Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Product: COc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-methoxyaniline (Aldrich) according to the method described in Example 1c. Melting Point: 144-146° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromophenyl acetic acid (7.5 g, 35.0 mmol) in DMF (60 mL) at rt were added Cs2CO3 (12.41 g, 38.15 mmol) and benzyl bromide (6.77 g, 39.6 mmol). The reaction mixture was stirred overnight at room temperature, and then at 100° C. for 1 h and cooled to rt. The solvent was removed under reduced pressure and poured into cold 1 N HCl (50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from hexanes to afford (4-bromo-phenyl)acetic acid benzyl ester as a white solid. (10.65 g, 100%): 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=8.4 Hz, 2H), 7.25-7.34 m, 5H), 7.14 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 3.61 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20]
Reactant: COC(=O)c1cc(F)ccc1N=Cc1cccc(Br)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-fluoro-benzoic acid methyl ester (50 g, 59.8 mmol) and ytterbium(III) triflate hydrate (3.7 g, 5.95 mmol) in dry tetrahydrofuran (30 mL) at 25° C. was added isobutyraldehyde (4.3 g, 59.5 mmol) and water (1.1 mL, 59.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (24.3 g, 100%) as a light yellow oil: LC/MS m/e calcd for C19H19BrFNO3 M+: 408.3, observed: 408.1.
Reaction SMILES: [CH3:1]N1CCCC1=O.[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][C:13]=1[NH2:19])[CH3:9].C[Sn](C)(C)C>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.O>[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:1])=[N:14][C:13]=1[NH2:19])[CH3:9]
Reactant: CCOC(=O)c1ccc(Cl)nc1N
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)C
Solvent: O
Product: CCOC(=O)c1ccc(C)nc1N
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a N-methylpyrrolidinone (20 mL) solution of 2-amino-6-chloro-nicotinic acid ethyl ester (2.00 g, 7.78 mmol) described in Manufacturing Example 170-1-1 were added tetramethyltin (1.62 mL, 11.7 mmol) and tetrakis(triphenylphosphine)palladium (0) (899 mg, 0.778 mmol), which was stirred under nitrogen atmosphere for 5 hours and 40 minutes at 130° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1), and then further purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (670 mg, 48%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH:15]=O)=[C:9]1[C:17](Cl)=[CH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:5]=[CH:6][CH3:7]>C(O)C>[CH2:4]([N:8]1[C:9]2=[C:17]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:2]=[N:3][CH:15]=[C:10]2[C:11]([CH3:14])=[C:12]1[CH3:13])[CH:5]=[CH:6][CH3:7]
Reactant: NN
Reactant: CC=CCn1c(C)c(C)c(C=O)c1C(Cl)=CCc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: CC=CCn1c(C)c(C)c2cnnc(CCc3ccc(F)cc3)c21
Temperature: 75 °C
Yield: 62.9 %

Procedure:
0.10 g (0.0020 mole) of hydrazine hydrate was added to a solution of 0.39 g (0.00113 mole) of 1-(2-butenyl)-2-[1-chloro-3-(4-fluorophenyl)-1-propenyl]-3-formyl-4,5-dimethylpyrrole in 7 ml of ethanol and the resulting mixture was stirred at 75° C. for an hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the concentrate was diluted with ice-water. The aqueous mixture was extracted twice with 30 ml of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography through silica gel using a 50:1 mixture of chloroform and methanol as an eluent to give 0.23 g of the title compound (cis/trans=22/78) as white powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
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: O
Solvent: C1COCCO1
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of 4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (206 mg, 0.45 mmol), 2-bromo-5-(trifluoromethyl)-benzonitrile (75 mg, 0.3 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), Na2CO3 (190.8 mg, 1.8 mmol) in dioxane/water (9/1, 1.5 mL), was heated at 95° C. for approximately 16 hrs after degassing of the solvent with a stream of nitrogen. The reaction was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried with MgSO4. The filtrate was evaporated and the residue purified by preparative TLC [eluent: 40% acetone in hexane] to afford 4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide 10-1 (120 mg). MS [M+H]+: 502.9; tR=8.15 min. (method 2)
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[CH:17]1([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:10]=[C:5]([NH:2][NH2:3])[N:6]=[CH:7][N:8]=3)[CH2:12][CH2:13]2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 4.4 ml (4.5 g, 89.7 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 1.9 g (7.5 mmol) of 4-chloro-6-(4-cyclobutylpiperazin-1-yl)pyrimidine in 28 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, the residue is triturated repeatedly with diethyl ether, and the precipitated solid is filtered off and dried under reduced pressure. The residue is then purified by column chromatography on silica gel (mobile phase dichloromethane/methanol 10/2). Yield: 1.5 g (80% of theory)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Yield: 94 %

Procedure:
2-Fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) and N-methylpiperazine (1.29 mL, 2 eq) were heated at 130° C. for 1 h. The reaction mixture was then diluted with 25 mL of THF and washed with a saturated aqueous solution of Na2CO3 and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (1.38 g, 94% yield). m/z (ESI) 252.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[CH:32]1([NH:37][C:38]([NH:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:28]([F:31])([F:29])[F:30])[CH:4]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C=NC1CCCC1
Solvent: C1COCCO1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Yield: 67 %

Procedure:
1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (300 mg, 0.67 mmol) and cyclopentyl isocyanate (0.4 mL, 5.3 eq) were stirred in 1,4-dioxane (2 mL) at room temperature overnight. The reaction mixture was concentrated, and purified by flash chromatography (silica gel, hexanes/EtOAc) to give the racemic mixture of 1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (250 mg, yield: 67%). The racemate (250 mg) was dissolved in 10% isopropanol in heptane, and was resolved by chiral prep HPLC using an AD column (10% isopropanol/heptane/0.1% DEA, isocratic) to give the fast eluting enantiomer 1 (110 mg) corresponding to (S)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=4.85 min) and the slow eluting enantiomer 2 (105 mg) corresponding to (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=14.11 min) LCMS (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=4.33 min, 557.32 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.44 (m, 2H), 7.23-7.29 (m, 3H), 7.13-7.21 (m, 4H), 6.68-6.74 (m, 2H), 4.84 (s, 1H), 4.40 (s, br, 1H), 3.84-3.95 (m, 3H), 1.88-1.98 (m, 2H), 1.56-1.68 (m, 4H), 1.34 (d, J=6.36 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:28])([F:27])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].[C:29](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:29][N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([O:24][C:25]([F:27])([F:28])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.30 g), potassium carbonate (1.05 g) and N,N-dimethylformamide (50 mL) was stirred at 0° C. for 30 min. Methyl iodide (1.08 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (9:1-3:1, volume ratio) to give the title compound (2.26 g, yield 66%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 149-150° C.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+]>CS(C)=O.C(OCC)C>[N:9]([CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: ICC1CCOCC1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Iodomethyl)tetrahydro-2H-pyran (4.76 g, 21.1 mmol) was dissolved in dimethyl sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was added and the mixture was stirred at ambient temperature overnight. The resulting slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound. The product was used directly in subsequent reactions without characterization.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([N:16]2[C:17](=[O:18])[C:19]3[C@@H:20]4[C:26]([CH3:28])([CH3:27])[C@@:23]([CH3:29])([CH2:22][CH2:21]4)[C:24]=3[NH:15]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(N(NC(=O)OC(C)(C)C)C(=O)C2C(=O)[C@]3(C)CC[C@H]2C3(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Trifluoroacetic acid (15 mL) was added to a cooled (0° C.) solution of crude N′-(4-methoxy-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜18.5 mmol) in dichloromethane (15 mL), and the solution was stirred at ˜0° C. for 15 min and then at room temperature for 2.5 h. The solvent was evaporated and the residue was dissolved in dichloromethane (150 mL) and washed with water (4×250 mL) until the pH of the aqueous washing was ˜5. The organic layer was washed with brine (150 mL), dried (magnesium sulfate), and then the flask was wrapped in aluminum and stored in a freezer overnight. The magnesium sulfate was filtered off, and the solvent was evaporated to give an orange/red semi-solid which was triturated with 10% dichloromethane/hexanes, filtered, and washed with hexanes. The solid was crushed, washed again with hexanes, and then dried under vacuum to give (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (3.95 g, 72%) as a tan solid.
Reaction SMILES: C([O-])(=O)C.[NH4+].C[O:7][C:8](=O)[C:9]([CH3:23])([CH3:22])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=O.C([BH3-])#[N:26].[Na+]>CO>[F:21][C:16]1[CH:15]=[C:14]([CH:12]2[NH:26][C:8](=[O:7])[C:9]([CH3:23])([CH3:22])[CH2:10][CH2:11]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COC(=O)C(C)(C)CCC(=O)c1ccc(F)c(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(c2ccc(F)c(F)c2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonium acetate (36.62 g, 475.1 mmol) was dissolved in 200 mL of methanol. To this solution was added methyl-5-(3,4-difluorophenyl)-2,2-dimethyl-5-oxopentanoate (12.76 g, 47.2 mmol) and sodium cyanoborohydride (2.96 g, 47.1 mmol). This reaction mixture was stirred at ambient temperature for 24 hours. Another portion of sodium cyanoborohydride (1.50 g, 23.9 mmol) was added, and the mixture was stirred at ambient temperature for another 66 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated sodium carbonate. A 1.0M solution of aqueous sodium hydroxide was added to the aqueous phase to achieve a pH of 10. The phases were then separated, and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were then washed once with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. This residue was purified by “flash” chromatography (98:2 dichloromethane:methanol). The product fractions were evaporated to dryness to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].[H][H]>C(OCC)(=O)C.O.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[CH:2][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1O
Yield: 58.4 %

Procedure:
A suspension of methyl 5-bromo-2-hydroxy-3-nitrobenzoate (38.4 g, 0.14 mol), sodium acetate (19.63 g, 0.24 mol) and 10% Pd/C (3.84 g) in ethyl acetate (500 mL) and water (30 mL) was stirred at 25° C. under 1 atm of hydrogen for 16 hr. The mixture was filtered and the filtrate was washed with water (500 mL×2), brine (300 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was washed with methanol at 0° C. to give methyl 3-amino-2-hydroxybenzoate (13.67 g, yield 59%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.88-3.94 (s, br, 2H), 3.91 (s, 3H), 6.70-6.74 (t, J=7.8 Hz, 1H), 6.88-6.90 (m, 1H), 7.24-7.26 (m, 1H), 10.91 (s, 1H); LC-MS (ESI) m/z 168 [M+1]−.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.[H-].[Na+].[CH3:19]I.[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[CH3:19][O:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1CN[C@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (25.6 g, 111 mmol), is treated under nitrogen with sodium hydride (9.3 g, 388 mmol) and methyl iodide (31.5 g, 222 mmol), using a procedure similar to that published for the CBZ analog in J. Med. Chem. 1988, 31, 875, except that reflux is carried out for 16 h. The crude extracted product of this alkylation reaction, (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid, is then dissolved in dichloromethane (200 mL), cooled to 0° C., treated with 4 N HCl in dioxane (100 mL), and then stirred at room temperature overnight. After further cooling at −20° C. for 3 h, the precipitate is collected by filtration, washed with ethyl ether, and dried in vacuo to give 18.5 g (92%) of the pure mono HCl salt of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid: MS: 146 (M+H)+; 1H NMR (d6-DMSO) δ 14.02 (brs, 1H), 10.30 (brs, 1H), 8.98 (brs, 1H), 4.33-4.22 (m, 1H), 4.10 (brs, 1H), 3.43-3.34 (m, 1H), 3.24 (s, 3H), 3.26-3.19 (m, 1H), 2.45-2.36 (m, 1H), 2.10-2.00 (m, 1H); [α]22D-29.7 (CH3OH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12].C[O-].[Na+].O>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
In an argon atmosphere at room temperature, 2-acetylpyridine (2.56 g) in methanol (26 mL) was added to dimethyl oxalate (5.00 g) and sodium methoxide (2.29 g) in methanol (26 mL), followed by stirring for 15 minutes. The mixture was stirred at 60° C. for 45 minutes, and then cooled in air. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether. The aqueous layer was partitioned by use of saturated aqueous ammonium chloride and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(2-pyridyl)-2,4-dioxobutanoic acid methyl ester as a solid (3.44 g, 79%).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[O:10][C:11]([C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.O>CCO>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:20][C:18]2[N:19]=[C:14]([C:11]3[O:10][C:9]([C:8]4[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=4)=[N:13][CH:12]=3)[CH:15]=[CH:16][CH:17]=2)[CH:26]=1
Reactant: COc1ncccc1-c1ncc(-c2cccc(Nc3cc(C)ccn3)n2)o1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc[nH]c4=O)o3)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of {6-[2-(2-methoxy-pyridin-3-yl)-oxazol-5-yl]-pyridin-2-yl}-(4-methyl-pyridin-2-yl)-amine above (236 mg, 0.655 mmol) in EtOH (10 ml) was treated with conc. HCl (1 ml) and heated to 80° C. for 3 h and then 60° C. for 18 h. The cooled mixture was treated with water and the product precipitated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.78 (s, 1H), 8.29-8.22 (m, 1H), 8.11 (d, J=5.0 Hz, 1H), 7.86 (s, 1H), 7.82-7.73 (m, 2H), 7.69-7.63 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 6.77 (d, J=5.0 Hz, 1H), 6.40 (t, J=6.7 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z 346 (M+H)+. Retention time=2.02 mins (method 1).