Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:40])([F:39])[F:38])[CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:43][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:34])([F:35])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:38])([F:40])[F:39])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2OC(F)(F)F)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (10) (0.039 g, 0.069 mmol) in anhydrous methanol (4 mL) was added a 37% aq. solution of formaldehyde (0.020 mL, 0.28 mmol) under an atmosphere of nitrogen followed by sodium triacetoxyborohydride (0.073 g, 0.34 mmol). The reaction was stirred at room temperature for 3 hours. The volatiles were then removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a gum which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting gum was then suspended in diethyl ether (5 mL) and the solvent was removed in vacuo. The procedure was repeated to give the title compound (I1) (0.037 g, 93% yield) as a white fluffy solid: 1H NMR (400 MHz, dr DMSO) δ 9.79 (s, 1H), 8.59 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 7.28 (dd, J=8.4, 1.9 Hz, 1H), 7.26-7.23 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.08 (m, 3H), 6.89 (s, 1H), 3.45 (s, 2H), 3.08-2.93 (m, 4H); 2.90-2.83 (m, 2H), 2.57-2.52 (m, 1H, obscured by residual solvent signal), 2.19 (s, 3H), 1.96 (td, J=11.5, 2.0 Hz, 2H), 1.80-1.72 (m, 2H), 1.65 (ddd, J=24.6, 12.4, 3.7 Hz, 2H). LCMS Method C: rt 5.11 min; m/z 582.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C@@H:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([C@H:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.766 g, 1.996 mmol), (5-((1R)-1-(4-(tert-butoxycarbonyl)-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 146, Step 4)(0.705 g, 1.996 mmol), PdCl2AmPhos (0.071 g, 0.100 mmol), and KOAc (0.588 g, 5.99 mmol) in a mixture of dioxane (16.6 mL) and water (3.3 mL) was sparged with nitrogen and then heated at 100° C. for 2.5 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were then dried over Na2SO4 and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.570 g, 0.868 mmol, 43.5% yield) as light-yellow foam. m/z (ESI, +ve) 657.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.22 Hz, 1H); 8.18 (s, 1H); 7.18 (d, J=7.24 Hz, 4H); 6.82-6.89 (m, 5H); 4.75 (br. s., 4H); 3.79 (s, 6H); 3.60 (d, J=7.04 Hz, 1H); 3.43 (br. s., 4H); 2.63 (s, 3H); 2.30-2.53 (m, 4H); 1.44 (s, 12H).
Reaction SMILES: [NH4+:1].[Cl-].C([O:5][C:6]([C:8]1[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=1)=O)C>[OH-].[NH4+]>[CH3:13][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]([NH2:1])=[O:5]
Reactant: CCOC(=O)c1nccn1C
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Product: Cn1ccnc1C(N)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 1969.4 %

Procedure:
NH4Cl (0.150 g, 2.8 mmol) is added to a solution of 1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (15.5 g, 101 mmol) in ammonium hydroxide 35% (112 mL) and the reaction is stirred for 6 h at 100° C. in a sealed reaction flask. The reaction is cooled to 0° C. and the solid formed filtered and washed with ice water and ether to give 1-methyl-1H-imidazole-2-carboxylic acid amide as brown crystals (6.9 g, 55%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][C:3]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2)=[O:5]
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(O)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc2cnccc2c1
Reaction time: 4 h

Procedure:
To chloroacetic acid in DMF was added EDC, DMAP and 6-aminoisoquinoline. This mixture was stirred for 4 hours. The reaction was washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave 2-chloro-N-(isoquinolin-6-yl)acetamide (E1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([C:25]#[N:26])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (140 mg, 0.36 mmol) and CuCN (64 mg, 0.72 mmol) in DMF (5 mL) was refluxed for 30 min. After the mixture was cooled to r.t., CH2Cl2 (50 mL) was added. 4M HCl was added with stirring until no solid was present. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined and dried over MgSO4. After evaporating the solvent in vacuo, the crude residue was chromatographed (20-100 EtOAc/hexanes+2% AcOH) to give 75 mg of the title compound. MS: (+) m/z 338.03 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([CH:11]1[CH:16](O)[CH2:15][CH2:14][N:13]([CH2:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)[CH2:12]1)=[O:10])[CH3:7].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[CH2:12][N:13]([CH2:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:15][CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CN(CC2CCCc3ccc(OC)cc32)CCC1O
Agent: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=CCCN(CC2CCCc3ccc(OC)cc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.06 g (18 mmol) of methanesulphonic acid chloride in 20 ml of toluene is added dropwise, while stirring at 0°-5°, to a solution of 5.2 g (15 mmol) of cis/trans mixture of 4-hydroxy-1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester and 11.4 g (75 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of toluene. The reaction mixture is then allowed to warm to room temperature and is stirred for a further 18 hours at room temperature. Ice-water is added to the reaction mixture and the organic phase is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with concentrated sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The oily residue (4.85 g) is chromatographed on 240 g of silica gel (0.040-0.063) with toluene/ethyl acetate (9:1) to yield 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester in the form of a light-yellow oil. The hydrochloride produced with hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether, m.p. 177°-179° (decomposition).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:24]([S:25][C:26]3[C:34]([Br:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:36])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:24]([S:25][C:26]3[C:34]([Br:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:36])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ccc(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.5 %

Procedure:
To a solution of (4-{2-[6-Amino-8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)purin-9-yl]-ethyl}-phenyl)-carbamic acid tert-butyl ester (0.03 g, 0.04 mmol) in dichloromethane (4.3 mL) was added TFA (0.02 mL, 0.22 mmol) and the reaction mixture was stirred at rt overnight. At the end of this period, reaction was diluted with 100 mL of toluene and then concentrated under reduced pressure. This process was repeated 3 more times to yield the title product (0.03 g, 95%) as TFA salt. 1H NMR (DMSO-d6) δ 8.19 (s, 1H), 7.24 (s, 1H), 7.19-7.02 (m, 4H), 7.00 (s, 1H), 6.13 (s, 2H), 4.45 (t, J=6.8 Hz, 2H), 3.18 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 486.3.
Reaction SMILES: C([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:10]=1[CH3:28])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:11]2[C:10]([CH3:28])=[C:9]([NH2:8])[C:14]([CH3:15])=[CH:13][C:12]=2[O:16][CH3:17])=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COc1cc(C)c(NCc2ccccc2)c(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C)c(N)c(C)c1Cc1ccc(C(C)C)cc1
Yield: 86 %

Procedure:
Using N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline obtained in Reference Example 267, the title compound was synthesized in the same manner as in Reference Example 30. Yield 86%. Melting point: 91-92° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CCO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[O:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC(C)(C)O1
Yield: 83.3 %

Procedure:
The hydrolysis procedure described for 191 was employed. Thus, methyl 4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoate (101) (0.212 g, 0.557 mmol) in THF/EtOH (1:1, 6 mL) was treated with 1 N NaOH (3 mL, excess). Standard work-up followed by purification gave 0.170 g (83%) of compound 102 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.77 (br s, 1H), 9.40 (br s, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 2.18 (s, 2H), 2.11 (s, 2H), 1.14 (s, 6H), 1.12 (s, 6H). LCMS (ESI): m/z 365 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15]([N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared according to EXAMPLE 229 using 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42) and 4-hydroxypiperidine. Purification by chromatography using dichloromethane/methanol (9:1) as the eluent gave the title compound as an orange powder. m/z (ES+)=427.35 [M+H]+; RT=2.99 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:7]2=[O:12].[CH:20]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:20]1([CH2:27][C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:7]3=[O:12])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCCCC1
Reactant: Nc1cccc2c(=O)n(CC3CCOCC3)ccc12
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCCCC1)Nc1cccc2c(=O)n(CC3CCOCC3)ccc12

Procedure:
5-Amino-2-(tetrahydro-pyran-4-ylmethyl)-2H-isoquinolin-1-one (40 mg, 0.0002 mot), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol), N,N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature over 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) to give a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.[CH3:61][O:62][C:63](=[O:70])[CH2:64][CH2:65][CH2:66][N+:67]([O-:69])=[O:68]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([O:16][C:7]2[C:8]([C:12]([F:13])([F:14])[F:15])=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:66]([N+:67]([O-:69])=[O:68])[CH2:65][CH2:64][C:63]([O:62][CH3:61])=[O:70])[CH:11]=[CH:10]3)[CH2:18][CH2:19]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2C(F)(F)F)CC1
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COC(=O)CCC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A 200 mL round-bottom flask containing a stir bar was charged with 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene (5.00 g, 11.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.400 g, 0.437 mmol; Strem), 2-(di-t-butylphosphino)-2′-methylbiphenyl (0.546 g, 1.75 mmol; Strem), and cesium carbonate (4.55 g, 14.0 mmol; Alfa Aesar). The reaction vessel was capped with a rubber septum, evacuated, backfilled with argon three times and 1,2-dimethoxyethane (100 mL, 1000 mmol) and 4-nitro-butyric acid methyl ester (3.02 mL, 24.4 mmol) were added via syringe under argon. After the mixture was stirred vigorously for 2 min at room temperature, the flask was equipped with a condensor and heated at 50° C. overnight. The reaction was allowed to cool to ambient temperature and quenched with a solution of sat. aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in methylene chloride and absorbed onto silica gel, then purified by flash column chromatography (0-20% hexanes in ethylacetate) to give 2.34 g of the title compound in 41% yield.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].C(=O)(O)[O-].[Na+].[N+](C1C=C(C=CC=1)CN)([O-])=O.[CH2:29]([O:31][C:32](=[O:46])[CH:33]([CH2:37][C:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34](=O)[CH3:35])[CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(OCC)C>[CH2:29]([O:31][C:32]([C:33]1[CH:37]=[C:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:9]([CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:34]=1[CH3:35])=[O:46])[CH3:30]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)n(Cc2cccc([N+](=O)[O-])c2)c1C

Procedure:
m-Nitrobenzylamine hydrochloride (3 g) was suspended in an aqueous solution of saturated sodium bicarbonate (30 mL), then extracted with chloroform. The organic layer was dried over MgSO4, the solids separated and solvents removed under vacuum to yield the free base. The m-nitrobenzylamine (5 mmol, 0.8 g) prepared above, 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The residue was resuspended in ethyl ether, and the benzylamine tosic acid salt was filtered from the mixture. The filtrate was concentrated under vacuum, and the resulting oil purified over silica to yield the named product, 1H-NMR (CDCl3, ppm): 1.24 t (3H), 2.36 s (3H), 4.07-4.30 q (2H), 5.11 s (2H), 6.58 s (1H), 6.98-7.44 bm (7H), 7.69 bs (1H) , 7.97 bd (1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1([CH2:51][C:52](O)=[O:53])[CH:50]=[N:49][CH:48]=[N:47]1.C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:4]2[CH:3]([CH2:2][NH:1][C:52](=[O:53])[CH2:51][N:46]3[CH:50]=[N:49][CH:48]=[N:47]3)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C(O)Cn1cncn1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)Cn2cncn2)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of tert-butyl (6SR,7SR)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMF (5 mL) were added WSC (100 mg), HOBt (90 mg), triethylamine (0.10 mL) and 2-(1H-1,2,4-triazol-1-yl)acetic acid (74 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (190 mg).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[K+].[CH:30](Br)=[CH2:31].ClOC(C)(C)C>ClCCl>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:31]=[CH:30][N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Reactant: C=CBr
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(N2C=C[NH+](c3c(C)cc(C)cc3C)N2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (5.63 g, 20 mmol) and anhydrous potassium hexafluorophosphate (3.68 g, 20 mmol) and excess vinyl bromide 11e (10 mL) in dry dichloromethane (100 mL) in the dark at 78° C. is added tert-butyl hypochlorite (3.33 mL, 30 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10be as an off-white solid (8.21 g, 91%). 1H-NMR (CD3CN, 300 MHz): δ=8.82 (s, 2H), 7.21 (s, 4H), 2.40 (s, 6H), 2.09 (s, 12H). 13C-NMR (CD3CN, 75 MHz): δ=144.3, 135.7, 135.1, 132.3, 130.9, 21.4, 17.5. HR-MS (ESI): Calcd. for C20H24N3 [M+]: 306.1965. found 306.1973.