Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(C(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)cc1C(F)(F)F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-fluoro-3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(C#N)cc1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-cyanophenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (58% yield); 1H-NMR (d6-DMSO) 1.09 (9H, s), 3.68 (2H, t), 4.13 (2H, t), 6.68 (1H, s), 7.37 (2H, d), 7.74 (2H, d); 13C-NMR (CDCl3) 27.7, 41.5, 66.8, 125.1, 131.8, 134.4; MS ES(+) 287.0 (M++1). IR λmax=2227, 1699 cm−1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccccc2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 898 %

Procedure:
To a solution of 40 mg (0.098 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro- 2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 0.5 mL of dry dimethylformamide at room temperature under nitrogen was added 5 mg of 60% sodium hydride oil dispersion (3 mg NaH, 0.13 mmol, 1.3 eq). After 5 minutes, 0.013 mL of benzyl bromide (19 mg, 0.11 mmol, 1.1 eq) was added and the mixture stirred for 1 hour at room temperature, then added to 20 mL of ethyl acetate and washed with water (2×) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to afford 44 mg (0.88 mmol, 90%) of product. 1H NMR (200 MHz, CDCl3): 1.37 (s,3 H), 1.38 (s,3 H), 1.73 (m,1 H), 2.3-2.6 (m,5 H), 4.48 (m,1 H), 4.80 (d,15 Hz,1 H), 5.07 (br s,2 H), 5.23 (d,15 Hz,1 H), 5.62 (br s,1 H), 6.67 (br d,7 Hz,1H), 7.1-7.4 (m,14 H). FAB-MS: calculated for C30H33N3O4 499; found 500 (M+H,100%).
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.BrC1C=C[C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.[Cu](C#N)C#N.N>O>[NH2:13][C:12]1[CH:3]=[CH:4][C:5]([C:6]#[N:2])=[CH:10][C:11]=1[CH3:16]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(Br)ccc1N
Agent: N#C[Cu]C#N
Agent: N
Solvent: O
Product: Cc1cc(C#N)ccc1N
Temperature: 200 °C

Procedure:
To an N-methylpyrrolidone (0.5 L) solution of 4-bromo-2-methylaniline (40 g) was added copper cyanide (38.5 g). The stirred mixture was heated at 200° C. for 2.5 hrs. The mixture was cooled to room temperature then water (1.9 L) and ammonia (0.5 L, 32%) were added. The mixture was extracted with ethyl acetate (2×1.2 L) and the combined organic phases then washed with a mixture of water/ammonia (0.5 L+0.2 L, 32%) and dried over Na2SO4. The solvent was evaporated under vacuum to give the title compound as a brown solid (27.5 g). This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:15])[C:6](=[O:14])[NH:7]2.S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[N+:21]([C:9]1[C:10]([F:13])=[C:11]([F:12])[C:2]([F:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:14])[C:5](=[O:15])[NH:4]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(F)c(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 5,6,7-trifluoro-1,4-dihydro-2,3-quinoxalinedione (93 mg, 0.43 mmol) is added concentrated sulfuric acid (0.5 mL). While the flask is in an ice bath, KNO3 is slowly added, giving a brown mixture, which is stirred overnight. The reaction mixture, now dark red, is then added to ice water (5 mL), instantly giving an orange precipitate, which is collected by centrifugation. The powder is crystallized from EtOH (5 mL) and dried in vacuo to yield 24 mg (20%) of pale orange microcrystals. 1H NMR (DMSO-d6), 11.9 (br s, 1H), 12.6 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].[Cl:8]/[C:9](=[CH:14]\N(C)C)/[CH:10]=[N+](C)C.CCN1C2C(S/C/1=C\C#C/C(/C)=C\C1SC3C(=CC=CC=3)[N+]=1CC)=CC=CC=2.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C.O>[Cl:8][C:9]1[CH:10]=[N:4][C:3]([C:2]([F:7])([F:6])[F:1])=[N:5][CH:14]=1
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Reactant: N=C(N)C(F)(F)F
Agent: CCN1/C(=C/C#C/C(C)=C\c2sc3ccccc3[n+]2CC)Sc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A solution of 4.70 g (85% purity, 35.65 mmol) of trifluoroacetamidine and 10.93 g (35.65 mmol) of ((Z)-2-chloro-3-dimethylamino-allylidene)-dimethyl-ammonium; hexafluoro phosphate [Davies, Ian W.; Marcoux, Jean-Francois; Wu, Jimmy; Palucki, Michael; Corley, Edward G.; Robbins, Michael A.; Tsou, Nancy, Ball, Richard G.; Dormer, Peter; Larsen, Robert D.; Reider, Paul J, Journal of Organic Chemistry 2000, 65(15), 4571-4574] in 70 ml acetonitrile was treated with 4.33 ml (42.78 mol) of triethylamine and stirred for 4 h at room temperature. The reaction was poured into 250 ml of water and extracted with ether (three times). The organic phases were washed with water (two times), dried (Na2SO4) and carefully evaporated to give 3.66 g of the title compound as an orange volatile liquid.
Reaction SMILES: OC1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1.ClCCl.ClC(Cl)(O[C:48](=[O:54])[O:49][C:50](Cl)(Cl)Cl)Cl.[CH3:56][NH2:57]>O1CCCC1.N1C=CC=CC=1>[CH3:56][NH:57][C:48](=[O:54])[O:49][CH:50]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([NH2:12])[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1
Reactant: CN
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)OC1CC2=NN(Cc3ncc(C)c(OC)c3C)N=C3C(N)=NSCC1=C23
Yield: 22 %

Procedure:
A mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg), dehydrated dichloromethane (1 mL), pyridine (11 μL) and triphosgene (8.7 mg) was stirred under cooling in an ice bath for three hours. A 2 N solution of methylamine in tetrahydrofuran (0.6 mL) was added to the reaction mixture. Then, the ice bath was removed and the mixture was stirred for 17 hours. After confirming that the raw material disappeared, the reaction mixture was diluted with chloroform and washed with water. The aqueous layer was extracted with chloroform, and then the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (6.6 mg, 22%) as a solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][CH:4]=1.[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].O>O1CCCC1>[CH2:19]([N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4]1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1cc(C(=O)OCC)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1 g of ethyl 3-trifluoromethyl-1H-pyrrole-4-carboxylate of Step A was introduced into 10 ml of tetrahydrofuran, followed, at 0° C. by 240 mg of sodium hydride at 50% in vaseline oil in small portions. After stirring for 30 minutes at 20° C. and cooling to 0° C., a solution of 0.45 ml of propargyl bromide in 1 ml of tetrahydrofuran was added with stirring for 30 minutes at 0° C., then for 1 hour at 20° C., followed by cooling again to 0° C. A little sodium hydride was added then 0.45 ml of propargyl bromide in solution in 1 ml of tetrahydrofuran with stirring at 0° C. The mixture was poured into water and extracted with methylene chloride. The extracts were concentrated to dryness by distilling under reduced pressure and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 0.950 g of ethyl 1-(2-propynyl)-3-trifluoromethyl-1H-pyrrole-4-carboxylate melting at 58° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1C(=O)CCC1.O>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:18])[CH:12]=1)[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)[nH]1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)cc(Br)c2)cc(=O)[nH]1
Temperature: 140 °C

Procedure:
4-Hydroxy-6-methylpyridin-2(1H)-one (3-2; 10.0 g; 80 mmol) and 1-bromo-3-chloro-5-fluorobenzene (16.74 g; 80 mmol) and potassium carbonate (33.1 g; 240 mmol) were suspended in NMP (200 mL) and then heated at 140° C. for 5 days. The reaction mixture was cooled to room temperature, diluted with water (900 mL) and the pH of the solution was adjusted to 5 with concentrated HCl. The solid was filtered off, washed with water and suctioned dry. The crude material was adsorbed onto silica and purified in 2 runs on a silica column eluted with DCM:MeOH to give the title product (9-1) as a yellow solid. Rf=0.6(DCM:MeOH, 95:5). LCMS: M+=315. 1H NMR (DMSO-d6): δ 11.48 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.36 (s,1H), 5.86 (s, 1H), 5.36 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[C:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)ccc1OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl bromoacetate (0.88 mL) was added to a mixture of 4-bromo-2-isopropylphenol (1.0 g) and potassium carbonate (0.96 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford benzyl (4-bromo-2-isopropylphenoxy)acetate (1.70 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.C(=O)=O>CO>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)cccn2n1
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Agent: O=C=O
Solvent: CO
Product: Cc1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)cccn2n1
Yield: 46 %

Procedure:
Trans-tert-butyl{[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methyl}carbamate (4.80 g) was fractionated by supercritical fluid chromatography (instrument: Multigram II (manufactured by Mettler-Toledo), column: CHIRALPAK AD-HKG-010 (20 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol 100%, mixing ratio: A/B=900/100, flow rate: 50 mL/min, column temperature: 35° C., sample concentration: 10 mg/mL (methanol), injection volume: 2.5 mL). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned supercritical fluid chromatography conditions was concentrated to give the title compound (2.21 g, 99.9% ee). Enantiomer excess (ee) was measured using supercritical fluid chromatography (column: CHIRALPAK AD-H LA-145 (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol 100%, mixing ratio: A/B=900/100, flow rate: 2.35 mL/min, column temperature: 35° C., sample concentration: 0.5 mg/mL (methanol), injection volume: 5 μL).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.C(O[C:13](=[S:15])[S-:14])C.[K+].CN1C(=O)CCC1.O>C(O)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]2[S:14][C:13]([SH:15])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: Sc1nc2ccc(Cl)nc2s1
Temperature: 170 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask was added 2,6-dichloropyridin-3-amine (21.4 g, 131 mmol), potassium ethoxy(thioxo)methanethiolate (42.1 g, 262 mmol), and anhydrous NMP (300 mL). The reaction mixture was then heated to 170° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and acidified to pH 5 with glacial acetic acid, which led to a precipitate which was collected by filtration. This precipitate was then suspended in ethyl acetate and washed with water, then brine, dried over sodium sulfate, filtered, and concentrated to give 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-thiol (1-1) as a tan solid. HRMS (M+H)+: observed=202.9502, calculated=202.9499.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[N:17]([CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][N:20]=1>CCN(C(C)C)C(C)C.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>[C:15]1([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:16]2[N:17]([CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: Clc1nccn2cccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3cccc23)C1
Temperature: 110 °C
Yield: 59.2 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.91 g, 4.9 mmol, 1 eq) in 2.6 mL of DIPEA was added 1-chloropyrrolo[1,2-a]pyrazine (0.75 g, 4.9 mmol, 1 eq) and 1 drop of 1-butyl-3-methylimidazolium tetrafluorborate. After heating for 3 h at 110° C., the mixture was concentrated and purified by silica gel flash chromatography (100% EtOAc) to afford (S)-tert-butyl N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate (0.88 g, 2.9 mmol, 59%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[NH2:22][C:23](=[N:35]O)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([Cl:34])[CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>CC#N.C1COCC1>[Cl:34][C:26]1[CH:25]=[C:24]([C:23]2[N:22]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=3)[O:14][N:35]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(NS(C)(=O)=O)c3)n2)cc1Cl
Temperature: 25 °C

Procedure:
In a 2-5 microwave vial, placed in a dry-ice acetone bath, was added THF (2 mL) and CH3CN (2 mL) to a mixture of Intermediate 25 (156.19 mg; 0.50 mmol), Intermediate 34 (114.32 mg; 0.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115.02 mg; 0.60 mmol). The reaction mixture was allowed to warm to RT for half a hour then DIEA (204.07 μL; 1.20 mmol) was added and the mixture was heated by microwave irradiation at 150° C. for 30 min. The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method B): 503.4 (M−H)−, 505.3 (M+H)+. HPLC (Method A) Rt 5.64 min (Purity: 100.0%).
Reaction SMILES: [OH-].[K+].C(S([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][N:9]=1)(=O)=O)C.[O:19]1CCCC1.Cl>O>[CH2:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:19])=[N:9][CH:10]=1)(=[O:16])=[O:15])[CH3:18]
Reactant: C1CCOC1
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)c1ccc(O)nc1

Procedure:
A solution of potassium hydroxide (11.0 g, 196 mmol, 50%) in water was added to a suspension of 2,5-bis-ethanesulfonyl-pyridine (12.0 g, 45.6 mmol, prepared using the method described above) in water and tetrahydrofuran (100 mL, 1:1, v/v). After being heated at reflux for 1 hour, the mixture was acidified with 0.5 N hydrochloric acid to pH 3 and concentrated in vacuo to remove the solvent. The residue was triturated with boiling ethanol (150 mL) and filtered. The filtrates were concentrated in vacuo to afford the crude product which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C=O)C>[CH2:10]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 15.6 %

Procedure:
Step 1 A solution of imidazolidin-2-one (500 mg, 5.81 mmol) in DMF (30 mL) was stirred on ice and treated with sodium hydride, 60% oil dispersion (264 mg, 6.60 mmol). The mixture was stirred at rt for 50 min, then was treated with (bromomethyl)benzene (0.691 mL, 5.81 mmol). After 2 h, the mixture was poured into water and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography (eluting with EtOAc) to provide 1-benzylimidazolidin-2-one as a white solid (160 mg, 16%). 1H NMR (400 MHz, chloroform-d) δ 7.22-7.39 (5H, m), 4.53 (1H, br. s.), 4.37 (2H, s), 3.25-3.46 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>C(N(CC)CC)C.C1COCC1>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([O:26][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Oc3ccc(C(=O)O)cc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (332 mg, 1.0 mmol), 4-hydroxybenzoic acid (138 mg, 1.0 mmol), and 2 drops of triethylamine in 3.0 mL of THF was stirred at room temperature overnight and concentrated. The residue was then purified on a silica gel column eluting with ethyl acetate-hexane (1:3) and 0.5% of acetic acid in ethyl acetate-dichloromethane (2:1) to afford 150 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-carboxy-phenyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, vbr, 1H, COOH), 12.60 (s, br, 1H, NH-1′), 8.12 (d, J=7.39 Hz, 2H), 7.86–7.88 (m, 1H), 7.64 (s, vbr, 1H), 7.51 (s, 1H, H-vinyl), 7.43 (d, J=7.39 Hz, 2H), 7.21–7.23 (m, 2H), 6.09 (s, br, 1H, H-4′), 2.40 (s, 3H, CH3), and 2.38 (s, 3H, CH3).