Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]([O:35]CC5C=CC=CC=5)=[O:34])[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.[OH-].[Na+]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]([OH:35])=[O:34])[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)OCc4ccccc4)ccc2O3)nc2c(OC)cccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)O)ccc2O3)nc2c(OC)cccc12

Procedure:
1′-[(4,8-Dimethoxyquinolin-2-yl)carbonyl]-6-(benzyloxycarbonyl)-spiro[chroman-2,4′-piperidin]-4-one (680 mg) was dissolved in 10 mL of THF and 10 mL of methanol, and vigorously stirred on 10% Pd/C under a hydrogen atmosphere for 21 hours. 1.2 mL of 1N NaOH was added to it, and filtered through Celite, and the filtrate was concentrated. 20 mL of water was added to the residue, and extracted with ethyl acetate (3×20 mL). The aqueous layer was acidified with 1N HCl, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated to obtain the intended compound. 1H-NMR (DMSO-d6) δ: 8.30 (1H, d, J=2.2 Hz), 8.11(1H, dd, J=8.7, 2.2 Hz), 7.68 (1H, dd, J=8.3, 1.2 Hz), 7.52 (1H, dd, J=8.3, 7.7 Hz), 7.23 (1H, dd, J=1.2, 7.7 Hz), 7.21 (1H, d, J=8.7 Hz), 7.18 (1H, s), 4.35-4.28 (1H, m), 4.07 (3H, s), 3.94 (3H, s), 3.69-3.62 (1H, m), 3.50-3.22 (2H, m), 2.97 (2H, s), 2.12-2.04 (1H, m), 1.96-1.80 (3H, m). MS [M+H]+=477.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[C:39]1[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Yield: 66.4 %

Procedure:
A mixture of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (100 mg, 0.21 mmol) and 4-iodo-1-methyl-1H-pyridin-2-one (40 mg, 0.17 mmol), Pd(PPh3)2Cl2 (20 mg), and aq. Cs2CO3 solution (2.0 mL, 2M) in 1,4-dioxane (5 mL) was stirred at reflux for 2 h. The organic phase was separated and concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (55 mg, 66%). LC-MS Method 2 tR=1.096 min, m/z=488.3; 1H NMR (CDCl3): δ 1.27 (s, 3H), 1.40 (s, 3H), 1.48 (d, 3H), 2.06 (s, 2H), 2.23 (m, 1H), 2.41 (m, 2H), 2.90 (m, 1H), 3.51 (s, 3H), 5.60 (m, 1H), 6.27 (m, 1H), 6.65 (d, 1H), 6.89 (d, 2H), 6.99 (t, 2H), 7.26 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O.[CH:20]1([C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH2:22][CH2:21]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:20]1([C:23]([C:24]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:25]=2[CH3:26])=[O:28])[CH2:22][CH2:21]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a stirred solution of 60 mg (0.22 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 10) in 2 ml acetic acid was added 37 mg (0.29 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 17 mg (22%) cyclopropyl-[4-(4-methoxy-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 364 (M+H+, 100).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:30]([C:29]1[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:35][CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1cccnc1Cl
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=3)=[CH:17][C:6]([C:7]([NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[O:8])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-trifluoromethylphenylboronic acid (commercially available) as starting materials. MS (ISP): 435.4 (M+H)+.
Reaction SMILES: [OH-].[K+].NC1[S:5][C:6]2[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.C(O)(=O)C>O>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=1[SH:5]
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1S
Yield: 63.2 %

Procedure:
Potassium hydroxide (39.6 g) was dissolved at 0° C. in water (80 mL), and 2-amino-6-bromobenzothiazole (6.87 g) was added to the solution, followed by refluxing under heating overnight. The mixture was returned to room temperature, and then neutralized with 5N aqueous acetic acid solution. The precipitated crystals were recovered through filtration, washed with water, and dried under reduced pressure with heating, followed by recrystallization from isopropyl ether, to thereby yield the title compound (3.87 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCCN1
Reactant: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCC1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (50 mg, 0.23 mmol) was dissolved in 1,1′-carbonyldiimidazole (56 mg, 0.34 mmol) in THF (1.5 mL), followed by stirring for 1 hour. Then, pyrrolidone (0.03 mL, 0.34 mmol) was added thereto, followed by stirring for 6 hours. Upon completion of the reaction, the experiment was completely terminated by addition of distilled water. EtOAc was added to the reaction product to separate an oil layer and a water layer from each other, followed by washing with a saturated solution of NaCl and then drying over anhydrous Na2SO4. The solvent was distilled under reduced pressure. The residue was purified by column chromatography using hexane/ethyl acetate (1/1) to give a target compound (36.1 mg, yield: 58.1%).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]=1[CH3:8].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:7]([CH3:8])=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=3)[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5]2)=[CH:11][CH:12]=1)#[N:17]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5b, 2.55 g, 7.34 mmol), 3-(trifluoromethyl)phenylboronic acid (1.65 g, 8.69 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (340 mg, 0.47 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in dioxane (20.0 mL) is heated for 72 h at 80° C. The reaction mixture is filtered over silica and the filtrate is concentrated under reduced pressure and purified by preparative reversed phase HPLC (first purification: Sunfire, gradient of methanol in water, 0.1% TFA; second purification: Xbridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 514 mg (17% of theory); ESI mass spectrum: [M+H]+=413; r.t. HPLC: 1.37 min (Z002_005).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:15](O)(=[O:20])[CH2:16][C:17](O)=[O:18].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([N:5]1[C:15](=[O:20])[CH2:16][C:17](=[O:18])[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCNC(=O)NC1CCCCC1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution was prepared by adding 15.87 gm (0.080 mole) of 1-(1-butyl)-3-cyclohexylurea and 8.33 gm (0.080 mole) of malonic acid to 35 mL of reagent grade acetic acid in a 250 mL 3-neck, round bottom flask equipped with a thermometer, pressure equalizing dropping funnel capped by a drying tube, nitrogen inlet and magnetic stirrer. The stirred mixture was gradually heated to 60° C. in a silicone oil bath. All of the solid dissolved before the temperature reached 60° C. A total of 32 mL of acetic anhydride was added to the dropping funnel and slowly (over a period of about 45 min.) dropped into the stirred reaction flask. The temperature was gradually increased to approximately 90° C. for 7 hours, then allowed to cool to room temperature and stand overnight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:6](=O)C(OCC)=O)[CH3:2].C=O.C(=O)([O-])[O-].[K+].[K+]>O.CCCCCC>[CH2:1]([O:3][C:4](=[O:27])[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(OCc2ccccc2)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: C=C(C(=O)OCC)c1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To 2-(3-Benzyloxy-phenyl)-3-oxo-succinic acid diethyl ester (1.28 g, 3.6 mmol) in water (5 ml) was added formaldehyde (600 uL, 37% solution, 6.6 mmol) and potassium carbonate (0.37 g, 2.7 mmol). The reaction was stirred vigorously overnight The organic products were extracted into diethyl ether which was dried (MgSO4), and evaporated. The residue was purified by column chromatography over silica gel (silica gel 60, EM Science) using 5% ethyl acetate:hexane as eluent to afford 0.99 g (55% yield) of the title compound as an oil. 1H NMR (CDCl3, 400 MHz) δ 7.48-7.27 (m, 6H), 7.10-6.97 (m, 3H), 6.35 (s, 1H), 5.90 (s, 1H), 5.10 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:16])=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCOc1ccc(CC(=O)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70° C. for 21/2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4](Br)[CH:3]=1.[CH3:19][S-:20].[Na+].C[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:20][CH3:19])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: C[S-]
Reactant: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Br)cc(SC)c2)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
1,3-Dibromo-5-(4-methoxy-benzyloxy)-benzene (4.0 g) was dissolved in DMF (60 mL), followed by addition of sodium thiomethoxide (829 mg). The resulting mixture was stirred at 75° C. for 5 h. Over the period of 4 hours additional amount of sodium methoxide (total 754 mg) was added in two equal portions. When the starting material was completely consumed the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.1 g, 60% yield). HRMS calcd for C15H15O2BrS [M+H]+ 339.0049, observed 339.0047.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37](O)=[O:38].ON1C(=O)CCC1=O.CN1CCOCC1>CN(C)C=O>[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37]([NH:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:38]
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Yield: 65.5 %

Procedure:
A mixture of p-toluenesulfonic acid salt of Phe-Gly-OBzl (3.06 g), Boc-Gly-OH (1.10 g), N-hydroxysuccinimide (941 mg), N-methylmorpholine (0.725 ml), and N,N-dimethylformamide (40 ml) was cooled to 4° C., and added with N,N′-dicyclohexylcarboduimide (1.56 g). The mixture was allowed to react overnight at room temperature with stirring, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=98:2 solution) to give Boc-Gly-Phe-Gly-OBzl (1.93 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:47]Br)[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1.O>CN(C)C=O>[CH2:12]([O:11][C:3]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH:16]([CH2:17][C:18]2[CH:19]=[C:20]3[C:26]4([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:46])[CH3:44])=[O:39])[C:21]3=[CH:22][CH:23]=2)[CH2:47]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC(CBr)CBr)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(Cc2ccc3c(c2)C2(CCN(C(=O)OC(C)(C)C)C2)CN3C(=O)OCC[Si](C)(C)C)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
Sodium hydride (10.0 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1 mL). Thereafter, diethyl malonate (13.0 μL, 0.086 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at 100° C. for 30 minutes. Thereafter, an N,N-dimethylformamide (0.5 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-bromo-2-(bromomethyl)propyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (51.1 mg, 0.080 mmol) was further added to the reaction solution under cooling on ice, and the thus obtained mixture was then stirred at 100° C. for 2 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-((3,3-bis(ethoxycarbonyl)cyclobutyl)methyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (20.8 mg, 41%) in the form of a colorless oily product.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]([NH2:17])[C:14]([Cl:18])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>C(Cl)Cl>[NH2:17][C:15]1[CH:16]=[C:7]([OH:6])[C:8](=[CH:13][C:14]=1[Cl:18])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 0 °C

Procedure:
A 0.1 molar solution of boron tribromide in methylene chloride (600 ml) is added to stirred suspension of methyl 2-methoxy-4-amino-5-chlorobenzoate (37 g) in methylene chloride (500 ml). After stirring for 20 hrs, the mixture is poured into ice water, and the precipitate remaining in the reaction container is washed in the ice water mixture with a solution of 5.5N NaOH (600 mls). The aqueous layer is separated and acidified to pH3. The resulting precipitate is filtered, washed with water and dried affording 4-amino-5-chlorosalicylic acid which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18]Br.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:3]1[CH:4]=[CH:5][N:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:1]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1nccnc1O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-3-pyrazinecarboxylate (103 mg, 0.67 mmol) (obtained from Fulcrum Scientific Ltd.) was placed in a 25-mL RBF and placed under a nitrogen atmosphere. DMF (3 mL) was added, followed by NaH (33 mg, 0.83 mmol) and the reaction was allowed to stir for twenty minutes at room temperature. 3,4-Difluorobenzyl bromide (0.094 mL, 0.735 mmol) was added, and the reaction was allowed to stir at room temperature overnight, and the reaction was found to be complete by LC-MS. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated and the organic layer was washed with brine and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography using 10-100% EtOAc in n-heptane to afford methyl 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylate as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 8.08 (d, 1H), 7.49 (t, 1H), 7.44 (d, 1H), 7.42 (t, 1H), 7.23 (m, 1H), 5.09 (s, 2H), 3.80 (s, 3H). LRMS (ESI) calc'd for (C13H11F2N2O3) [M+H]+, 281.1; found 281.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 94.6 %

Procedure:
A solution of 4-(2-keto-1-benzimidazolinyl)piperidine (10.0 g, 46 mmol), ethyl bromoacetate (5.1 mL, 46 mmol) and N,N-diisopropylethylamine (8.8 mL, 50.6 mmol) in acetonitrile (200 mL) was heated at reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was suspended in water (˜200 mL). The suspension was made basic with the addition of a saturated aqueous solution of sodium bicarbonate. The resultant solid was collected by filtration, washed with water and dried in vacuo to give the ethyl (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetate as a colorless solid (13.2 g, 94%). MS m/z 304 (MH+); NMR(CDCl3): δ 1.32 (t, 3 H), 1.84 (br d, 2 H), 2.40-2.66 (m, 4 H), 3.13 (br d, 2 H), 3.31 (s, 2 H), 4.23 (q, 2 H), 4.45-4.49 (m, 1 H), 6.99-7.10 (m, 2 H), 7.12-7.19 (m, 1 H), 7.27-7.34 (m, 1 H) and 10.54 (br s, 1 H).