Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][C:10]=1[C:22]#[N:23].C(Br)(Br)[Br:25]>>[Br:25][C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][C:10]=1[C:22]#[N:23]
Reactant: BrC(Br)Br
Reactant: CCCCc1nc(C#N)c(N)n1CC(C)C
Agent: CC(C)(C)ON=O
Product: CCCCc1nc(C#N)c(Br)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
tert-Butyl nitrite (6.2 g, 0.060 mol) was added over a period of five minutes to solution of 5-amino-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (6.60 g, 30.0 mmol) in bromoform (50 mL). After about ten minutes, an exotherm occurred, and the reaction was poured into ice water. The reaction temperature peaked at 55° C. The reaction was stirred at room temperature for 45 minutes and then concentrated under reduced pressure while heating at about 55° C. The crude product (20 g) was purified by column chromatography on silica gel (eluting sequentially with dichloromethane and 5% ethyl acetate in dichloromethane) to provide 3.37 g (39%) of 5-bromo-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:7]2=[O:23].[CH3:24][C@@H:25]1[C:29]2[NH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:28]=2[C:27](=[O:42])[NH:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[C:13]([NH:12][C:9]1[N:8]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:7](=[O:23])[C:6]2[C:11](=[C:2]([C:31]3[NH:30][C:29]4[C@@H:25]([CH3:24])[NH:26][C:27](=[O:42])[C:28]=4[CH:32]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCS(C)(=O)=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCS(C)(=O)=O)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 45 °C
Yield: 71.7 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-2-(tert-butylamino)-3-(2-(methylsulfonyl)ethyl)quinazolin-4(3H)-one (516c; 88 mg, 0.219 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (86 mg, 0.262 mmol) in 1,4-dioxane (1.0 mL)/water (0.2 mL) followed by potassium phosphate (0.054 mL, 0.656 mmol) and XPhos precatalyst II (8.6 mg, 10.94 μmol, Sigma Aldrich). The reaction mixture was stirred and heated in an oil bath at 45° C. for 6 h, then cooled to RT. The mixture was diluted with water (25 mL) and the suspension was filtered and the solid was further purified with silica gel chromatography (eluted with 0-4% MeOH in DCM) to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2-(methylsulfonyl)ethyl)quinazolin-4(3H)-one (72 mg, 0.157 mmol, 72% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 458 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (1H, s), 7.89 (2H, d, J=7.8 Hz), 7.61 (1H, s), 7.20 (1H, t, J=7.7 Hz), 6.71 (1H, d, J=1.4 Hz), 6.09 (1H, s), 4.47-4.62 (3H, m), 3.56 (2H, t, J=6.7 Hz), 3.12 (3H, s), 1.49 (9H, s), 1.37 (3H, d, J=6.7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]=4[OH:19])[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]=4[OH:19])[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cccc(O)c24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3cccc(O)c23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(4-hydroxy-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.031 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(4-hydroxy-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.010 g, 75%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH:7]([NH:15]C=O)[CH2:6][CH:5]1[CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCCC1CC(NC=O)c2cc(Br)ccc2N1C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC[C@H]1C[C@@H](N)c2cc(Br)ccc2N1C(C)=O
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
(1-acetyl-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see intermediate 88) (0.5 g, 1.474 mmol) was suspended in ethanol (4 mL) and treated with HCl (5N in water, 1 ml, 5.00 mmol). The resulting mixture was stirred at 75° C. for 40 min under microwave irradiation then cooled to room temperature. The reaction mixture was basified with a saturated NaHCO3 aqueous solution (50 mL), and the aqueous phase was extracted with AcOEt (3×50 mL). The combined organic phases were dried over MgSO4 then concentrated in vacuo to give (cis)-1-acetyl-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinamine (399 mg, 1.28 mmol, 87%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:17][OH:18]
Reactant: NO
Reactant: CC(C)C(C)n1ccc(Cl)c(C=O)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)C(C)n1ccc(Cl)c(C=NO)c1=O
Temperature: 75 °C
Yield: 76.9 %

Procedure:
A mixture of 4-chloro-1-(3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (400 mg), hydroxylamine hydrochloride (244 mg) and sodium acetate (288 mg) in methanol/water (4:1, 6.0 mL) was heated at 75° C. for 1 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (328 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=[CH2:2].[OH-:16].C([N+](C)(C)C)C1C=CC=CC=1>N1C=CC=CC=1>[CH:1]([C:3]1[C:4](=[O:16])[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: c1ccncc1
Product: C=CC1=CC=C2C(=Cc3ccccc32)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The 2-vinylfluorene prepared in Example I is dissolved in 800 milliliters of pyridine and cooled to 0° C. One-half milliliter of a 40% solution of benzyltrimethyl ammonium hydroxide in pyridine is slowly added with air being bubbled through the reaction solution. The initially formed red coloration fades over a period of 1 to 2 hours and the solution is poured into water and extracted with benzene to yield 9 grams (90% theory) of a yellow solid. The residue is chromatographed on alumina (Woehlm basic) and eluted with benzene. Recrystallization from hexane gives 2-vinylfluorenone as a pale yellow material (melting point 69°-70° C). The structure of the product is confirmed by nuclear magnetic resonance and elemental analysis.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21](/[CH:23]=[N:24]/[OH:25])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([C:23]([Cl:1])=[N:24][OH:25])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(OCc2ccccc2)cc1/C=N/O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cc1C(Cl)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
N-Chlorosuccinimide (3.72 g) was added in small portions to a solution of (E)-1-(5-(benzyloxy)-2-methylphenyl)-N-hydroxymethanimine (6.40 g) in DMF (60 mL) at room temperature, and the obtained mixture was stirred at room temperature for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.05 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Br:24][C:25]1[C:26]([C:30]([OH:32])=[O:31])=[CH:27][S:28][CH:29]=1.CON(C)[C:36]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)=[O:37]>C1COCC1>[Br:24][C:25]1[C:26]([C:30]([OH:32])=[O:31])=[C:27]([C:36](=[O:37])[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[S:28][CH:29]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: O=C(O)c1cscc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(c1ccncc1)c1scc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
To a solution of diisoproplyamine (5.3 g, 53 mmol) in anhydrous THF (40 mL) at −30° C. was added n-BuLi (23.2 mL, 58 mmol, 2.5M in hexanes) dropwise. The mixture was stirred at the same temperature for 0.5 h, then cooled to −78° C. and HMPA (0.86 g, 4.8 mmol) was added slowly. Then the solution of 4-bromothiophene-3-carboxylic acid (5.0 g, 24 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred at the same temperature for 1 h, N-methoxy-N-methyl-4-pyridinecarboxamide (8.0 g, 48 mmol) was added dropwise into the stirring mixture at −78° C. The reaction mixture was stirred for another 1 h at room temperature and was then quenched with H2O (10 mL). The aqueous layer was acidified with 5% aq. HCl to pH 1-2, the precipitate was collected by filtration. The filter cake was washed with DCM (10*50 mL). The title compound was dissolved in DCM; the solid insoluble in DCM was the side product. The filtrate was extracted with DCM (3×200 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with DCM to give the title compound (0.8 g, yield 10.7%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.O.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(=O)([O-])[O-].[K+].[K+].Cl>[Cl-].C([N+](CCC)(CCC)CCC)CC>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:36]([CH3:35])(=[O:38])=[O:37]
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CS(=O)(=O)Cl
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reaction time: 0.75 h

Procedure:
The solid 1-(5-amino-2,4-dichlorophenyl)-4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazol-5(1H)-one (1.0 equiv.) was suspended in 20 equivalent of water and the reaction mixture chilled to 10 C. Vigorous stirring was commenced and 0.05 equiv of tetra-n-propylammonium chloride in 0.05 equiv of xylene was added. Using a pH meter, the of the suspension was brought to 7.8 by adding adequate quantity of 1 molar sodium carbonate aqueous solution. Simultaneous addition of 1.2 equiv methanesulfonyl chloride was started into the reaction while keeping the flow of the aqueous potassium carbonate on such that the of 7.8 was maintained throughout. After 45 minutes the reaction was complete and the suspension was replaced by a clear solution. Concentrated hydrochloric acid was added slowly to bring the pH of the reaction to 2.0 wherein a precipitate was formed. The precipitate was collected by filtration, washed with water and dried to give the N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl]methanesulfonamide as a white solid (0.95 equiv and 97% purity).
Reaction SMILES: [C:1]([C:9]1[NH:13][C:12]([C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>[C:1]([C:9]1[N:13]2[C:12](=[CH:11][CH:10]=1)[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:30]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCCl
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture of triethyl (5-benzoylpyrrol-2-yl)-methanetricarboxylate (2.00 g, 5 mmol), tetra-butylammonium bromide (1.61 g, 5 mmol) and potassium carbonate (19.0 g, 250 mmol) in 1,2-dichloroethane (100 mL) was refluxed for 2 days. The mixture was cooled to room temperature and filtered. The filter cake was washed with methylene chloride. The filtrate and methylene chloride wash solution were combined and concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water, dried, and concentrated. The crude product was purified by flash chromatography on flash silica eluting with hexane/ethyl acetate (90:10) to provide 1.42 g (80%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate. The IR and NMR spectral properties were identical to those of the authentic sample.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:4](=[O:18])[NH:3]1.[NH2-].[Na+].N.[CH3:22]I>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:22][N:3]1[CH:2]([CH3:1])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:5][C:4]1=[O:18]
Reactant: CC1NC(=O)OC12CCCCC2c1ccccc1
Reactant: CI
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC1N(C)C(=O)OC12CCCCC2c1ccccc1
Reaction time: 1 h

Procedure:
4-Methyl-6-phenyl-1-oxa-3-azaspiro [4.5] decan-2-one (Example XXIII) (23.6 g) in hexamethylphosphoric triamide (HMPT) is added dropwise to 5 g sodium amide in 35 ml HMPT. The mixture is stirred until NH3 evolution is essentially finished and 11 ml methyl iodide added at about 40° over a 1/2 hour period. The mixture is stirred 1 hour, added to 700 ml water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 25 g crude product. A sample of the crude product, recrystallized from cyclohexane, gave the crystalline product, m. 85°-6°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:17]([CH3:19])[CH3:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.[OH-].[NH4+]>ClCCl>[NH2:27][C:14]([C:11]1([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: CN(C)C=O
Reactant: CC(C)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-isopropylpiperidine-4-carboxylic acid (500 mg, 1.843 mmol) in dichloromethane (5 ml) were added oxalyl chloride (2.76 ml, 5.53 mmol) and a drop (ca. 10 μl) of dimethylformamide. After stirring 1 h at room temperature, the mixture was concentrated and then dissolved in tetrahydrofuran (5 ml). Concentrated ammonium hydroxide (5 ml, 36.0 mmol) was added and the mixture was stirred overnight at room temperature, and then concentrated to a small volume, poured into 50 ml of 1 M NaOH, and diluted with 50 ml of ethyl acetate. The phases were separated, the aqueous was extracted with 2×25 ml of ethyl acetate, and then the combined organics were washed with 25 ml of brine, dried (Na2SO4), and concentrated to provide the title compound (411 mg, 1.520 mmol, 82% yield). Mass spectrum (ESI) 174.0 (M-Boc).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:47][C@@H:48](O)[CH2:49][CH:50]=[CH2:51].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:46])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[O:33][C@H:50]([CH2:49][CH:48]=[CH2:47])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O)c4)nn23)CC1
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.43 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.132 mL, 1.28 mmol, 3 equiv), and PPh3 (0.23 g, 0.86 mmol, 2 equiv) in THF (2.1 mL) was added DIAD (0.166 mL, 0.86 mmol, 2 equiv). After stirring 18 h, diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless glass (0.29 g, 97%). LCMS (M+1)=699.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3,4-Dichlorobenzyl chloride (3.95 g) was added to 2-amino-2-methylpropan-1-ol (17.8 g) and the mixture was stirred at 60° C. under nitrogen for 2 h. Excess amine was removed by distillation under vacuum and the residue was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The phases were separated, the organic layer was washed with water (4×100 ml) and brine (100 ml), dried (Na2SO4) and concentrated under vacuum to give the title compound as a white solid (4.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])[CH3:20]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:26])[CH:23]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:24])[CH3:20]
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(Br)cc21
Temperature: 70 °C
Yield: 84.5 %

Procedure:
To a suspension of 6-bromo-4H-benzo[1,4]oxazin-3-one (27 g, 118.4 mmol) and K2CO3 (49.1 g, 355.2 mmol) in acetone (200 mL) was added 2-bromo-propionic acid ethyl ester (32.1 g, 177.6 mmol) and the reaction mixture was heated at 70° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo and the residue was dissolved in DCM (50 mL). The organic phase was washed with water (3×20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness and the residue was purified by chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a colorless liquid (32.5 g, 100 mmol, 84%). 1H NMR (CDCl3, 400 MHz): δ 7.09 (dd, J=8 Hz, J=2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.28 (q, J=14.8 Hz, 1H), 5.21 (q, J=5.4 Hz, 1H), 4.55 (d, J=15.2 Hz, 2H), 4.17 (m, 1H), 1.63 (d, J=1.2 Hz, 3H), 1.22 (t, J=1.2 Hz, 3H).
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:6]=1[O:7][C:8]([C:11]1[N:12]([CH3:35])[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20](CC2C=CC(OC)=CC=2)[CH2:19]3)=[N:14][N:15]=1)([CH3:10])[CH3:9].[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[F:4][C:5]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:6]=1[O:7][C:8]([C:11]1[N:12]([CH3:35])[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH2:19]3)=[N:14][N:15]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CN2Cc3cc(-c4nnc(C(C)(C)Oc5ccc(F)cc5F)n4C)ccc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cn1c(-c2ccc3c(c2)CNC3=O)nnc1C(C)(C)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
Acetonitrile (25 ml) and water (8.3 ml) were added to 5-{5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-(4-methoxybenzyl)isoindolin-1-one (629 mg), and cerium (IV) ammonium nitrate (1.71 g) was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:20% methanol-chloroform solution=100:0 to 0:100), the solvent was evaporated under reduced pressure, and the residue was solidified with 2-propanol:diisopropylether (1:1) to obtain, as a colorless powdery solid, 5-{5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-triazol-3-yl}isoindolin-1-one (247 mg).
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =-47.6° (c=1.0, methanol).