Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C(C(F)(F)F)=C)C=C(Cl)C=1.[Br:40]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl.O>[Br:40][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:22]([F:24])([F:23])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:21]
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: O
Product: Fc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Temperature: 25 °C

Procedure:
In a solution of 1.50 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole synthesized from 3-fluoro-4-methylphenylaldoxime and 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene similarly to Step 2 of Synthetic Example 3 in 50 ml of 1,2-dichloroethane, 0.68 g of N-bromosuccinic acid imide and a catalytic amount of azobisisobutyronitrile were added, and stirred under nitrogen atmosphere and under reflux with heat for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, poured in 50 ml of water, extracted with chloroform (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.C=O.[C:28]([BH3-])#[N:29].[Na+].[C:32](O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:29]([CH3:28])[CH3:32])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: [BH3-]C#N
Reactant: NCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-chloro-1-(aminomethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-chloro-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25]C(O)=O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([CH2:44][OH:45])=[C:39]([CH3:46])[CH:38]=1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-:69].[Na+]>C(Cl)Cl>[OH:45][CH2:44][C:40]1[C:39]([CH3:46])=[CH:38][C:37]([NH:36][C:25]([CH2:24][CH2:23][CH2:22][N:21]([CH3:29])[C:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:15]2)=[O:20])=[O:69])=[C:42]([CH3:43])[CH:41]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(CO)c(C)cc1N
Reactant: CN(CCCCC(=O)O)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A solution of 5-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionyl}-methylamino)pentanoic acid (1.19 g, 2.46 mmol); (4-amino-2,5-dimethylphenyl)-methanol (372 mg, 2.46 mmol) and N,N-diisopropylethylamine (858 μL, 4.93 mmol) in DCM (18.5 mL) was stirred at room temperature for 30 min. N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (708 mg, 3.69 mmol) was added and the resulting mixture was stirred at room temperature for 3 h. Saturated aqueous sodium bicarbonate solution (5 mL) was added and this mixture was extracted with DCM (2×2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (460 mg, 31% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N-:8]=[N+:9]=[N-:10].[Na+].[CH:12](OC)(OC)OC.CCOC(C)=O>CC(O)=O>[N:1]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[N:10][N:9]=[N:8]1
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccnc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1cncc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 3-aminopyridine (1.3 g, 13.4 mmol) in HOAc (20 mL) was added sodium azide (1.3 g, 20.1 mmol) and trimethyl orthoformate (2.36 mL, 21.6 mmol) and the resultant slurry was stirred at room temperature overnight and subsequently refluxed for 6 h. The reaction was cooled to room temperature and stopped by pouring into 50 mL of ice water. EtOAc (50 mL) was added, collected and subsequently washed with aqueous sodium hydroxide (1 N). The organic layer was collected, dried (MgSO4) and concentrated in vacuo to afford the title compound 65 (1.0 g, 52%) as a white solid: mp=74-76° C.; 1H NMR (CDCl3) δ 10.37 (s, 1H), 9.36 (m, 1H), 8.98 (m, 1H), 8.56 (m, 1H), 7.88 (m, 1H); LRMS (ESI) m/z calcd for C6H6N3 [M+H—N2]+ 120. found 120; HRMS (ESI) m/z calcd for C6H6N5 [M+H]+ 148.0623. found 148.0636; HPLC>99% (tR=3.44 min, 60 (A):40 (B): 0.009 (C); tR=2.71 min, 60 (A):40 (B): 0.02 (C)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8]1.Cl.[F:15][C:16]1[C:22](F)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1.O>CN(C=O)C>[F:15][C:16]1[C:22]([N:9]2[CH2:8][CH2:7][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: C1CNCCOC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCOCC2)c(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.7 %

Procedure:
19.4 g of potassium carbonate and 11.9 g of homomorph-oline hydrochloride are added to a solution of 5 g of 4,5-difluoro-2-nitroaniline in 98 mL of anhydrous DMF. The reaction medium is heated at 80° C. using an oil bath for 2 hours. The reaction medium is cooled to ambient temperature, then 300 mL of water are added thereto, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with 3 times 100 mL of water. The solid is dried in an oven at 70° C. 6.5 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine are obtained in the form of an orange solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.91 (m, 2H); from 3.52 to 3.61 (m, 4H); 3.66 (m, 2H); 3.74 (m, 2H); 6.28 (d, J=8.5 Hz, 1H); 7.24 (broad s, 2H); 7.61 (d, J=15.5 Hz, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:34])([F:35])[F:33])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: NC(=O)c1cc(NCc2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Benzylbromide (140 μL, 0.5 M in anhydrous DCM, 0.07 mmol, 1.1 equiv.) was added to a solution of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (25 mg, 0.06 mmol, 1.0 equiv.) and cesium carbonate (62 mg, 0.19 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at 50° C. overnight. The title compound was obtained by pre-HPLC in 17% yield. Mass: M+H+: 486.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)=[CH:11][CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
In DMF (75 mL) was dissolved 3-nitro-7-hydroxyquinoline (5.0 g, 26.2 mmol.). Under chilling with ice, to the solution was added sodium hydride (1.15 g, 29 mmol.). After 20 minutes, benzyl bromide (3.4 mL, 29 mmol.) was further added for 10 minutes. The mixture was then stirred overnight at room temperature. After the completion of reaction was confirmed, the mixture was poured into a mixture of ice and water. The precipitated crystalline product was collected by filtration, washed with water, and dried, to give the desired compound (7 g) as a white crystalline product (yield 95%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:12][C:13]([NH2:23])([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>>[ClH:21].[OH:1][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:23][C:13]([CH3:22])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC(C)(N)Cc1ccc(Cl)cc1
Product: CC(C)(Cc1ccc(Cl)cc1)NCC(O)COc1ccccc1
Product: Cl
Yield: 10.3 %

Procedure:
Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (950 mg, 6.3 mmol) and 1,1-dimethyl-2-(4-chlorophenyl)ethylamine (1.45 g, 7.9 mmol) were used to prepare 150 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 318 (M−15, 7), 209 (47), 208 (100), 127 (11), 125 (33), 114 (13), 107 (12), 77 (23), 71 (16), 70 (29), 58 (13).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:37])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[CH3:18].C(=O)(O)[O-].[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>[CH2:17]([O:19][C:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)=[O:37])[CH3:18]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(=O)O)cc2)cc1

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (2.0 g, 7.07 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (2.46 g, 8.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.70 mmol), and sodium bicarbonate (4.3 g, 52 mmol) were combined in 1,4-dioxane (50 mL) and water (10 mL), and the reaction was stirred overnight at 80° C. to give the title compound.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1/[CH:20]=[N:21]/[S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23]>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C@@H:20]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCCBr
Reactant: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1Br
Agent: II
Solvent: C1CCOC1
Product: C=CCCC[C@H](NS(=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1Br
Temperature: 40 °C
Yield: 53.8 %

Procedure:
To a 100 mL three-neck RBF equipped with stir bar and condenser was added Mg (excess), catalytic iodine, THF (20 mL), followed by 5-bromopent-1-ene (1.93 g, 12.9 mmol) added in small increments. The mixture was heated to 40° C. for 1 hour. The reaction was cooled to room temperature and the freshly made Grignard reagent was added via syringe into a 250 mL RBF with N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (2.3 g, 6.5 mmol) in THF (20 mL). Upon completion, the reaction was quenched with saturated aqueous NH4Cl and partitioned with ethyl acetate. The organic was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to yield N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}-2-methylpropane-2-sulfinamide (1.5 g, 3.5 mmol). 1H NMR (500 MHz, CDCl3) δ7.71 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.41 (d, J=6.4 Hz, 1H), 5.77 (m, 1H), 5.03 (m, 2H), 4.87 (m, 1H), 3.65 (m, 1H), 2.11 (m, 2H), 1.86 (m, 1H), 1.82 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.22 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[C:20](=[O:23])([O-])[O-:21].[K+].[K+]>CO.O.C(Cl)Cl>[C:4]([O:21][C:20]([N:8]1[CH2:9][CH2:10][C:4]2[C:3]([OH:19])=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7]1)=[O:23])([CH3:10])([CH3:5])[CH3:3]
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Yield: 209.4 %

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0 g, 6.80 mmol) in methanol (100 mL). Add potassium carbonate (14.08 g, 102 mmol) in water (50 mL) slowly. Stir the reaction at RT for 2 h, add tert-butoxycarbonyl anhydride (1.59 g, 7.48 mmol) in DCM (70 mL) and stir vigorously for 17 h. Concentrate the organic layer, wash the aqueous layer with DCM (3×50 mL), combine the organic layers, dry (MgSO4) and concentrate to give the title compound (2.12 g, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:16]([CH:20](OC(F)(F)F)[OH:21])([F:19])([F:18])[F:17]>CO.C(OCC)(=O)C>[OH:1][C:2]1[C:7](=[O:8])[C:6]([CH:20]([OH:21])[C:16]([F:19])([F:18])[F:17])=[CH:5][NH:4][C:3]=1[CH3:9]
Reactant: Cc1[nH]ccc(=O)c1O
Reactant: OC(OC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O

Procedure:
A mixture of 3-hydroxy-2-methyl-1H-pyridin-4-one (6.1 g, 48.7 mmol), potassium carbonate (17 g, 123 mmol), and CF3CH(OH)OCF3 (25 mL, 0.25 mol) was heated to reflux under a blanket of nitrogen for 30 h. The progress of the reaction was monitored by HPLC Method 1 (Example 24), which indicated 63% (peak percent area) of conversion to the product. The reaction mixture was diluted with methanol (50 mL), then filtered to remove solid particulates. The filtrate was evaporated to dryness to afford an oil. The oily residue was taken up in ethyl acetate (150 mL) and washed with a saturated ammonium chloride solution (80 mL). The organic fraction was collected and set aside. The pH of the aqueous fraction was adjusted to 6 with a dilute hydrochloric acid solution, and the resulting aqueous solution was extracted with ethyl acetate (2×40 mL). All the organic fractions were combined, then washed with saturated ammonium chloride, dried over Na2SO4, filtered and then evaporated to dryness to give an oil. On trituration with ether, 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one separated as a solid product and was collected by suction filtration (3.5 g, 33%). NMR data is described in Part C above.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>C(Cl)Cl>[N:66]1[CH:67]=[CH:68][CH:69]=[C:64]([NH:63][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[NH:17]2)=[O:37])[CH:65]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccnc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccnc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a colorless solution. DIPEA (240 μl, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. 3-Amino-pyridine (38.9 mg, 413 μmol, Eq: 1.2) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 2% to 5% MeOH in DCM) to give a white solid as the product. 185 mg. MS (ES+) m/z Calcd: [(M+H)+]: 543. found: 543.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([OH:34])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:13][CH:12]=1.Br.N1[CH2:41][CH2:40]N=C1NN>C(O)CCC>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([O:34][CH2:40][CH3:41])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:13][CH:12]=1
Reactant: NNC1=NCCN1
Reactant: CC(CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)=NNC1=NCCN1
Agent: Br
Solvent: CCCCO
Product: CCOC(=O)[C@H](CCOc1ccc(CCC(C)=NNC2=NCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 110 °C
Yield: 109.9 %

Procedure:
The mixture constituted by 430 mg of the ketone prepared in Stage A, 549 mg of 4,5-dihydro-1H-imidazol-2-yl-hydrazine hydrobromide in 20 ml of butanol is heated at the temperature of 110° C. for 2 hours then evaporated under reduced pressure until 1.1 g of crude product is obtained which is purified by chromatography (Kieselgel 60, 40-63 μm) eluting with a dichloromethane/methanol mixture 90/10. 500 mg of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[N:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]2=[N:16]1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccccc2n1
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 62.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 90 mg of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=O)=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:26].CO>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:17])[NH:26][CH2:19][C:13]=3[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reactant: N
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNC1=O)N2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The product from Example 25B (0.22 g, 0.46 mmol) was treated with 1:1 ammonia/methanol mixture (60 mL) in a metal Parr stirred reactor for 2.5 days at ambient temperature. The solvent was allowed to evaporate and the residue was purified by chromatography on silica gel (5% and then 10% methanol in methylene chloride) to provide the title compound (0.026 g) as a solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[O+:19]=2)=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:37]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][C:53](=O)[CH:54]=2)=[CH:45][CH:44]=1)[CH2:38][CH2:39][CH2:40][CH3:41].C(OC(=O)C)(=O)C.O>C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([CH:24]=[C:53]3[CH:52]=[C:51]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[O:50][C:49]([C:46]4[CH:45]=[CH:44][C:43]([O:42][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:48][CH:47]=4)=[CH:54]3)[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[O+:19]=2)=[CH:16][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCOc1ccc(-c2cc(=O)cc(-c3ccccc3)o2)cc1
Reactant: CCCCCOc1ccc(-c2cc(C)cc(-c3ccc(OCCCCC)cc3)[o+]2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCCCCOc1ccc(C2=CC(=Cc3cc(-c4ccc(OCCCCC)cc4)[o+]c(-c4ccc(OCCCCC)cc4)c3)C=C(c3ccccc3)O2)cc1

Procedure:
A mixture of 3.1 g. of 2,6-bis(4-amyloxyphenyl)-4-methylpyrylium perchlorate, 2.0 g. of 2-(4-amyloxyphenyl)-6-phenyl-4-pyrone, and 20 ml. of acetic anhydride are stirred and heated at its boiling temperature for 5 to 10 minutes, cooled, diluted with ethanol with stirring, and chilled in a freezer. A solid separates from the mixture and is collected and washed with water. Another crop is obtained by adding water to the reaction mixture, extracting with dichloromethane, removing the solvent by evaporation, and recrystallizing the residue from acetic acid. The two crops are combined and recrystallized again from acetic acid. mp = 68°C. The theoretical values calculated for C50H55ClO, and the actual values found are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Br)cc2)cc1
Product: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(Br)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-bromophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-bromophenoxy)phenyl)-3-(4-fluorobenzyloxy)propanamide (200 mg, 50%).