Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:15])=[CH:12][CH:11]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:15])=[CH:12][CH:11]=1
Reactant: CCOC(CCCNC(=O)c1ccc(COc2cccc(C(N=[N+]=[N-])c3ccccc3)c2)cc1)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CCCNC(=O)c1ccc(COc2cccc(C(N)c3ccccc3)c2)cc1)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 4-((3-(azido(phenyl)methyl)phenoxy)methyl)-N-(4,4-diethoxybutyl)benzamide (0.51 g, 1.03 mmol) in tetrahydrofuran (10 mL), was added polymer supported triphenylphosphine (3 mmol/g, 0.38 g, 1.13 mmol) and water (0.2 mL). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered, the filter-cake washed with dichloromethane and concentrated under reduced pressure to give the title compound (0.41 g, 83%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:15]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(F)c(F)cc2[nH]1
Yield: 53 %

Procedure:
4,5-Difluoro-1,2-phenylenediamine (2.87 g, 19.91 mmol), isopropyl isothiocyanate (2.19 g, 21.65 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (11.38 g, 26.87 mmol) and pyridine (75 mL) were used according to general method I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid; m.p. 188-189° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:14]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(F)(F)F)cc1
Reaction time: 12 h
Yield: 51.3 %

Procedure:
4-(Trifluoromethyl)phenol (1.50 g, 9.25 mmol), allyl bromide (14.55 g, 12.03 mmol), Cs2CO3 (3.62 g, 11.10 mmol), and water (15 drops) were combined in DMF (40 mL) and the mixture stirred for 12 h. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 0.96 g (51%) of the title compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.32 (d, 1H), 5.43 (d, 1H), 6.05 (m, 1H), 6.97 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl>C(OCC)(=O)C>[C:8]([NH:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:21])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89 %

Procedure:
Triethylamine (2.22 g; 22.0 mmol) was added dropwise to a stirred solution of 5-(Boc-amino)-4-oxopentanoic acid (4.62 g; 20.0 mmol) and t-butyl bromoacetate (4.30 g; 22.0 mmol) in ethyl acetate (60 mL) under argon at ambient temperature. The mixture (slurry) was refluxed for 17 h, then cooled to ambient temperature, poured into 0.5 M HCl (100 mL) and shaken thoroughly. The aqueous portion was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with saturated NaHCO3 solution (1×20 mL) and saturated NaCl solution (1×20 mL) then dried (MgSO4), filtered and evaporated. Evaporation resulted in an amber oil that was purified by flash chromatography on a 40×55-mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (600 mL), collecting 5×100 mL fractions. Evaporation of fractions 1 and 2 resulted in 6.15 g (89%) product (yellow oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:15])[CH:8]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)CCc1cccc(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g, 72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution (10 mL) of NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145 mmol) in concentrated HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64](O)=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:65])[CH3:63])=[O:60])([CH3:56])([CH3:57])[CH3:55]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 90%. [α]D =-8.1° (c=0.98, tetrahydrofuran).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25]Br>>[CH3:31][O:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 68 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (279 mg, yield: 68.0%).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)([C:18](=[O:26])[NH:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl.[CH3:44][NH:45][CH3:46].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:20]1([NH:19][C:18]([C:15]2([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32](=[O:33])[N:45]([CH3:46])[CH3:44])=[CH:35][CH:36]=3)[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH2:13][CH2:14]2)=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(C(=O)O)cc2)(C(=O)NC2CCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[1-(2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid (0.201 mmol; 0.12 g) in DMF (1.5 mL) was added N,N-dimethylamine hydrochloride (0.241 mmol; 0.02 g), N,N-diisopropyl-N-ethylamine (0.502 mmol; 0.089 mL) and HBTU (0.241 mmol; 0.091 g), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in a 4N HCl solution in 1,4-dioxane (3 mL) and the resulting solution was stirred for 5 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(4-dimethylcarbamoyl-benzyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][CH:15]([CH3:25])[C:16](=O)[CH:17]([CH3:23])[C:18](OCC)=[O:19]>CO>[F:14][CH:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[C:17]=1[CH3:23])[CH3:25]
Reactant: CCOC(=O)C(C)C(=O)C(C)F
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C(C)F)nc[nH]c1=O
Temperature: 64 °C
Yield: 59.4 %

Procedure:
To a solution in which 2.09 g of ethyl 4-fluoro-2-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 4.59 g of a 28 % sodium methoxide methanol solution and 1.61 g of formamidine acetate, and the mixture was stirred under reflux (64° C.) for 3 hours. Then, the reaction mixture was cooled to 10° C. or lower, 2.5 g of conc. hydrochloric acid was added to the mixture and the resulting mixture was concentrated under reduced pressure. To the concentrated solution was added 50 ml of acetone, and the mixture was stirred at 60° C. for 10 minutes, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the concentrated solution was recrystallized from 10 ml of acetone to obtain 1.10 g of 6-(1-fluoroethyl)-5-methyl-4-pyrimidone (isolated yield: 59.2%).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[F:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.[NH4+].[Cl-]>O1CCCC1>[F:18][C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][CH:20]=1)[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)=[O:5]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2cccc(F)c2)C1
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice cooled solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (D26) (61.8 mg, 0.25 mmol) in dry tetrahydrofuran (2 ml), 3-Fluorophenylmagnesiumbromide (1M in tetrahyfrofuran) (0.506 ml, 0.506 mmol) was added dropwise the under stirring under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h then NH4Cl sat. sol. (10 ml) was added and the mixture was extracted with ethylacetate (3×20 ml). The organic layers were collected, dried with Na2SO4 and filtrated. The solvent was evaporated in vacuo to afford the title compound (D27) (69 mg).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[F:8][C:9]([F:45])([F:44])[C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:36])[CH:16]([NH:27][C:28](=[O:35])C1C=CC=CC=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.CN=C=O>O1CCCC1>[F:43][C:40]([F:42])([F:41])[C:38]1[CH:37]=[C:12]([CH:11]=[C:10]([C:9]([F:8])([F:44])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:36])[CH:16]([NH:27][C:28]([NH:3][CH3:1])=[O:35])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Triethylamine (0.3 ml) was added to a stirred solution of the compound of Example 26 (1 g) in tetrahydrofuran (15 ml), at room temperature under a nitrogen atmosphere. After 5 minutes methyl isocyanate (0.13 ml) was added and the solution was stirred for 3 hours. The solvent was removed and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. After drying over Na2SO4 removal of the solvent gave the title compound (0.9 g) after recrystallisation from ethyl acetate/petroleum ethereum ether, m.p. 213°-215° C. Found: C, 54.62; H, 4.28; N, 11.41. C22H20N4O2F6 requires C, 54.32; H, 4.14; N, 11.51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:25]([O:29][NH2:30])[CH:26]([CH3:28])[CH3:27]>C(O)C>[CH2:25]([O:29][N:30]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CON
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 4.65 g of 2',4'-dichloro-2-(3-pyridyl)acetophenone in 25 ml of ethanol is treated with 2.70 g of anhydrous sodium carbonate and 2.63 g of O-isobutylhydroxylamine hydrochloride and the reaction mixture is then heated to reflux temperature with stirring. After 4 hours, it is poured onto ice and extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2',4'-Dichloro-2-(3-pyridyl)acetophenone O-isobutyloxime is obtained as an E/Z isomer mixture in the form of a brownish oil. In the chromatographic separation on silica gel using n-hexane/ethyl acetate (7:3), the E isomer [1H-NMR (CDCl3, 200 MHz): 2.055 ppm (heptet, HC(CH3)2)] is eluted first and then the Z isomer [1H-NMR (CDCl3, 200 MHz): 1.928 ppm (heptet, HC(CH3)2)].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COCCc1nc(C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.0 min; [M+H]+=435.31.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C:26]3([CH3:36])[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:35][C:26]1([CH3:36])[CH2:27][N:28]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:39]4[CH2:51][CH2:50][N:42]5[C:43]6[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=6[CH:49]=[C:41]5[C:40]4=[O:52])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with (4-(5-(5-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 190i (100 mg, 1 eq., 0.14 mmol), lithium hydroxide(54 mg, 10 eq., 1.4 mmol), i-propanol (3 mL), THF (3 mL) and water (2 mL). The mixture was stirred at 30° C. for 1 h. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 190 as a white solid (43 mg, 46%). MS-ESI: [M+H]+ 665.3. 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.42-7.40 (m, 1H), 7.35 (d, J=5.0 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.58 (s, 1H), 4.98 (brs, 1H), 4.54 (t, J=6.0 Hz, 2H), 4.46-4.38 (m, 4H), 4.25-3.85 (m, 4H), 3.60 (s, 3H), 3.38-3.35 (m, 1H), 3.03-2.54 (m, 4H), 2.47 (t, J=6.0 Hz, 2H), 2.32-2.12 (m, 4H), 1.79-1.67 (m, 4H), 0.97 (s, 6H)
Reaction SMILES: C(OC(=O)C(C)CCCCC[C:11]1([CH3:28])[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12]1)C.[OH-:31].[Na+].[CH3:33][OH:34]>>[CH3:23][CH:22]([CH2:13][CH2:14][CH2:16][CH2:17][CH2:18][N:15]1[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=[C:11]1[CH3:28])[C:33]([OH:34])=[O:31]
Reactant: CCOC(=O)C(C)CCCCCC1(C)N=C(c2ccccc2)C(c2ccccc2)=N1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCC(C)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
(Scheme 3 (P)) A solution of starting material 2-Methyl-7-(2-methyl-4,5-diphenyl-imidazol-2-yl)-heptanoic acid ethyl ester (130 mg, 0.32 mmole) in Methanol (5 ml) and Sodium Hydroxide (64 mg, 1.61 mmole) was let stirred under reflux for 18 hrs. The next day, the reaction was let cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and acidified with Hydrochloric Acid (3N). The aqueous layer was extracted with Dichloromethane (3×10 ml). The organic layers were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo to afford product as a white solid (120 mg, 99%). Mass Spec: 377 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(B(O)O)c1

Procedure:
3-Acrylamido-phenylboronic acid (“3-APB”) was synthesized by reacting 3-amino phenylboronic acid with an excess of acryloyl chloride in an aqueous alkaline solution. The product was extracted in acetone and dried using a rotary evaporator. The structure of 3-APB was confirmed using NMR. The purity was about 90%, TLC showing very little contamination.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27]C)=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[C:25]([OH:27])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Temperature: 70 °C
Yield: 72.1 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (30 mg, 0.061 mmol) in Methanol (0.500 mL), Tetrahydrofuran (THF) (0.500 mL) and Water (0.500 mL) was treated with NaOH (54.7 mg, 1.368 mmol) and heated to 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (21.5 mg, 0.044 mmol, 73% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) ppm 13.33 (s, 1H) 7.58-7.69 (m, 2H) 7.42-7.54 (m, 3H) 7.23-7.38 (m, 4H) 5.89-5.95 (m, 1H) 5.74-5.81 (m, 1H) 5.07-5.15 (m, 1H) 3.50-3.59 (m, 3H) 0.88 (s, 9H); LCMS (m/z) ES+=479 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].CS(C)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide-pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%).