Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:47][CH3:48])=[C:40]([CH:46]=1)[C:41]([N:43]([CH3:45])[CH3:44])=[O:42]>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:47][CH3:48])=[C:40]([CH:46]=2)[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: COc1ncc(Br)cc1C(=O)N(C)C
Product: COc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cc1C(=O)N(C)C
Yield: 38 %

Procedure:
The title compound was synthesized as described for Intermediate I-28 in 38% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman -3-amine and 5-bromo-2-methoxy-N,N-dimethylnicotinamide. The reaction mixture was irradiated in a microwave at 140° C. for 45 min: 1H NMR (400 MHz, DMSO-d6) ppm 8.19 (d, 1 H), 7.68 (d, 1 H), 7.25-7.40 (m, 8 H), 7.11-7.22 (m, 3 H), 6.70-6.80 (m, 2 H), 4.32-4.38 (m, 1 H), 3.97-4.04 (m, 1 H), 3.96 (s, 3 H), 3.62-3.75 (m, 4 H), 3.02-3.13 (m, 2 H), 2.99 (s, 3 H), 2.91-2.98 (m, 1 H), 2.85 (s, 3 H); MS (ESI) m/z 508[M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[NH:24][N:23]=2)[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][NH2:39])[CH2:33][CH2:32]1>C(O)CCC.CO>[CH:27]([C:25]1[NH:24][N:23]=[C:22]([NH:21][C:4]2[CH:3]=[C:2]([NH:39][CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[N:7]=[C:6]([NH:8][CH2:9][C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[N:5]=2)[CH:26]=1)([CH3:29])[CH3:28]
Reactant: CN1CCN(CCN)CC1
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Solvent: CO
Solvent: CCCCO
Product: CC(C)c1cc(Nc2cc(NCCN3CCN(C)CC3)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 180 °C
Yield: 29.5 %

Procedure:
A mixture of 6-chloro-N4-(5-isopropyl-1H-pyrazol-3-yl)-N2-(3-phenylisoxazol-5-ylmethyl)-pyrimidine-2,4-diamine (250 mg, 0.611 mmol) and 2-(4-methylpiperazin-1-yl)-ethylamine (500 mg, 3.50 mmol) in 1-butanol (2 mL) was heated to 180° C. in a 50 mL sealed tube. The mixture was heated for 1 h, then cooled to room temperature and diluted with methanol (10 mL). The mixture thus obtained was purified via preparative reverse phase HPLC to give the desired product (93 mg, 29%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reaction time: 24 h

Procedure:
3-Benzyl-2-(1-bromopropyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-6, 0.032 g, 0.088 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.03 mL, 0.26 mmol). The reaction was to 80° C. for 24 h. The reaction was diluted with EtOAc (20 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-7). MS 371.1 found 370.5 required.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:30]=[C:29]([CH3:31])[C:18]([O:19][CH2:20][C@H:21]([OH:28])[CH2:22][NH:23][C:24](=[O:27])[CH2:25][OH:26])=[C:17]([CH2:32][CH3:33])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:34])[N:5]=1)[CH3:2].NC[C@H](O)COC1C(C)=CC(C2N=C(C3C=C(C)N=C(N(CC)CC)C=3)ON=2)=CC=1CC>>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:30]=[C:29]([CH3:31])[C:18]([O:19][CH2:20][C@@H:21]([OH:28])[CH2:22][NH:23][C:24](=[O:27])[CH2:25][OH:26])=[C:17]([CH2:32][CH3:33])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:34])[N:5]=1)[CH3:36]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H](O)CNC(=O)CO
Agent: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
N-(3-{4-[5-(2-Diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-(S)-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N-(3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-(R)-2-hydroxy-propyl)-2-hydroxy-acetamide starting from (S)-1-amino-3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol; LC-MS: tR=0.78 min; [M+1]+=498.20; 1H NMR (CDCl3): δ 1.24 (t, J=7.0 Hz, 6H), 1.32 (t, J=7.3 Hz, 3H), 2.39 (s, 3H), 2.49 (s, 3H), 2.75 (q, J=7.5 Hz, 2H), 2.83 (s br, 1H), 3.44 (s br, 1H), 3.48-3.57 (m, 1H), 3.62 (q, J=6.8 Hz, 4H), 3.75-3.94 (m, 3H), 4.17-4.25 (m, 3H), 7.00 (s, 1H), 7.05 (t, J=4.5 Hz, 1H), 7.09 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][N:15]=[CH:16][C:9]=23)[CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[NH:14]1[C:10]2=[N:11][CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[C:4]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:7]=3)=[C:9]2[CH:16]=[N:15]1
Reactant: CC(C)(C#N)c1cc(Br)cc(-c2ccnc3[nH]ncc23)c1
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cc(-c2ccccc2)cc(-c2ccnc3[nH]ncc23)c1
Temperature: 150 °C
Yield: 34.2 %

Procedure:
A mixture of 2-(3-bromo-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-methylpropanenitrile (50 mg, 0.147 mmol) and phenyl boronic acid (26.76 mg, 0.220 mmol) were placed in a microwave vial. Ethylene glycol dimethyl ether (1.5 ml) was then added followed by sodium carbonate (269.0 mg, 243.9 μL of 2 M, 0.488 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.2 mg, 0.012 mmol). The reaction mixture was heated under microwave irradiation at 150° C. for 60 minutes. The reaction mixture was allowed to cool down to room temperature and was diluted with ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (17 mg, 34% yield).
Reaction SMILES: [OH2:1].S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][CH2:17][C:18]([OH:1])=[O:19]
Reactant: O
Reactant: OCCCCc1ccc(Cl)cc1Cl
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C(O)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step A, 3.63 g (0.0363 mole) of chromium trioxide, 5 mL of water, 5.6 g (0.056 mole) of 18M sulfuric acid, 10.4 mL of water, and 11.4 g (0.052 mole) of 4-(2,4-dichlorophenyl)-1-butanol in 332 mL of acetone are reacted, yielding 4-(2,4-dichlorophenyl)butanoic acid.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].C(O)(=O)C(O)=O.[CH2:31]([NH:33][NH2:34])[CH3:32].C(OCC)C>C(O)(=O)C>[CH2:31]([N:33]1[C:9]([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:34]1)[CH3:32]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(CC)n1
Reaction time: 2 h

Procedure:
A modification of the method described in Part A of Example 11 was followed. A solution of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt (37.64 g, 0.110 mol) in glacial acetic acid (160 L) was cooled to 10° C. before the addition of ethylhydrazine oxalate (16.52 g, 0.110 mol). During the addition, the reaction temperature was maintained between 9 and 11° C. The reaction was complete in two hours. The crude product, a reddish-orange oil, was treated with diethyl ether (150 mL) to form a solid, which was isolated by filtration to provide 26.5 g of ethyl 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxylate as a tan solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH:17]=[N:16]1.CCN(CC)CC.O>C1COCC1.CCOC(C)=O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:2]3[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:22]=2)[CH:17]=[N:16]1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1ccc2cn[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of methyl 2,6-dichloro-4-cyanonicotinate (250 mg, 1.082 mmol), 1H-indazol-6-amine (173 mg, 1.299 mmol) and Et3N (0.226 mL, 1.623 mmol) in THF (10 mL) was stirred at 80° C. overnight. Water and EtOAc were added to the mixture. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2(Hexane/EtOAc=5/1) to give the title compound as a yellow solid (120 mg, 38.5%).
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([NH:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:40])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([CH2:8][NH:9][C:10]([NH:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:40])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: COc1cc2c(N=C(NCC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCCN1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCC(=O)O)Nc3c(C)cccc3C)ncnc2cc1OCCN1CCCC1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 4, N-(tert-butoxycarbonylmethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]guanidine was reacted with trifluoroacetic acid to give the title compound in 65% yield; NMR Spectrum: (DMSOd6, 100° C.) 1.78 (m, 4H), 2.32 (s, 6H), 2.67 (m, 4H), 2.94 (t, 2H), 3.85 (s, 3H), 4.09 (s, 2H), 4.28 (t, 2H), 7.1 (s, 1H), 7.19 (s, 3H), 7.74 (s, 1H), 8.48 (s, 1H), 10.8–11.7 (br s, 1H); Mass Spectrum: M+H+ 493.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:1]([C:8]1[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1c(Cc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 52.6 %

Procedure:
2-Benzyl-4,5-diphenylimidazole (3.3 g) (Weiss, M, J. ,Am. Chem. Soc., 1952, 74, 5193-5) was reacted with ethyl 8-bromooctanoate as in Example 9. Colnmn chromatography on silica gel eluted with a dichloromethane:ethanol gradient followed by distillation at 200° C./0.1 torr to remove volatile impurities gave a yellow oil. Recrystallisation from hexane gave 2-benzyl-1-(7-ethoxycarbonylheptyl)-4,5-diphenylimidazole (2.69 g, 52.6%) as a white solid, m.p. 82°-3°. Found: C, 80.35; H, 7.58; N, 6.08%; C32H36N2O2 requires: C, 79.96; H, 7.55; N. 5.83%.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.O=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:29][C:16]1=2.[H-].[Na+]>C(COC)OC>[CH3:13][O:12][C:10]([CH:9]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:29][C:16]1=2)=[O:11]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: O=C1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C=C1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
1.1 ml of methyl diethylphosphonoacetate dissolved in 10 ml of dimethoxyethane was added to 1.84 g of 11-oxo-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 0.3 g of 64% by weight sodium hydride suspended in 20 ml of dimethoxyethane and the mixture was refluxed under heating for 5 hours. The solvent was removed from the reaction mixture, the residue was dissolved in ethyl acetate and the organic layer was washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. After the solvent was removed from the solution, the residue was applied to silica gel column chromatography to obtain 2.3 g of 11-methoxycarbonylmethylene-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine as a brown oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[CH:56][N:55]=[CH:54]1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][N:53]2[CH:57]=[CH:56][N:55]=[CH:54]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (k) the (3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with imidazol and sodium hydride in N,N-dimethylformamide to yield the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 783 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CCC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH2:15][CH3:14])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCCCN
Solvent: CC#N
Product: CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 208.3 %

Procedure:
4-Azidobenzoic acid (843 mg, 5.06 mmol), HOBt (691 mg, 5.06 mmol, 1.0 eq.) and n-butylamine (0.667 ml, 6.58 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.19 g, 6.08 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (2.3 g, including residual solvent).
Reaction SMILES: COC(=O)C1C=CC(C([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Br:18])[C:12]=2[CH3:19])=O)=C(F)C=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[Br:18][C:13]1[C:12]([CH3:19])=[C:11]([NH:10][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: Cc1c(Br)cc(F)cc1NC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Intermediate 37 was prepared analogue to Intermediate 34 by replacing Intermediate 33 with 4-tert-butyl-benzoyl chloride.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Si]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[C:30]([F:33])([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C)C.[Cl-].[NH4+].[F-].C([NH3+])(C)(C)C>C1COCC1.O.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:21])[C:30]([F:32])([F:31])[F:33])=[CH:8][CH:9]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: CC(C)(C)[NH3+]
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
n-BuLi (2.5 M in hexanes, 42 mL) was added to a −70° C. THF (400 mL) solution of 1,4-dibromobenzene (25.8 g) and the mixture was stirred for 25 minutes. A THF (30 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (31 g) was then added dropwise and the mixture was stirred for 1.5 hour. It was then poured slowly into a mixture of ethyl acetate (500 mL), water (2 L), ice (300 g) and ammonium chloride (100 g) under vigorous stirring. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue, which was used as such. The residue from above was dissolved in THF (250 mL) and the solution was cooled to 0° C. A 1 M THF solution of t-butylammonium fluoride (110 mL) was added dropwise and the mixture was reacted for 4 hours. It was poured into ethyl acetate (300 mL), water (2 L) and ammonium chloride (100 g) under vigorous stirring. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified purified on SiO2 using a gradient of ethyl acetate and hexanes (1:5 to 1:4) as eluant to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([C:20]1([CH3:25])OCC[O:21]1)[C:16]([O:18][CH3:19])=[O:17])[C:7]2=[O:26])([O-:3])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([C:20](=[O:21])[CH3:25])[C:16]([O:18][CH3:19])=[O:17])[C:7]2=[O:26])([O-:3])=[O:2]
Reactant: COC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (95 mg, 35%) in the same manner as described in the above example 6 (1) from methyl 3-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.29 g, 0.82 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[I:1][C:2]1[C:3]2[C:11](=[O:12])[O:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(I)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c(I)cccc21
Yield: 65.2 %

Procedure:
A solution of 3-iodophthalic acid (0.9 g, 3.08 mmol) in acetic anhydride (5 mL) was heated to reflux under nitrogen overnight. After cooling, the solvent was removed in vacuo and the residue purified by trituration with ethanol to give 4-iodo-2-benzofuran-1,3-dione (0.55 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:32]([F:33])=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=2[F:34])[C:6](=[O:35])[CH:5]=[CH:4][C:3]=1[C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:34])=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:31][C:32]=2[F:33])[C:6](=[O:35])[CH:5]=[CH:4][C:3]=1[C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44]
Reactant: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
From Example 54. To a solution of tert-butyl N-(5-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucinate (21 mg, 0.04 mmol) in DCM (2.5 ml) was added TFA (2.5 ml). The mixture was stirred at room temperature for 20 hours, before concentrating under reduced pressure. The residue was dissolved in minimal MeOH and azeotroped with 1:1 toluene/DCM three times. The title compound was afforded as a cream coloured solid as the mono-TFA salt (21 mg, 92% yield).