Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:9][C:10](=[O:28])[CH:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:12][N:13]([CH:22]=[O:23])[O:14]CC1C=CC=CC=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:9][C:10](=[O:28])[CH:11]([CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:12][N:13]([CH:22]=[O:23])[OH:14])[CH3:2]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CN(C=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CN(O)C=O
Yield: 98.6 %

Procedure:
0.4 g of [N-formyl-N-benzyloxy 2(RS)-isobutyl-3-aminopropionyl]-L-leucylglycine ethyl ester in 20 ml of ethanol was hydrogenated for 0.75 hour in the presence of 5% palladium/carbon. The mixture was filtered, the filtrate was evaporated and the residue was dried in vacuo to yield 0.32 g (98%) of [N-formyl-N-hydroxy 2(RS)-isobutyl-3-aminopropionyl]-L-leucylglycine ethyl ester as a foam.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][OH:13])=[CH:4][CH:3]=[N:2]1>C1COCC1.[O-2].[O-2].[Mn+4]>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]=[O:13])=[CH:4][CH:3]=[N:2]1
Reactant: OCc1ccccc1-c1ccno1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1ccno1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.8 %

Procedure:
To a solution of (2-isoxazol-5-yl-phenyl)-methanol (170 mg, 0.97 mmol) in THF (9 mL) is added manganese dioxide (1.29 g, 14.55 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is filtered through celite and the filtrate is concentrated in vacuo and is redissolved in THF (11 mL) and more manganese dioxide (1.07 g, 10.46 mmol) is added. The reaction mixture is stirred at room temperature for 65 hours. After this time, the reaction mixture is filtered through celite and the celite is washed with EtOAc (20 mL). The filtrate is concentrated in vacuo and the residue is purified using silica gel flash column chromatography with 20-100% EtOAc in heptane as the eluent to give 2-isoxazol-5-yl-benzaldehyde (50 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:13][NH2:14])=[O:8]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cncc(Br)c1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a solution methyl 5-bromonicotinate (5 g, 23 mmol) in ethanol (40 mL) was added hydrazine hydrate (6 mL, 115 mmol). The reaction mixture was refluxed at 90° C. for 4 h. After this time, the reaction mixture was evaporated to dryness and then redissolved in ethyl acetate. The organic layer was washed with water, dried and evaporated to yield 5-bromonicotinohydrazide (3.4 g, 72%). LCMS Method T: retention time 0.573 min; [M+1]=216.0, 218.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17]C(OC(C)(C)C)=O)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:25][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:25][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1nc2cc(N)ccc2n1CC(=O)OC(C)(C)C

Procedure:
The product of example 25, step d.) (140 mg, 0.359 mmol) was stirred in 4 M HCl in dioxane (1 mL) at ambient temperature for an hour. The reaction was concentrated to give the sub-title compound that was used in crude form without purification. MS: ESI (positive): 290 (M+H).
Reaction SMILES: [OH:1][C@@:2]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:3](O)=[O:4].[Cl:11][C:12]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C1(C2C=CC=C(C3C=CC=CC=3)N=2)C=CC=CC=1>>[N+:19]([C:18]1[C:12]([Cl:11])=[C:13]([NH:14][C:3](=[O:4])[C@:2]([OH:1])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: Nc1cccc([N+](=O)[O-])c1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: c1ccc(-c2cccc(-c3ccccc3)n2)cc1
Product: C[C@@](O)(C(=O)Nc1cccc([N+](=O)[O-])c1Cl)C(F)(F)F

Procedure:
The title compound was prepared by the method of Example 6 using (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 3) and 2-chloro-3-nitroaniline (Tetrahedron, 1999, 56 (2), 165-173) except that 2,6-diphenylpyridine was used instead of 2,6-di-t-butylpyridine. NMR (CDCl3) 1.77 (s, 3H), 3.58 (s, 1H), 7.44 (t, 1H), 7.63 (d, 1H), 8.66 (d, 1H), 9.27 (s, 1H); m/z 311.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:12]1[CH:10]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[OH:11])[N:14]=[N:13]1)[CH3:20]
Reactant: C#CC(O)c1cccc(Br)n1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(C(O)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-ol (Example 512, Step 1) (500 mg, 2.36 mmol) and ethyl azidoacetate (1.46 mL, 2.59 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL). CuSO4.5H2O (29 mg, 0.12 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (93 mg, 0.47 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](F)=[C:5]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]>C1COCC1.C(O[K])(C)(C)C>[CH:16]1([N:15]2[C:4]3[C:5](=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:3]=3[O:2][CH3:1])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CCCC1)C(=O)c1cc(F)c(F)c(OC)c1F
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
To a solution of 14 (9.5 g, 25 mmol) in THF (100 mL), 1M tBuOK in THF (25 mL, 25 mmol) was added dropwise under ice-cooling. After 1.5 h, the reaction mixture was poured into ice-water (20 mL) and the product extracted with CH2Cl2 (3×20 mL). After evaporation of the solvent, 15 was obtained as an orange solid (6.1 g, 69%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.12 g, 0.2 mmol) prepared in Example 88 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.36 g, 3.2 mmol), then aqueous solution (1N) of NaOH (1.1 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 66 mg, 53%)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:18]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][NH:19]1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)C.CCOC(C)=O>[CH2:18]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][N:19]1[C:5](=[O:7])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:2][Br:1]
Reactant: C1CCC2CNCC2C1
Reactant: O=C(O)C(CCBr)c1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(C(CCBr)c1ccccc1)N1CC2CCCCC2C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
4-Bromo-2-phenylbutanoic acid (4.86 g, 0.02 mol) and thionyl chloride (2.2 mL, 0.03 mol) were refluxed in dichloromethane (100 mL) under nitrogen for 3 hours. The solution was evaporated and flushed with benzene three times. The residue was dissolved in diethyl ether (50 mL) and cooled in an ice bath. Octahydroisoindole (2.5 g, 0.02 mol) and diisopropylethylamine (3.5 mL, 0.02 mol) dissolved in diethyl ether (50 mL) were added and the reaction was stirred for 60 hours at room temperature. TLC (Uniplate/EtOAc) showed essentially complete reaction. The solution was washed with water, sat. NaHCO3, and dried (Na2SO4). Evaporation of solvent left crude product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[N:20]([CH2:12][C@@H:13]1[O:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH2:17]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(C)(C)O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC[C@H](CN=[N+]=[N-])O1
Temperature: 70 °C

Procedure:
(R)-(5,5-Dimethyltetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (step 1) (12.8 g, 45.0 mmol) in DMF (50 ml) was treated with sodium azide (3.80 g, 58.5 mmol) at RT overnight then warmed to 70° C. for 3 hrs. Sodium azide (3.80 g, 58.5 mmol) was added and the mixture was warmed to 100° C. for 3 hrs, allowed to cool to RT. The mixture was diluted with water and ethyl acetate. The ethyl acetate layer was washed with 0.5 M lithium chloride in water and the organic layers were dried MgSO4, filtered and evaporated to dryness to afford the title compound;
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[OH:20])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:29][S:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[CH:7]([C:5]2[S:6][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:30][CH3:29])[CH:36]=3)=[CH:3][CH:4]=2)[CH2:8][C:9]([C:19]([C:21]([F:22])([F:24])[F:23])([C:25]([F:27])([F:26])[F:28])[OH:20])=[N:10]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1)(C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)s2)c1
Temperature: 88 °C
Reaction time: 4 h
Yield: 8.3 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (100.0 mg, 0.20 mmol) prepared in Step 5 of Preparation 23, 3-methylthiophenylboronic acid (50.4 mg, 0.30 mmol), Pd(PPh3)4 (23.0 mg, 0.02 mmol), and a 2N sodium carbonate solution (1.0 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (1.0 mL). The reaction mixture was stirred at 88° C. for 4 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 9.2 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[CH2:6]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:6]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:4][C@H:2]3[O:3][CH2:1]3)=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: ClC[C@H]1CO1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC[C@H]1CC[C@H](c2ccc(OC[C@@H]3CO3)cc2)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a mixture of the above R-(-)-epichlorohydrin (5.55 g), 4-(trans-4-n-pentylcyclohexyl)phenol (2.46 g) of the following formula: ##STR15## and benzyltriethylammonium chloride (0.04 g) is added dropwise aqueous sodium hydroxide (NaOH 0.45 g, water 15 ml) with stirring at 60° C. over a period of 20 minutes, and the mixture is further refluxed for one hour. The reaction mixture is cooled to room temperature and extracted twice with ether. The extract is washed once with a saturated saline solution and distilled under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography to give (S)-2,3-epoxypropyl 4-(trans-4-n-pentylcyclohexyl)phenyl ether (1.8 g) of the following formula: ##STR16##
Reaction SMILES: [CH3:1][C:2]([N:13]=[C:14]=[O:15])([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>CC(C)([O-])C.[K+].CCCCCC>[C:16]([O:20][C:14](=[O:15])[NH:13][C:2]([CH3:1])([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:11])=[CH2:10])[CH:4]=1)[CH3:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Product: C=C(C)c1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Into a 3-neck, 10 L round bottom flask equipped with a mechanical stirrer, condenser, and a nitrogen inlet was placed α,α-dimethyl-m-isopropenylbenzyl isocyanate (1083 g, 5.38 mol), hexane (6 L), and t-butyl alcohol (398.8 g, 5.38 mol). While the mixture was stirred at room temperature, potassium t-butoxide (18.0 g, 160 mmol) was added in portions. Throughout the addition the reaction temperature increased to 50° C. The reaction was complete within an hour. The reaction mixture was washed with water (5 L), and thereafter, the organics were separated from the aqueous layer. The organics were dried over magnesium sulfate, filtered, and evaporated to yield a yellow-brown semi-solid. Recrystallization from hexane afforded essentially pure {1-methyl-1-[3-(1-methylethenyl)phenyl]ethyl}carbamic acid t-butyl ester (1193 g, 81% isolated yield), as shown by proton and carbon-13 NMR spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-:3])=[O:2].P([O-])(O)(O)=[O:24].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O.O1CCCC1.C(O)(C)(C)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:24])=[O:20])=[CH:21][CH:22]=2)=[N:12][N:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Reaction time: 3 h
Yield: 102 %

Procedure:
To a mixture of 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (0.930 g), sodium dihydrogen phosphate (0.490 g), 2-methyl-2-butene (1.95 ml), t-butanol (20 ml), tetrahydrofuran (20 ml) and water (20 ml) was added sodium chlorite (0.570 g) at 0° C., and the mixture was stirred for 3 hrs. To the mixture was added an aqueous sodium sulfite solution, and the mixture was stirred at room temperature for 15 min., and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (1.00 g, yield 78%). Recrystallization from hexane-tetrahydrofuran gave pale-yellow prism crystals. melting point: 239–240° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:35]=[CH:36][CH:37]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:47][O:48][CH:49]([O:56][CH3:57])[CH2:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[CH2:52]([N:51]([CH2:50][CH:49]([O:48][CH3:47])[O:56][CH3:57])[C:32](=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27][C:26]1[CH:35]=[CH:36][CH:37]=[C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][C:15]3([O:14][CH2:13][CH2:12][N:11]([C:9]([C:7]4[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=4)=[O:10])[CH2:16]3)[CH2:17][CH2:18]2)[CH:25]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reactant: CCCCNCC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(3-(2-(4-(2-Isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 34, step c] (0.50 g), Hunig's base (0.58 mL), and N-(2,2-dimethoxyethyl)butan-1-amine [J. Am. Chem. Soc. 1949, 71(6), 2272] (0.12 g) were dissolved in dichloromethane (10 mL). HATU (0.33 g) was then added and the mixture was stirred at room temperature for 24 hours. The mixture was poured into water and extracted with dichloromethane. The organic extracts were combined and evaporated under reduced pressure to give the subtitled compound. Yield 0.45 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:41]
Reactant: CCN(CC)CCOS(C)(=O)=O
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by chromatography (silica, EtOAc) to give 6-(3-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (18 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.59-7.53 (m, 3H), 7.45-7.36 (m, 2H), 7.28 (s, 1H), 7.04 (d, 1H, J=8.4 Hz), 6.23 (d, 1H, J=8.1 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.29-4.15 (m, 3H), 3.68 (brs, 1H), 3.52-3.49 (m, 1H), 2.97-2.93 (m, 2H), 2.72-2.65 (m, 4 h), 2.15-2.04 (m, 3H), 1.77 (brs, 3H), 1.26 (d, 3H, J=6.3 Hz), 1.11 (t, 6H, J=7.1 Hz). LC/MS: 486 [M+H]+, tR=1.48 min. HPLC: 95.50% at 214 nm, 96.62% at 254 nm, tR=5.45 min.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][CH:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH2:25][OH:26].O>ClCCl.C(OCC)C>[CH3:23][CH:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH:25]=[O:26]
Reactant: CC(CO)CC1CCCC(C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)CC1CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of Dess Martin periodinane (4.1 g, 9.7 mmol, 1.1 eq) in dichloromethane (43 mL) was charged into a 250 mL three-necked round-bottom flask, equipped with a mechanical stirrer and a reflux condenser. 2-methyl-3-(3-methylcyclohexyl)propan-1-ol (1.5 g, 8.8 mmol) was added dropwise, followed by a mixture of water (127 L) in dichloromethane (127 mL) at ambient temperature, over 1 h. After stirring for 1 h at ambient temperature, the mixture was diluted with diethyl ether (100 mL) and washed with a 1:1 mixture of saturated aqueous NaHCO3 and 10% aqueous Na2S2O3 (50 mL) and brine (50 mL), dried over magnesium sulphate and concentrated. The crude product was chromatographed on a silica gel column with 5% EtOAc in hexane as elution agent giving 2-methyl-3-(3-methylcyclohexyl)propanal (800 mg, gc purity>90%; yield 54%).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.50 mg, 22.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30–7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.81 (M+) 499.6 (M+H)+.