Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18](C)[CH2:17]2)[C@H:13]([OH:28])[CH2:12]1)([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O.[Cl-].[Cl-].[Zn+2]>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:28])[CH2:12]1)([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c2nc(N)[nH]c(=O)c21
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
GMP (purchased from Sigma, converted to the TEA salt, 29 mg, 0.05 mmol), imidazole (17 mg, 0.25 mmol), and 2,2′-dithiodipyridine (22 mg, 0.1 mmol, purchased from Aldrich) were mixed in anhydrous DMF (1.2 mL) and TEA (7 μL). Triphenylphosphine (26 mg, 0.1 mmol) was added, and the mixture was stirred for 5 h at room temperature. The mixture was placed in a centrifuge tube, and sodium perchlorate (25 mg, anhydrous) dissolved in acetone (6 mL) was added. The procedure for washing the precipitate with acetone and drying over P4O10 was the same as for Compound 5. The imidazolide of GMP thus obtained was dissolved in DMF (1.2 mL), and Compound 7 (10 mg, TEA salt, 0.015 mmol) was added. Next ZnCl2 (40 mg) was added. The mixture was stirred at room temperature overnight, poured into a beaker containing a solution of 125 mg of EDTA in 15 mL of water, and neutralized with 1 M NaHCO3. Chromatographic isolation as for Compound 5 gave Compound 9 (13 mg, 88% based on the amount of Compound 7 used).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of (±)-tert-butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indole-1-carboxylate (0.46 g, 1.28 mmol) in DCM (13 mL), Dess-Martin periodinane (0.814 g, 1.920 mmol) was added, and the reaction was stirred at room temperature. After 10 minutes the reaction mixture was quenched with aq. NaHCO3 and aq. sodium thiosulfate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 358.3 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]=[C:8]=[O:9].[N+:10](=[C:12]1[N:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:11]=[N:10][C:12]2=[C:13]([C:17]([NH2:19])=[O:18])[N:14]=[CH:15][N:16]12
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: O=C=NCc1cccs1
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(Cc3cccs3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophen-2-ylmethyl isocyanate (0.350 g, 2.5 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.314 g, 2.3 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) was removed by filtration, washed with water and ethyl acetate and air dried to give the title compound. Yield: 0.405 g, 64%. IR vmax/cm−1 3094, 1732, 1690, 1607. 1H NMR δH (DMSO-d6) 5.68 (2H, s, CH2Ar), 7.03 (1H, dd, J=5.1, 3.5, ArH), 7.25 (1H, dd, J=3.5, 1.0, ArH), 7.55 (1H, dd, J=5.1, 1.0, ArH), 7.71 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][C@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:38][CH:37]([CH3:39])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:34]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5]1)=[O:35]
Reactant: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.025 g, 0.058 mmol, see Example 50), (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.0138 g, 0.0637 mmol), HOBT-H2O (0.0124 g, 0.0811 mmol) and EDCI (0.0144 g, 0.0752 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.0504 mL, 0.290 mmol) was then added, and the reaction was stirred for 2 hours. The reaction was quenched with saturated Na2CO3. The mixture was then extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (500:20-500:28) to give (R)-tert-butyl 3-methyl-1-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxobutan-2-ylcarbamate (0.009 g, 29.7% yield).
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].N#N>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[C:2]([CH3:1])([OH:20])[CH3:19])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)C(C)(C)O)CC2
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1N)N(C(=O)C(C)(C)O)CC2
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A solution of 2-methyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanol (840 mg, 3.00 mmol) in ethyl acetate (100 mL) and Ethanol (50 mL) was degassed with N2 and to this was added 10% Pd/C (31.9 mg, 0.300 mmol). The reaction was maintained at 50 psi H2(g) overnight at rt on the Fisher-Porter apparatus. The catalyst was removed by vacuum filtration, rinsed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure to provide 1-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-methyl-1-oxo-2-propanol (0.7 g, 93%). ESIMS (M+H)+=251. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 6H) 2.91 (t, J=8.03 Hz, 2 H) 3.71 (s, 3 H) 4.31 (t, J=8.03 Hz, 2 H) 4.57 (s, 2 H) 5.36 (s, 1 H), 6.70 (s, 1 H) 7.57 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([O:37]CC)=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].C1COCC1.[OH-].[Na+]>C(O)C>[F:43][C:2]([F:1])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-n4cc5c(n4)CCCC5)cc3C)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (9.61 g), THF (32 mL) and ethanol (32 mL) was added 1M aqueous sodium hydroxide solution (32.2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, the reaction mixture was neutralized with 1M hydrochloric acid (32.2 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. The crudely purified product obtained here and separately synthesized crudely purified product (1.68 g) were combined, and recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (8.49 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(C2CCCCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CCCCC2)c2ccccc2c1=O

Procedure:
The product of Example 74A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.32 (dd, J=7.9, 1.4 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.97-8.02 (m, 1H), 7.87-7.92 (m, 1H), 7.37-7.47 (m, 4H), 3.68 (s, 2H), 3.22-3.29 (bs, 1H), 1.87-1.92 (m, 2H), 1.78-1.82 (m, 2H), 1.70-1.76 (m, 1H), 1.41-1.54 (m, 4H), 1.18-1.29 (m, 1H); MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11](Cl)=[C:10]([O:15][CH3:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[C:10]([O:15][CH3:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cnn(-c2ccccc2)c(=O)c1Cl
Product: COc1cnn(-c2ccccc2)c(=O)c1-c1ccc(F)cc1
Yield: 96 %

Procedure:
The 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone product was coupled with 4-fluorophenylboronic acid according to the method of Example 6 to provide 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone (yield: 1.1 g; 96%). 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 7.10 (t, J=9 Hz, 2H), 7.45 (m, 3H), 7.60 (m, 4H), 8.06 (s, 1H). MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:27][C:25]1[NH:26][C:22]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[C:23]([CH3:28])[N:24]=1
Reactant: Cc1nc(C)c(I)[nH]1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Temperature: 90 °C
Yield: 76.8 %

Procedure:
Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 3.56 g, 12.9 mmol), 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 3.43 g, 15.4 mmol), K2CO3 (5.33 g, 38.6 mmol) and PdCl2(dppf).CH2Cl2 (1.05 g, 1.29 mmol) were added to a round bottom flask. The flask was purged with argon, then dioxane (70 mL) and water (20 mL) were added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled then additional K2CO3 (1M, 25 mL, 25.0 mmol) and catalyst PdCl2(dppf).CH2Cl2 (1.0 g, 1.2 mmol) were added. The mixture was heated at 90° C. for an additional 10 hours, then cooled to room temperature and filtered through Celite®. The solvent was removed under reduced pressure and the residue was cooled to 0° C. and acidified to pH 3-4 with aqueous HCl (2 M). The acidic mixture was washed with EtOAc (150 mL) and then the aqueous material was adjusted to pH 10-11 with aqueous sodium hydroxide (2 M) and extracted with EtOAc (5×200 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM to 5% MeOH in DCM) to yield the title compound as a thick brown oil (2.42 g, 77%). m/z (ES+) 245(M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.89-7.87 (m, 2H), 7.31 (d with fine str, J=8.6 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=[C:34]([CH3:38])[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=[C:34]([CH3:38])[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=Cc1ccc2c(ccn2Cc2ccccc2)c1)C(=O)O
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CC(=Cc1ccc2c(ccn2Cc2ccccc2)c1)C(=O)Nc1ccccc1OCCCC(=O)O

Procedure:
0.67 g of compound 28 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.69 g of ethyl 4-(2-aminophenoxy)butyrate and 1.10 g of 3-(1-benzylindol-5-yl)methacrylic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.NC1C=C([C:47]2[N:48]=[N:49][N:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[N:51]=2)C=CC=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:47]4[N:48]=[N:49][N:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:57])([CH3:56])[CH3:58])[N:51]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2cccc(N)c2)n1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 2,2-dimethyl-propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (CDCl3) 8.86 (1H, s), 8.18 (1H, m), 7.79 (1H, m), 7.46-7.24 (6H, m), 6.97 (1H, m), 4.73 (1H, d), 4.63 (1H, d), 4.27 (1H, d), 4.22 (1H, d), 2.77 (1H, m), 1.97-1.68 (6H, m), 1.24-1.11 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 55.36; H, 7.36; N, 16.01%; C29H34N8O3.C7H17NO5.2.5H2O requires: C, 55.23; H, 7.21; N, 16.10%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][O:39]1>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][O:39]1)[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2
Reactant: BrCC1CCCO1
Reactant: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2n1CC1CCCO1
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A solution of ethyl 5-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]-1H-indole-2-carboxylate 220 (40.7 mg, 0.100 mmol) in N,N-dimethylformamide (0.9 mL) was added to a stirred mixture of cesium carbonate (325 mg, 1.00 mmol) and 2-(bromomethyl)tetrahydrofuran (19.8 mg, 0.120 mmol) in N,N-dimethylformamide (2.4 mL). The reaction was stirred for 16 h and then the mixture was filtered though a plug (500 mg) of silica gel using ethyl acetate to rinse. The filtrate was concentrated in vacuo and then reverse phase preparative HPLC chromatography gave 19.8 mg of product (retention time=2.4 min.). This material was taken to the next reaction without further purification or analysis.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[N:17]=1)=[O:11].O[Li].O.Cl>CO.O>[N+:24]([C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[S:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of compound 14 (0.391 g, 1.0 mmol) in a mixture of MeOH (10 ml) and water (10 ml) was added LiOH—H2O (0.839 g, 20.0 mmol), and the mixture was stirred at room temperature for 3 hour. Then the reaction mixture was acidified with 1N HCl dropwise to pH 5 and extracted with EtOAc. The organic layer was washed with water and saturated brine and dried over Na2SO4. The solvent was evaporated to give compound 18 (0.322 g, 85.6%). 1H NMR (300 MHz, DMSO-d6) δ12.3 (1H, s), 8.72 (1H, s), 8.33 (1H, d, J=7.6 Hz), 8.16 (1H, dd, J=7.9, 2.8 Hz), 7.91 (1H, s), 7.72 (1H, t, J=8.0 Hz), 2.45 (2H, t, J=6.5 Hz), 2.19 (2H, t, J=5.7 Hz), 1.60 (2H, brs), 1.49 (2H, t, J=6.3 Hz), 1.30-1.18 (4H, m). 13C NMR (75 MHz, DMSO-d6) M75.3, 172.5, 159.2, 149.1, 147.1, 136.6, 132.5, 131.2, 123.0, 120.9, 111.2, 35.7, 34.4, 31.2, 29.1, 25.3, 25.1.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)=[C:10]([Br:24])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CO>[Br:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:25])=[O:3])[CH:9]=[C:10]([Br:24])[C:11]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)Nc1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Temperature: 25 °C

Procedure:
Ethyl-N-[3,5-dibromo-4-(3-bromobenzyloxy)phenyl]oxamate (18 mg) was dissolved in methanol (1 mL) and treated with sodium hydroxide (1N, 6-8 equivalents). After stirring over night at room temperature, the reaction mixture was acidified to pH 5. The mixture was purified on semi-preperative HPLC using the same conditions as described for Examples 27, 28 and 30. This gave 7.8 mg (46%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)phenyl]oxamic acid. MS: m/z 508.0 (M+−1).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:16]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([NH:18][CH2:17][C:14]2[S:13][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:28])=[O:5])(=[O:10])=[O:11])=[CH:16][CH:15]=2)=[O:20])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 1c (400 mg, 0.9 mmole) in CH2Cl2 (10 ml) at 0° C. is added TFA (10 ml) and the reaction is stirred for 1 h at 0° C. and a further hour at room temperature. Evaporating the solvents to dryness gave 1d (300 mg, 86%) as a white solid. 1H NMR (d6-DMSO) δ 9.34 (t, J=5.65 Hz, 1H), 8.20 (t, J=6.03 Hz, 1H), 7.89 (d, J=8.67 Hz, 2H), 7.56 (d, J=8.67 Hz, 2H), 7.43 (d, J=3.77 Hz, 1H), 7.05 (d, J=3.77 Hz, 1H), 4.63 (d, J=5.65 Hz, 2H), 3.59 (d, J=6.03 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>COCCOC>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(F)c(Cl)c1
Yield: 40.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-chloro-4-fluoro-phenylboronic acid (34 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (23 mg, 41%). LC-MS m/e 439.25 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]([CH3:19])=[N:17][N:16]=[N:15]3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].CN1C(=O)CCC1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[CH3:33][O:34][CH2:35][CH:36]([NH:38][C:20]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([N:14]2[C:18]([CH3:19])=[N:17][N:16]=[N:15]2)[CH:11]=1)=[O:22])[CH3:37]
Reactant: COCC(C)N
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (0.3402 mmol, 100 mg), HOBt (0.6804 mmol, 91.9 mg), 2-methoxy-1-methyl-ethylamine (0.4083 mmol, 43 μL) and NMP (1.0206 mmol, 112 μL) in CH2Cl2 (1 mL) and DMF (0.5 mL) was added EDCI (0.6804 mmol, 130.4 mg) at room temperature, and the mixture was stirred at room temperature for 18 hours. The mixture was extracted with ethyl acetate and the organic layer was washed with 2N aqueous NaOH, 1 N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Flash column chromatography, eluting with n-hexane:ethyl acetate (4:1) to give 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (white powder, 90% yield). MS (M+H)=366.