Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=O)(C)(C)C.C(O[K])(C)(C)C.[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(N(C)C)=O>[NH2:8][C:9]1([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10]1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A suspension of 7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (10.0 g, 41.6 mmol) in dimethylacetamide (100 mL) was cooled with ice, and t-butoxy potassium (4.67 g, 1.0 eq.) and benzyl chloride (5.27 mL, 1.1 eq.) were added thereto. The reaction mixture was returned to room temperature, followed by stirring for 2 hours. Thereafter, water was added to the mixture, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield 5-benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane as a crude product. The crude product was dissolved in toluene (100 mL), and methanesulfonic acid (2.97 mL) was added to the solution, followed by stirring under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the cooled mixture for extraction, and the formed organic layer was removed. Aqueous sodium hydroxide solution (5N) was added to the remaining aqueous layer so as to alkalify the layer, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield the title product as a pale brown solid (8.63 g, yield: 90.1%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1.N.C(O)(=[O:37])C>Cl.O.CO>[OH:11][CH2:10][C@@H:9]([NH:8][C:4]1[N:5]=[CH:6][NH:7][C:2](=[O:37])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)nc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 37 %

Procedure:
To a solution of (S)-2-[6-chloro-5-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-pyrimidin-4-ylamino]-3-phenyl-propan-1-ol in 4 N HCl (0.5 mL) and acetic acid (0.5 mL) was added two drops of water. The reaction mixture was heated to 100° C. for 8 h, cooled to room temperature, and neutralized with ammonia in methanol. After concentration, the residue was purified by prep. HPLC to yield the title compound (26 mg, 37% for two steps). 1H NMR (400 MHz, CD3OD) δ 9.41 (1H, narrow t, J=1.5 Hz), 8.06 (1H, narrow dd, J=1.6, 1.9 Hz), 7.93 91H, s), 7.77 (1H, narrow dd, J=1.6, 1.8 Hz), 7.73 (1H, narrow d, J=1.9 Hz), 7.11–7.21 (6H, m), 4.70–4.74 (1H, m), 3.74 (2H, d, J=4.7 Hz), 3.11 (1H, dd, J=6.1, 13.5 Hz), 3.00 (1H, dd, J=7.8, 13.5 Hz), 2.70 (3H, s). LCMS (M+H)+ m/z 442 (t=2.17 min.).
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[CH:1]1([CH:4]([C:15](=[O:17])[CH3:16])[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: N#CCC1CC1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C(C#N)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of argon, was placed a solution of 2-cyclopropylacetonitrile (3.70 mL, 40.1 mmol) in THF (20 mL). The solution was cooled to −78° C., then LDA (2 M in THF, 30 mL, 60 mmol) was added drop-wise and the mixture was stirred for 1 h at −78° C. A solution of acetic anhydride (4.54 mL, 48.0 mmol) in tetrahydrofuran (10 mL) was added drop-wise at −78° C. The mixture was stirred for 1 h at 15° C., then carefully quenched with citric acid (10% aq, 200 mL). The mixture was extracted with diethyl ether (2×70 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound, which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:15](=[O:54])[NH:16][C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:45]4[CH:50]=[CH:49][N:48]=[C:47]([CH:51]5[CH2:53][CH2:52]5)[CH:46]=4)=[N:22][N:23]3[C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:57]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:15](=[O:54])[N:16]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:45]4[CH:50]=[CH:49][N:48]=[C:47]([CH:51]5[CH2:52][CH2:53]5)[CH:46]=4)=[N:22][N:23]3[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:19][CH:18]=2)[CH3:57])([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(C(=O)Nc2ccc3c(-c4ccnc(C5CC5)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3c2)CCN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(=O)N(C)c2ccc3c(-c4ccnc(C5CC5)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3c2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h

Procedure:
3-[3-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-6-ylcarbamoyl]-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3M (216 mg, 0.3 mmol) was dissolved in THF (10 mL) at r.t. To this solution was added NaH (40 mg, 60% suspension in mineral oil, 1 mmol). After stirring for 10 min, CH3I (0.6 mL, 9.6 mmol) was added. The reaction was worked up after 4 hrs by quenching with sat. NH4Cl solution. After extraction with ethyl acetate, the combined organic layers was dried and concentrated in vacuo to obtain 4M. 4M is used as the resulting crude.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:29]([Br:30])=[C:28]([Br:31])[C:27]([Br:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[C:29]([Br:30])=[C:28]([Br:31])[C:27]([Br:32])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Br)c(Br)c(Br)c1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Br)c(Br)c(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,4,5-Tetrabromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,4,5-tetrabromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [C:1]([C:4](=[N:10][O:11][CH:12]1[CH2:14][CH2:13]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[NH2:2].F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(N(CC)CC)C>C(Cl)Cl.C(OC(C)C)(C)C>[CH2:20]([O:3][C:1](=[NH:2])[C:4](=[N:10][O:11][CH:12]1[CH2:13][CH2:14]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:21]
Reactant: CC[O+](CC)CC
Reactant: CCOC(=O)C(=NOC1CC1)C(N)=O
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CCOC(=N)C(=NOC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-carbamoyl-2-(cyclopropyloxyimino)acetate (syn isomer)(8.14 g) and triethyloxonium fluoroborate (11.5 g) in methylene chloride (110 ml) was stirred at ambient temperature for 16 hours. To the mixture was added triethylamine (17 ml) under ice-cooling. The mixture was washed with water, dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was dissolved in diisopropyl ether. The solution was washed with water, dried over sodium sulfate, and concentrated in vacuo to give ethyl 3-ethoxy-3-imino-2-(cyclopropyloxyimino)propionate (syn isomer(9.60 g) as an oil.
Reaction SMILES: CC[C@@H]([C@H](N[C:34]([CH2:36][C@H:37]([OH:70])[C@@H:38]([NH:43]C([C@@H](N(C([C@@H](NC([C@H](O)[C@H](CC)C)=O)CC(C)C)=O)C)CCC(N)=O)=O)[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:35])C(NCC(N([C@@H](C(N1[C@H](C(OC)=O)CCC1)=O)CC1C=CC=CC=1)C)=O)=O)C.CC(C[C@H](NC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(F)C=1)C(N)=[O:77])C.CO.C(O)=O>O>[NH2:43][C@H:38]([C@H:37]([CH2:36][C:34](=[O:35])[OH:77])[OH:70])[CH2:39][CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C[C@H](Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-])C(N)=O
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](O)[C@@H](C)CC)C(=O)NCC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC
Solvent: O=CO
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](N)[C@@H](O)CC(=O)O

Procedure:
Samples of both compounds 1 and 3 (35 μg) were subjected to acid hydrolysis, derivatized with L-FDLA, and analyzed by reversed-phase HPLC [column, Alltima HP C18 HL (4.6×250 mm), 5 μm, Alltech; flow rate, 0.5 mL/min; detection by ESIMS in negative ion mode (MRM scan, 468→408)], using a linear gradient of MeOH in H2O (both containing 0.1% HCOOH, 40-100% MeOH over 50 min). Two peaks, corresponding to (3S,4S)-Sta-L-FDLA and (3R,4S)-Sta-L-FDLA, were observed in both samples in a 1:1 ratio at tR 35.5 and 35.9 min, respectively. The retention times (tR, min) of the authentic standards were as follows: (3S,4S)-Sta-L-FDLA (35.5), (3R,4S)-Sta-L-FDLA (35.9), (3S,4S)-Sta-D-FDLA [corresponding to (3R,4R)-Sta-L-FDLA, 45.7], (3R,4S)-Sta-D-FDLA [corresponding to (3S,4R)-Sta-L-FDLA, 46.4]. The MS parameters used were as follows: DP −60.0, EP −7.0, CE −28.0, CXP −7.4, CUR 40, CAD High, IS −4500, TEM 750, GS1 40, GS2 40.
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C>>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:9])[O:13][C:11](=[O:12])[CH2:10]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Solvent: CC(=O)Cl
Product: CC(C)CC1CC(=O)OC(=O)C1
Yield: 91.4 %

Procedure:
3-Isobutylglutaric acid (156 g) and acetyl chloride (130 g) are combined and placed under reflux for 16 hours. The mixture is distilled at atmospheric pressure until a distillate reflux temperature of 135° C. is reached. The mixture is then cooled and placed under vacuum distillation to give 129 g of 3-isobutylglutaric acid anhydride (boiling point 127°-128° C., 1 mm Hg). 1H-NMR (CDCl3, 200 MHz): δ 0.91 (d, 6H, J=6.6 Hz), 1.20-1.24 (m, 2H), 1.52-1.78 (m, 1H), 2.10-2.45 (m, 3H), 2.79-2.91 (m, 2H). 13C-NMR (CDCl3, 50 MHz): δ 166.53, 43.99, 36.48, 26.79, 25.08, 22.57. IR (neat): 559.3, 592.0, 609.4, 659.5, 837.0, 954.6, 1033.7, 1070.3, 1184.1, 1241.9, 1288.2, 1369.2, 1388.5, 1411.6, 1425.1, 1469.5, 1760.7, 1810.8, 2873.4, 2958.3, 3552.2 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:23](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:24].B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([CH:23]=[CH2:24])[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester (2.0 g), Cs2CO3 (3.4 g), tri(tert.-butyl)phosphine (0.04 eq.), tris(dibenzylidenacetone)dipalladium (0.02 eq.), and 2,4,6-trivinylcyclotriboroxane pyridine complex (2.0 g) in dioxane (30 mL) is degassed and heated at 100° C. for 15 h. The mixture is cooled to rt, and diluted with diethyl ether (200 mL). The mixture is extracted with 1M aq. NaOH (2×50 mL) and brine (50 mL). The org. phase is dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EA-heptane) to give 5,6-divinyl-nicotinic acid tert.-butyl ester (0.89 g) as an oil. LC-MS: tR=1.01 min, [M+1]+=232.04.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCCl
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, thionyl chloride (1.7 mL, 23 mmol) was added to a mixture of 5-{[6-(benzyloxy)-3-nitroquinolin-4-yl]amino}pentan-1-ol (5.95 g, 15.6 mmol) and anhydrous dichloromethane (78 mL). The reaction became homogeneous and was heated at reflux for 1.5 hours, at which time a yellow precipitate formed. The volatiles were removed under reduced pressure, and the residue was partitioned between dilute aqueous sodium carbonate (100 mL) and dichloromethane (150 mL). The aqueous layer was washed with dichloromethane (50 mL), and the combined organic solutions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 6.24 g of 6-benzyloxy-N-(5-chloropentyl)-3-nitroquinolin-4-amine as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[Se:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[Se:11][S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1c2ccccc2[se]n1-c1ccc([N+](=O)[O-])cc1
Reactant: Sc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1[Se]Sc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (15,7 mmol) of 2-(4-nitrophenyl)-1,2-benzisoselenazole-3(2H)-one and 1,75 g (15,9 mmol) thiophenol.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]([CH2:6][SH:7])[CH2:4][OH:5].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[CH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]([CH:3]1[CH2:4][O:5][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([C:10]#[CH:11])=[CH:13][CH:14]=2)[S:7][CH2:6]1)([CH3:9])([CH3:8])[CH3:1]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)C(CO)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#Cc1ccc(C2OCC(C(C)(C)C)CS2)cc1

Procedure:
A solution of 3,3-dimethyl-2-mercaptomethylbutan-1-ol (1.46 g), 4-ethynylbenzaldehyde (1.30 g) (W.B. Austin et al. J. Org. Chem., 1981, 46. 2280) and para-toluenesulphonic acid (10 mg) in benzene (50 ml) was heated to reflux overnight under Dean and Stark conditions. The resulting solution was evaporated under reduced pressure and the residue was purified on silica. Elution with 4:1 hexane: dichloromethane gave 5-t-butyl-2-(4-ethynylphenyl)-1,3-oxathiane as a mixture of isomers.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:36][C:6]1[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:29])[N:11]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1-phenethyl-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.063 mmol), β-alanine (560 mg, 6.3 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (10-85% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: CC(OC([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[NH:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:14]1[CH:13]=[CH:12][C:11]([CH:10]([C@@H:9]([NH2:8])[C:23]([OH:25])=[O:24])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1.[NH:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of Boc-D-3,3-diphenylalanine-L-proline-N-(trans-4-imidazoleallyl) amide (55 mg, 0.1 mmol) in 2:1 methylene chloride/TFA (30 ml) was stirred at room temperature for 4 h. The solvents were removed in vacuo and the residue was purified by preparative HPLC. 1H NMR (CH3OD) d 1.10-1.37 (m, 2 H), 1.70-1.90 (br s, 2 H), 2.70-2.90 (br m, 1 H), 3.50-3.65 (br m, 1 H) 3.95 (br s, 2 H), 4.00-4.10 (br m, 1 H), 4.45 (d, J=11.5 Hz, 1 H), 4.95 (d, J=11.5 Hz, 1 H) 6.30-6.40 (m, 1 H), 6.58 (d, J=16 Hz, 1 H), 7.25-7.70 (m, 11 H), 7.85 (s, 1 H); MS (FAB) 444 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:31](=[O:42])[C@@H:32](OS(C(F)(F)F)(=O)=O)[CH3:33]>CN1CCCC1=O.O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:31](=[O:42])[C@H:32]([N:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:20])[CH:17]([F:19])[F:18])=[CH:6][CH:7]=2)[C:12]1=[O:16])[CH3:33]
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.5 %

Procedure:
1-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (6.58 g) was dissolved in 45 ml of 1-methyl-2-pyrrolidone, to which 0.86 g of 60% sodium hydride in oil was added. The mixture was stirred at room temperature for 15 hours. The ice-cooled mixture was added dropwise under nitrogen atmosphere over the period of 15 minutes to a solu- tion of 7.98 g of (2S)-2',4'-difluoro-2-trifluoromethanesulfonyloxypropiophenone in 150 ml of tetrahydrofuran which was cooled to -40° C. After the reaction temperature was raised to -20° C. over the period of 20 minutes, the reaction solution was stirred for 10 minutes. The reaction solution was diluted with 16 ml of acetic acid and 200 ml of ethyl acetate, washed with water (100 ml×2), 0.5N-hydrochloric acid (100 ml×2) and 100 ml of a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium chloride. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 1 kg, eluent; hexane:ethyl acetate:acetic acid=2:1:0.08) and recrystallized from 20 ml of diisopropyl ether to give 4 g of 1-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](O)=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH2:25])=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2oc(C(=O)O)c(OCc3ccccc3)c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2oc(C(N)=O)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A suspension of 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxylic acid (157 mg, 0.50 mmol) and 1,1'-carbonyldiimidazole (96 mg, 0.59 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1.5 hours. The reaction solution is cooled to room temperature, aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxamide in 47% yield; mp=70°-72° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:29])[CH3:28])[C:6]2[O:10][C:9]([C:11]3[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:26]=1)#[N:2].C(N(CC)CC)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1>CO>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:21]2[CH2:22][CH2:23][CH:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:27]([CH3:29])[CH3:28])=[CH:4][C:3]([C:1]#[N:2])=[CH:26][C:7]=5[N:8]=4)=[CH:25][CH:24]=3)[CH2:20]2)=[CH:40][CH:39]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNC4)cc3)oc12
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(Cc5ccc(Br)cc5)C4)cc3)oc12
Temperature: 150 °C
Yield: 67.2 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(pyrrolidin-3-ylmethyl)benzamide (78 mg) in 2 ml of methanol was added 558 μl of triethylamine and 50 mg of 1-bromo-4-(bromomethyl)benzene. The solution was heated to 150° C. via microwave for 30 min, cooled, and purified via column chromatography on a Biotage Horizon 40M column eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 6 column volumes at 100% ethyl acetate to provide the title compound (75 mg, 68%). Mass spectrum (ESI) 559.0 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H), 7.96 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.52 (s, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 3.52 (m, 3H), 2.98 (td, J=9.1, 2.9, 1H), 2.76 (d, J=9.6 Hz, 1H), 2.58 (m, 2H), 2.32 (m, 1H), 2.14 (m, 1H), 1.68 (m, 1H), 1.48 (d, J=6.8 Hz, 6H).