Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:23]3[CH:24]=[N:20][NH:21][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
A solution of 2.39 g of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1.08 g of 4-pyrazolecarboxylic acid in 40 ml of dry dimethylformamide was stirred for 5 minutes, whilst ice-cooling. 1.89 g of diethyl cyanophosphonate and 1.65 ml of triethylamine were added to the mixture, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.65 g (yield 51%) of the title compound as a white powder, melting at 121°-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[O:17]C.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[OH:17]
Reactant: COc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1O

Procedure:
4-Amino-3-methoxy-3′-nitro-biphenyl was then stirred with boron tribromide in dichloromethane to give 4-amino-3′-nitro-biphenyl-3-ol as an orange solid: mp 175-176° C.; 1H-NMR (DMSO-d6) δ9.3 (s, 1H), 8.25 (bs, 1H), 8.05 (d, 1H, J=8.33 Hz), 7.95 (d, 1H, J=8.33 Hz), 7.66 (t, 1H, J=7.5 Hz), 7.06-7.02 (m, 2H), 6.70 (d, 1H, J=8.33 Hz), 4.9 (s, 2H); MS (ES) m/z 229 ([M−H]−, 100%).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:20](OC)=[O:21])=[CH:16][NH:17][C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[CH:16][NH:17][C:18]=3[CH3:19])[C:20](=[O:21])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:24]([N:26]1[CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]1)=[O:25]
Reactant: NN
Reactant: COC(=O)c1c[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Solvent: CC(=O)O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
Hydrazine hydrate (0.023 mL, 0.31 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-5-methyl-1H-pyrrole-3-carboxylate (62) (0.117 g, 0.28 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.022 g, 19.65% yield); 1H NMR (400.132 MHz, DMSO) δ 1.21 (1H, m), 1.34 (1H, m), 1.62 (1H, m), 1.77 (1H, m), 2.25 (3H, s), 2.96 (1H, m), 3.15-3.36 (6H, m), 3.82 (1H, s), 4.05 (2H, s), 7.07-7.15 (2H, m), 7.19 (1H, m), 7.33 (1H, s), 11.22 (1H, s), 12.15 (1H, s); m/z (LC-MS, ESI+), RT=1.39 min (M+H=399.15).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1CO)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C[CH:21]=1.[Br-:26].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:21][Br:26])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccncc1
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2C1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(CBr)ccc2C1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of intermediate 24-95 (2.0 g, 7.6 mmol) and pyridine (1.2 mL, 11 mmol) in DCM (100 mL) is treated in one portion with triphenylphosphine dibromide (4.8 g, 11 mmol) at 0° C. The mixture is allowed to stir for 30 min, then concentrated in vacuo. The resulting crude material is purified by column chromatography on silica gel (using a gradient of 5-60% EtOAc/heptane) to afford the title compound (2.2 g).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:1]=1[CH3:9])[C:7]#[N:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C#N)cc1
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]

Procedure:
399 g (2.56 mol) of p-toluonitrile were added over the course of 90 minutes to 1 l of fuming nitric acid at −10° C. 1 h after the addition, the mixture was poured onto 2.5 l of ice/H2O, whereupon a solid precipitated and was removed on a suction filter funnel and washed to neutral pH with water. The yield of the product was 363 g (88%). 1H-NMR (CDCl3; δ in ppm): 8.3 (d, 1H); 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (s, 3H)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][CH:24]([NH2:28])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=[CH:12][CH:11]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CCN(C(C)C)C(C)C>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][CH:24]([NH:28][C:31](=[O:38])[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine trifluoroacetate salt (0.092 g, 0.21 mmol) in dichloromethane (5 mL) and Hunig's Base (0.20 mL) was added benzoyl chloride (50 μL, 0.43 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue partitioned between EtOAc and 1.0N NaOH. The organic layer was then separated, washed with brine (2×10 mL) and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC to give the desired product, N-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzamide as an off-white solid (0.046 g, 51%). Alternatively the crude product could be used in the next step without any further purification. M.p.>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.50 (d, J=7.6 Hz, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.87 (m, 2H), 7.48 (m, 3H), 7.17 (m, 2H), 6.85 (m, 2H), 5.53 (m, 2H), 4.30 (m, 1H), 3.70 (s, 3H), 3.24-3.13 (m, 3H), 2.95 (m, 1H), 2.16 (m, 1H), 1.99 (m, 1H); LCMS [M+H]: 413.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]2=[O:34])=[CH:22][N:21]=1>>[CH3:32][C:29]1([CH3:33])[NH:28][C:27](=[O:34])[N:26]([C:23]2[CH:24]=[N:25][C:20]([O:13][C:5]3[C:6]4[C:10]5([CH2:9][O:8][C:7]=4[C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]5)=[N:21][CH:22]=2)[C:30]1=[O:31]
Reactant: Cc1ccc(O)c2c1OCC21CC1
Reactant: CC1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncc(N3C(=O)NC(C)(C)C3=O)cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 156, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate (27.6 mg, 0.2 mmol) and then 3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 166, 20 mg, 0.083 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title compound (18 mg) as a light beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:30]([O:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4.4 g 4-amino-piperidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate and 5.3 ml triethylamine in 100 ml dichloromethane were added 1.8 ml butylchloroformate dropwise at 0° C. The suspension was stirred for 12 h, diluted with dichloromethane and washed with 0.1 M HCl and aqueous NaHCO3. The crude product was purified by flash chromatography on silica using ethyl acetate/heptan 1:2 as eluent.
Reaction SMILES: C([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([NH2:19])=[C:13]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:29]>>[ClH:29].[NH2:19][C:12]1[N:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:20])=[O:5])=[CH:14][C:13]=1[C:15]([OH:18])([CH3:16])[CH3:17]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cc(/C=C/C(=O)O)cnc1N
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of (E)-3-[6-Amino-5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-acrylic acid tert-butyl ester (0.13 g, 0.47 mmol) in CH2Cl2 (6 mL) was treated with TFA (6 mL). After stirring at room temperature for 2 h, the solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl in dioxane (3 mL, 4.0 M) and sonicated until the oil was converted to a fine off-white solid. After stirring for 20 min, the suspension was concentrated. The solid was washed with Et2O, isolated by filtration and dried under vacuum. Yield: 0.11 g (92%); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=1.5 Hz, 1H), 8.23 (br, s, 2H), 8.13 (d, J=1.8 Hz, 1H), 7.52 (d, J=16.1 Hz, 1H), 6.65 (d, J=16.1 Hz, 1H), 4.29 (s, 1H), 1.56 (s, 6H); ESI MS m/z 223 [C11H10N2O4+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8][CH2:7][CH2:6]2.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([OH:30])[CH:29]=1)[CH:25]=O.[N+]([CH2:34][CH3:35])([O-])=O.N1CCCCC1>C(O)C.C(O)(C)C.C(O)(C)C>[OH:21][C:22]1[CH:23]=[C:24]([C:25]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]3[C:10]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=4)[CH2:6][CH2:7][N:8]3[C:34]=2[CH3:35])[CH:27]=[C:28]([OH:30])[CH:29]=1
Reactant: CCOC(=O)C=C1NCCc2cc(OC)c(OC)cc21
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CC[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)c1c(-c2cc(O)cc(O)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A mixture of 500 mg (1.8 mmol) of ethyl (6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (Example III.1), 499 mg (3.61 mmol) of 3,5-dihydroxybenzaldehyde, 281 mg (3.61 mmol) of nitroethane and 61.4 mg (0.72 mmol) of piperidine in 10 mL of an ethanol/isopropanol 1:1 mixture was stirred at 80° C. overnight. 40 mL of isopropanol were added, the mixture was cooled to 0° C., and the resulting precipitate was filtered off. The solid was washed with ethanol and dried in vacuo to give the title compound as a white solid which was readily recrystallized from ethyl acetate to furnish white needles.
Reaction SMILES: C(OC(=O)[N:7]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:8][CH2:9][NH:10][CH2:11][C:12]1([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:28]1[CH:27]=[C:26]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CN1CCC(CNCCN(C(=O)OC(C)(C)C)c2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(CNCCNc2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a stirred solution of (3,4-difluoro-phenyl)-(2-{[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester (2.03 g, 3.47 mmol) in CH2Cl2 (25 mL) at 0° C. was added TFA (6 mL, to give a 25% v/v solution). The mixture was stirred and warmed to room temperature for 4 h. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc (50 mL) and washed with 10% aqueous NaHCO3 (2×50 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give N-(3,4-difluoro-phenyl)—N′-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-ethane-1,2-diamine (1.20 g, 96%) as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:14])[CH:7](CCCCO)Cl)[CH2:2][CH2:3][CH3:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]2[C@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:26]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH2:25][NH:24]2)=[CH:19][CH:18]=1.C(O)(=O)[C@H:43]([C:45]1[CH:50]=[CH:49]C=CC=1)[OH:44].COC1C=CC([C@H]2[C@H](C(OCC)=O)[C@@H](C3C=CC4OCOC=4C=3)CN2)=CC=1.C(N(CC)C(C)C)(C)C>O.CS(C)=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]2[C@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:26]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH2:25][N:24]2[CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:49][CH2:50][CH2:45][CH2:43][OH:44])=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](c2ccc3c(c2)OCO3)CN[C@@H]1c1ccc(OC)cc1
Reactant: CCCCNC(=O)C(Cl)CCCCO
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CCOC(=O)[C@@H]1[C@@H](c2ccc3c(c2)OCO3)CN[C@H]1c1ccc(OC)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCCO)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)OCC)[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl (2S,3R,4S)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (prepared by neutralization of the compound of Example 501G), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3×25 mL). The combined ether layers were washed with water (1×25 mL), 4% (v/v) H3PO4 (1×25 mL), saturated aqueous NaHCO3 solution (1×25 mL), and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol to give 3.0 g (79%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:36])=[C:11](C2(C([O-])=O)CN(C(OCC3C=CC=CC=3)=O)C2)[C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:39]([OH:42])(=O)[CH3:40].Cl.[CH3:44][N:45]([CH3:48])[CH:46]=[O:47]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH3:36])=[C:11]2[C:12]([C:15](=[O:18])[C:16]([CH3:17])=[C:1]([CH:2]3[CH2:48][N:45]([C:46]([O:42][CH2:39][C:40]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:47])[CH2:44]3)[O:8]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCC(=O)c1ccc(OCc2ccccc2)c(C)c1C1(C(=O)[O-])CN(C(=O)OCc2ccccc2)C1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C2CN(C(=O)OCc3ccccc3)C2)oc2c(C)c(OCc3ccccc3)ccc2c1=O
Reaction time: 1 h
Yield: 11 %

Procedure:
To a solution of 1-benzyl 3-[3-(benzyloxy)-2-methyl-6-propanoylphenyl]azetidine-1,3-dicarboxylate (2.77 g, 5.68 mmol) obtained in Example 1-1 in dimethylformamide (16 mL), 60% sodium hydride (568 mg, 14.2 mmol) was added in small portions under cooling with ice, and then the mixture was brought back to room temperature and stirred for 1 hour. The reaction solution was cooled with ice. Then, acetic acid (1.30 mL, 22.7 mmol) was added dropwise thereto, subsequently methanol (40 mL) and concentrated hydrochloric acid (4 mL) were added thereto, and the mixture was heated with stirring at a bath temperature of 75° C. for 3 hours. The reaction solution was allowed to cool, and then methanol in the mixture was distilled off under reduced pressure. Water was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=80/20→50/50) to obtain 295 mg of the title compound (yield: 11%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6](OC)=[O:7].O.[NH2:14][NH2:15]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-fluorosalicylate (500 mg, 2.94 mmol, commercially available from e.g. Apollo, Alfa Aesar or ABCR) in methanol (15 ml) stirred under argon at room temp was added neat hydrazine monohydrate (0.722 ml, 14.69 mmol). The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (˜50 ml) and water (˜25 ml). The aqueous phase was extracted with ethyl acetate (2×25 ml) and the combined organic extracts washed with brine (25 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40° C., 24 hr) to afford the crude product as an off-white solid in 385 mg.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH:33]([F:35])[F:34])[CH:23]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:21].[OH-].[Na+].Cl>O1CCCC1.O>[F:35][CH:33]([F:34])[O:32][C:24]1[CH:23]=[C:22]([CH:5]([N:6]2[CH2:14][C:13]3[C:8](=[C:9]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:21])[CH2:4][C:3]([OH:36])=[O:2])[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([F:31])[F:30]
Reactant: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester (2.0 g, 4 mmol) in tetrahydrofurane (20 ml) was added NaOH (0.8 ml of 10 N) at room temperature. The solution was stirred overnight at room temperature. The resulted suspension was filtered to get a white solid. The solid was dissolved in water (30 ml) and added conc. HCl dropwise until the pH is about 4. The resulted mixture was extracted with CH2Cl2 (3×40 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid as a white solid (1.4 g, 70%): mp, 94–96° C.; 1H NMR (CDCl3) δ 0.86–0.93 (m, 2H, cyclopropyl ring CH2), 1.06–1.12 (m, 2H, cyclopropyl ring CH2), 1.65–1.71(m, 1H, cyclopropyl ring CH), 3.13 (dd, J=6, 16 Hz, 1H, CHHCO), 3.32 (dd, J=9, 16 Hz, 1H, CHHCO), 4.15 (d, J=15 Hz, 1H, CHHN), 4.36 (d, J=15 Hz, 1H, CHHN), 5.78–5.84 (m, 1H, CHN), 6.21 (t, JH-F=75 Hz, 1H, OCF2H), 6.24 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=7.5 Hz, 1H, Ar), 7.26–7.28 (m, 3H, Ar), 7.44 (t, J=7.5 Hz, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.42 (s, 1H, NHCO); 13C NMR (CDCl3):8.35, 8.38, 16.14,36.55,47.00, 51.29,99.24, 111.36, 111.42, 115.60, 116.84, 117.02, 118.03, 119.74, 119.79, 121.59, 122.76, 125.46, 133.61, 137.09, 138.03, 141.12, 142.21, 142.38, 142.43, 169.63, 173.03, 173.82. Anal. Calcd. for C23H20F4N2O6: C, 55.65; H, 4.06; N, 5.64. Found: C, 55.33; H, 3.96; N, 5.38.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[O:13][CH3:12])[N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15m mol) and 2-methoxy-4-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol), in a manner analogous to Example 2c. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.73 (m, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.303 (s, 1H), 7.10 (d, J=7.3 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH3:12])[CH:5]=[N:4][CH:3]=1.[C:19](=[O:22])([O-])[O-].[Na+].[Na+].[C:25]([O:28][CH2:29][CH3:30])(=O)C>C(O)CC.C1(C)C=CC=CC=1.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>[CH3:25][O:28][C:29]1[CH:30]=[C:12]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:11][CH3:12])[N:7]=2)[CH:11]=[CH:10][C:9]=1[NH:8][C:19]([NH:4][CH2:3][CH3:2])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCC[C@H](Nc1cncc(Cl)n1)c1cccnc1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCC[C@H](Nc1cncc(-c2ccc(NC(=O)NCC)c(OC)c2)n1)c1cccnc1
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere a mixture of 6-chloro-N-[(1S)-1-pyridin-3-ylbutyl]pyrazin-2-amine (53 g, 0.2 mmol), 4-{[(ethylamino)carbonyl]amino}-3-methoxyphenylboronic acid pinacol diester (69 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene-n-propanol (2.6 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.15 mL, 0.3 mmol). The resulting mixture was stirred vigorously whilst being heated at 100° C. for 22 hours. Once cool ethyl acetate (10 mL) was added and the mixture washed with H2O (6×10 mL) and brine (10 mL) and then dried (Na2SO4). Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane-methanol-aqueous ammonia (93:7:1) as eluent to furnish the product (60 mg).