Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21]CC)=[O:20])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([OH:21])=[O:20])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(OCCC2CCN(C(=O)NC(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethyl 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoate (0.67 g, 1.8 mmol) was dissolved in ethanol (25 ml), wereupon NaOH (1 N, 10 ml) was added, and the solution was stirred overnight at 20° C. The reaction mixture was concentrated in vacuo, dissolved in HCl (1 N, 25 ml) and the resulting solution was extracted with EtOAc (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 0.62 of the title compound. LC-MS (m/z): 336 (M+2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])O.[Na+].O.[C:23]([O:27][C@@H:28]([C:33]1[C:34](I)=[C:35]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:41]=3[S:40][C:36]2=[N:37][C:38]=1[CH3:39])[C:29]([O:31][CH3:32])=[O:30])([CH3:26])([CH3:25])[CH3:24]>CN(C)C(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:34]2[C:33]([C@H:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])[C:29]([O:31][CH3:32])=[O:30])=[C:38]([CH3:39])[N:37]=[C:36]3[S:40][C:41]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:35]=23)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(N)cc1)CCCC3
Temperature: 100 °C
Yield: 61.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.63 mmol), sodium hydrogen carbonate (178 mg, 2.1 mmol) and water (200 μL) were added to a stirred solution of (S)-methyl 2-(tert-butoxy)-2-(4-iodo-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (200 mg, 0.42 mmol) in N,N-dimethylacetamide (4 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, then bis(tri-tert-butylphosphine)palladium(0) (22 mg, 42 μmol) was added and the vessel was sealed and heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane (30 mL) and water (30 mL). The layers were separated and the organic layer was dried (MgSO4) and concentrated in vacuo to yield the crude product as a brown gum. The residue was purified by flash column chromatography on silica eluting with ethyl acetate in heptane (25%) to give the title compound (114 mg, 67%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 0.97 (s, 9H), 1.95-1.30 (m, 6H), 2.68 (s, 3H), 2.85-2.77 (m, 2H), 3.65 (s, 3H), 3.80 (brs, 2H), 5.19 (s, 1H), 6.75-6.68 (m, 2H), 6.99 (d, 1H), 7.19 (d, 1H).
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl.CC1(C)[O:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[S:50][CH:51]=[CH:52][CH:53]=2)[C:43](=[O:54])[O:42]1>>[S:50]1[CH:51]=[CH:52][CH:53]=[C:49]1[CH2:48][CH:44]([C:45]([OH:47])=[O:46])[C:43]([OH:54])=[O:42]
Reactant: CC1(C)OC(=O)C(Cc2cccs2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: O=C(O)C(Cc1cccs1)C(=O)O

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 2,2-dimethyl-5-(thiophen-2-ylmethyl)-1,3-dioxane-4,6-dione (Intermediate 9: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.O[C@H]1[C@@H](CNC(OCC2C=CC=CC=2)=O)CN(C(OC(C)(C)C)=O)C1.FC(F)(F)C(O)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl.CO>[OH:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@@H](O)C1
Agent: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (3R,4R)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (for a synthesis see WO2006002047, Preparation 24(c) (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate E2 isomer) (2 g, 5.7 mmol) in DCM (50 ml) was added trifluoracetic acid (50 mL) and stirred for 2 h. The reaction mixture was concentrated and placed under high-vac for 3 h. To the TFA salt dissolved in 100 ml of 10:1 CHCl3:MeOH was added MP-carbonate resin (8 g; 22.8 mmol) and stirred overnight. The reaction mixture was filtered and concentrated to provide the title compound as a pale yellow oil (1.4 g; 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:30][C:31]([CH2:32][NH:33][C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:2])=[O:34])[CH3:29]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 21 from (Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, glycine ethyl ester, TBTU, HOBt and triethylamine in DMF.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.NN.Cl>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
5-Methylisatin (15.0 g) and 60 mL of hydrazine hydrate were heated at 140 to 160° C. for 4 hours. Thin layer chromatography (ethyl acetate:hexane 1:2, silica gel) showed no starting material remaining. The reaction mixture was cooled to room temperature, poured into 300 mL of ice water and acidified to pH 2 with 6N hydrochloric acid. After standing at room temperature for 2 days the precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 6.5 g (47% yield) of 5-methyl-2-oxindole.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 89%), MS (ISP) m/z=413.5 [(M+H)+], mp 183.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:10])[C:4]#[C:5][Si](C)(C)C.[Cl:11][C:12]1[CH:13]=[C:14](C#CC=NO)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:5]#[C:4][C:3]([Cl:10])=[N:2][OH:1])[CH:15]=[CH:14][CH:13]=1
Reactant: ON=CC#Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)C#CC(Cl)=NO
Product: ON=C(Cl)C#Cc1cccc(Cl)c1
Yield: 96.4 %

Procedure:
The title compound was prepared following the method herein described for Compound 3b, using Compound 31e instead of 3-trimethylsilylprop-2-ynal oxime. The pale brown residue was used in the next step without further purification. Yield: 96.4%.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:37])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=4)=[C:17]4[C:22](=[CH:23][C:14]=3[S:13][C:12]=2[CH:36]=1)[CH:21]=[CH:20][CH:19]=[CH:18]4>C1COCC1.CO.O>[C:32]([CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]3[C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]([OH:37])=[O:4])=[CH:36][C:12]=4[S:13][C:14]=3[CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:25][CH:26]=1)([OH:34])=[O:33]
Reactant: COC(=O)COc1ccc(-c2c3ccccc3cc3sc4cc(OCC(=O)OC)ccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2c3ccccc3cc3sc4cc(OCC(=O)O)ccc4c23)cc1
Reaction time: 3 h
Yield: 71 %

Procedure:
1.0 N Aqueous potassium hydroxide (8.0 mL, 8.0 mmol) was added to a stirred suspension of [11 -(4-methoxycarbonylmethoxy-phenyl)-benzo[b]naphtho[2,3-d ]thiophen-3-yloxy]-acetic acid methyl ester (0.750 g, 1.54 mmol) in THF (20 mL) and methanol (13 mL). Dissolution occurred. After 3 h at ambient temperature, the reaction mixture was diluted with water and extracted with ether (100 mL). The aqueous phase was acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide a grey solid. This solid was recrystalized from acetic acid to provide the title compound as a white solid (0.502, 71%): mp 220-222° C.: NMR (DMSO-d6); δ12.8 (broad s, 2 H), 8.54 (s, 1 H), 8.02 (d, J=8 Hz, 1 H), 7.56-7.40 (m, 4 H), 7.31 (d, J=8 Hz, 2 H), 7.23 (d, J=8 Hz, 2 H), 6.73 (dd, J=9, 1 Hz, 1 H), 6.56 (d, J=9 Hz, 1 H), 4.85 (s, 2 H), 4.74 (s, 2 H), 1.97 (s, 2.49 H, 0.83 mol acetic acid); MS (FAB+): 459 (20%, M+H); Anal. Calc. for C26H18O6S.0.83CH3CO2 H: C, 65.46, H, 4.24, N, 0.00. Found: C, 64.47, H, 4.05, N, 0.03.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14].O1CCOCC1>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][C:4]([F:10])=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:14]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(F)c(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution comprising 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5M, 7.5 mmol) was stirred at room temperature for 3 hours to give a fine white precipitate. The mixture was diluted with an equal volume of water to dissolve the white precipitate and give yellow crystals. The crystals were isolated were collected and dried to provide 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yellow needles; m.p. 66° C.; 1H NMR (CDCl3) δ 6.4 (1H, m), δ 6.0 (2H, s).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([OH:22])=O)=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[NH:34][C:33]2=[O:41])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.CCOC(C)=O>[O:41]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:14]([N:9]4[CH2:8][C:7]5[CH:6]=[N:5][C:4]6[NH:3][N:2]=[CH:1][C:13]=6[C:12]=5[CH2:11][CH2:10]4)=[O:15])[CH:25]=[CH:24][CH:23]=3)=[O:22])[CH2:31][CH2:30]2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34]1
Reactant: O=C(O)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a solution of 3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid (0.080 g, 0.24 mmol) and 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.057 g, 0.264 mmol) in dimethylacetamide (5 mL) and Hunig's Base (0.124 mL, 0.71 mmol) was added HBTU (0.107 g, 0.284 mmol). The reaction mixture was vortexed and then shaken at room temperature for 2 hours. On completion of the reaction, 1M NaHCO3 (20 mL) and EtOAc (30 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (2×20 mL) and concentrated under reduced pressure to give a white solid. The white solid was washed with EtOAc and dried under reduced pressure to give the desired product, N-(3-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carbonyl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide (0.035 g, 27%) as a white solid. Alternatively, the crude product can be purified either by flash column chromatography (SiO2) or reverse phase HPLC (using TFA as a modifier). White solid; M.p.=>215° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.59 (s, 1H), 10.88 (s, 1H), 8.9 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.64-7.56 (m, 2H), 7.38-7.26 (m, 2H), 7.08-6.94 (m, 4H), 4.79 (s, 2H), 4.65 (br s, 1H), 4.52-4.4 (m, 1H), 3.84 (t, J=6 Hz, 2H), 3.85-3.7 (m, 1H), 3.4-3.3 (m, 1H), 3.2-3.1 (m, 2H), 3.0-2.85 (m, 1H), 2.4-2.2 (m, 2H), 1.9-1.6 (m, 2H); LCMS [M+H]: 537.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 80 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][N:65]([C:13](=[O:15])[C:12]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([F:20])[C:11]=2[F:10])[CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:54][CH:55]=1)=[O:49]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)ccc(F)c2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,3,6-trifluoro-benzoic acid (45.3 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 45 mg (36.2% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(2,3,6-trifluoro-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 92.11%, 1H NMR: (DMSO) δ 7.97-7.9 (d, 2H), 7.74-7.6 (q, 4H), 7.52-7.44 (t, 2H), 7.44-7.36 (m, 1H), 7.36-7.28 (m, 1H), 7.02-6.92 (m, 1H), 4.4-4.26 (dd, 2H), 3.98-3.82 (m, 3H), 3.78-3.72 (t, 1H), 3.68-3.62 (t, 1H), 3.58-3.52 (m, 1H), 3.48-3.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[CH3:13][C:14]1[C:19]([NH2:20])=[C:18]([CH3:21])[CH:17]=[C:16]([CH3:22])[N:15]=1>C(#N)C>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:20][C:19]2[C:14]([CH3:13])=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH3:21])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cc(C)c(N)c(C)n1
Solvent: CC#N
Product: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00 mmol) in 2.5 ml of acetonitrile was treated with 2,4,6-trimethyl-3-amino-pyridine (273 mg, 2 mmol) stirred at room temperature 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give red residue. The residue was purified through silica gel column chromatography using chloroform to 6% methanol in chloroform as eluent to give the title compound (110 mg, 36%) as an orange oil. 1H NMR (CDCl3) δ 8.78 (brs, 1H), 6.97 (s, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:37]([NH:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH3:39]>>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:43][CH2:42][CH2:41][NH:40][CH2:37][CH2:38][CH3:39])[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCNCCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: CCCNCCNc1nc(-c2cc(C(=O)NC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound is prepared from N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and N-propyl-1,2-ethanediamine following the General Procedure for Sulfoxide/Sulfone Displacement, disclosed above. The concentrated reaction mixture is purified via reversed-phase HPLC. The desired product is obtained as a yellow solid (m.p. 120-134) >95% pure by HPLC (65 mg, 61%): LC-MS m/z 533 (M+H)+, 1.84 min (ret time).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:14]2[CH2:15][CH2:16][N:12]([CH:11]=[N:10][C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)[C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:24][N:23]=1
Reactant: CC(=O)c1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A mixture of 3.00 g of 1-(4-acetylphenyliminomethyl)-2-nitroiminoimidazolidine, 2.12 g of 2-chloro-5-chloromethylpyridine, 3.01 g of potassium carbonate, and 7 ml of DMSO was agitated at 60° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to obtain an oily residue. To the resultant oily residue was added ethyl acetate, followed by separation of the resultant crystals by filtration and drying to give 1.73 g of 1-(2-chloropyridine-5-ylmethyl)-2-nitroimino-3-(4-acetylphenyliminomethyl)imidazolidine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:34])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:34])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(N3CCOCC3)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1C=C(Nc2ccc(N3CCOCC3)cc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A solution of the compound (0.080 g, 0.17 mmol) of Example 42 in N,N-dimethylacetamide (3.0 mL) was stirred at 160° C. for 4 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water, tetrahydrofuran and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 22%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([NH2:18])=[CH:13][C:12]=2[O:19][C@@H:20]([CH3:24])[C:21]#[C:22][CH3:23])[CH2:7][CH2:6][NH:5][CH2:4]1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C>[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:25])[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([NH2:18])=[CH:13][C:12]=3[O:19][C@@H:20]([CH3:24])[C:21]#[C:22][CH3:23])[C@H:3]([O:2][CH3:1])[CH2:4]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(OCCCBr)cc1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A mixture comprising 0.10 g of the cis-N-(3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide, 0.07 g of 3-(4-fluorophenoxy)propyl bromide, 0.20 g of triethylamine and 10 ml of DMF was stirred at 50° C. for 2 hours and cooled. Ethyl acetate was poured into the resulting mixture. The obtained mixture was washed with water thrice, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane) to give 0.13 g of the title compound.