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: c1ccc2cc(Nc3ccnc4[nH]c5c(c34)CNCC5)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5ccccc5c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
Naphthalen-2-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (79 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (104 μL, 0.75 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 60 (24 mg, 26% yield) as a tan powder. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: C1(CCC(O)CCC2C=CC=CC=2)C=CC=CC=1.[O:19]([CH2:26][CH:27]([OH:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:37]([O:40][CH2:41]C)(=O)C>CCCCCC>[O:19]([CH2:26][CH:27]([O:36][CH2:37][O:40][CH3:41])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: OC(COc1ccccc1)COc1ccccc1
Agent: OC(CCc1ccccc1)CCc1ccccc1
Solvent: CCCCCC
Product: COCOC(COc1ccccc1)COc1ccccc1

Procedure:
Using the procedure of Example 51 but replacing 1,5-diphenyl-3-pentanol with the resultant compound of Example 4 gave, after silica gel chromatography using 10% ethyl acetate in hexane, 80 mg (49%) of the desired compound (Rf 0.42, 20% ethyl acetate in hexane). 1H NMR (CDCl3) δ 3.44 (s, 3H), 4.18 (dd, J=10, 6 Hz, 2H), 4.22 (dd, J=15, 6 Hz, 2H), 4.33 (pentet, J=6 Hz, 1H), 4.85 (s, 2H), 6.9-7.0 (m, 6H), 7.25-7.35 (m, 4H). Mass spectrum (M+NH4)+ =306.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26](F)[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:49]1COCC1.O[Li].O>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:49])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Agent: [Pd]
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 60 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (20 mg, 0.030 mmol, 1 equiv) in MeOH (2 mL) was added 10% Pd/C (6 mg, 0.006 mmol, 0.2 equiv). The reaction was then stirred under a balloon of H2 for 2 h. The reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The crude hydrogenation product was taken upon in MeOH (1.5 mL), water (1 mL0, and THF (0.5 mL) and LiOH.H2O (37 mg, 0.913 mmol, 30 equiv) was added. The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (5.2 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 8.07 (br. s., 2H), 7.97 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.08 (d, J=11.0 Hz, 1H), 6.83 (t, J=8.1 Hz, 1H), 5.79 (br. s., 1H), 4.70 (br. s., 1H), 3.82 (t, J=11.3 Hz, 1H), 2.63 (d, J=8.2 Hz, 1H), 2.39 (s, 3H), 1.94-1.57 (m, 12H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.12 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 644.35.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[OH:36][C:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1>>[OH:36][C:37]1([C:40]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(O)C1(O)CC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C6(O)CC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-hydroxycyclopropanecarboxylic acid (Aldrich, Cat. No. 293881). LCMS (M+H)+: m/z=569.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[N:7]=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O1CCCC1>[C:20]1([O:26][C:27](=[O:28])[NH:2][C:3]2[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[O:11])[N:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1noc(C)c1C(=O)N(C)Cc1csc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
N-((2-aminothiazol-4-yl)methyl)-N,3,5-trimethylisoxazole-4-carboxamide hydrochloride (6.16 g, 20.34 mmol) was dissolved in pyridine (35 mL) and DMAP (150 mg, 5 mol %) was added. The solution was cooled to 0° C. and a solution of phenylchloroformate (2.55 mL, 3.18 g, 20.34 mmol) in tetrahydrofuran (35 mL) was added dropwise. The mixture was stirred overnight at room temperature and the volatiles were evaporated in vacuo. The residue was taken up in water/EtOAc. The organic phase was dried over MgSO4 and the volatiles were evaporated under reduced pressure. The material was crystallized from EtOAc/i-Pr2O to afford (4-{[methyl(3,5-dimethylisoxazole-4-carbonyl)-amino]-methyl}-thiazol-2-yl) carbamic acid phenyl ester (1.80 g) as a tan-colored solid (purity ˜85%). 1H NMR (CDCl3): δ 9.85 (bs, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.20 (m, 2H), 6.80 (b, 1H), 4.75 (bs, 1H), 4.45 (bs, 1H), 3.00 (bs, 3H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][NH2:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].[OH-].[Na+].[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[C:22]([O:21][C:19]([NH:15][CH2:14][C:6]1[CH:7]=[C:8]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
A solution of methyl 5-nitro-3-aminomethybenzoate (1980 mg, 9.4 mmol) in 1N NaOH (28 mL, 28 mmol) and tert-BuOH (20 mL) was stirred at r.t. for 10 hours and then added BOC2O (4100 mg, 18.8 mmol) and stirred for 17 hours. The reaction mixture was added hexanes (50 mL) and water (50 mL). The aqueous layer was acidified with 5% citric acid aq. and extracted with CH2 Cl2 (2×70 mL). The CH2Cl2 layers were combined and washed with water (50 mL). The organic layer was evaporated to give the desired compound (2450 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 13.725 (s, 1H), 8.476 (s, 1H), 8.307 (s, 1H), 8.216 (s, 1H), 7.639 (t, J=5.7 Hz, 1H), 4.398 (d, J=5.7 Hz, 2H), 1.385 (s, 9H); 13C NMR (300 MHz, DMSO-d6) δ 165.5, 155.9, 147.9, 143.5, 133.6, 132.5, 125.4, 122.2, 78.3, 42.6, 28.2.