Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[O:32][CH:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[NH2:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH:37]1([NH:36][C:33]([C:30]2[CH:29]=[C:28]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)[O:32][CH:31]=2)=[O:35])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1
Reactant: NC1CCc2ccccc21
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)co1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NC3CCc4ccccc43)co1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-furoic acid (0.100 g, 0.209 mmol) was dissolved in CH2Cl2. 1-aminoindane (0.037 mL, 0.313 mmol) was added followed by EDCI (0. 048 g, 0.251 mmol) and HOBt (0.034 g, 0.251 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 4:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.062 g, 0.105 mmol, 50% yield): 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 8.11 (d, J=9.5 Hz, 1H), 7.32 (m, 1H), 7.25–7.15 (m, 5H), 6.96 (t, J=8.6 Hz, 2H), 6.32 (m, 1H), 5.69 (dd, J=15.5, 7.7 Hz, 1H), 4.65 (dd, J=10.4, 6.2 Hz, 1H), 4.37 (dd, J=14.2, 7.0), 3.73–3.63 (m, 1H), 3.44–3.38 (m, 1H), 3.17–3.01 (m, 5H), 2.92–2.83 (m, 1H), 2.68–2.60 (m, 1H), 2.48–2.40 (m,1H), 2.37–2.25 (m, 2H), 1.96–1.86 (m, 1H), 1.38–1.30 (m, 1H), 1.27 (t, J=7.1 Hz, 3H); ESMS m/z 594 (M+H)+, 592 (M−H)+; Anal. Calcd. For C35H32FN3O5.½H2O: C, 69.75; H, 5.52; N, 6.97; found: C, 69.58; H, 5.43; N, 7.05.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH2:12]O.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 70 °C

Procedure:
To a solution of cis-4-hydroxycyclohexanecarboxylic acid (4.00 g, 27.7 mmol) in EtOH (20 mL, 300 mmol) was added sulfuric acid (0.1 mL, 2 mmol), and the solution was heated to 70° C. for 2 h. After cooling to rt, Na2CO3 solution was added slowly to bring to pH=8. The organic solvent was removed in vacuo, and the material was extracted with EtOAc and washed with water. The organic layer was concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.17 (t, J=7.1 Hz, 3H), 1.42-1.56 (m, 6H), 1.73-1.86 (m, 2H), 2.26-2.39 (m, 1H), 3.60-3.71 (m, 1H), 4.04 (q, J=7.1 Hz, 2H), 4.38 (d, J=3.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:24](N(OC)C)=[O:25]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:24]([C:23]2[CH:22]=[C:21]([Cl:20])[CH:32]=[C:31]([Cl:33])[CH:30]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C#Cc1ccc(Br)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of the intermediate from step A (2.1 g, 11.6 mmol) in anhydrous THF (80 mL) cooled to −78° C. under a N2 atmosphere was added LHMDS (1.0 M solution in THF, 11.6 mL). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methyl benzamide (2.71 g, 11.6 mmol) in THF (20 mL) was added to the reaction. The reaction was slowly warmed to 0° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a bright yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.07 (d, J=1.8 Hz, 2H), 7.66 (t, J=1.9 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.6 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl.C([N:5]1[CH2:10][CH2:9][C:8]2(N3CCCC3)[O:11][N:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]2[CH:6]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C>>[C:24]1([CH:6]2[C:7]3[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][O:11][C:8]=3[CH2:9][CH2:10][NH:5]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)C(c3ccccc3)C12
Agent: Cl
Product: CCOC(=O)c1noc2c1C(c1ccccc1)NCC2
Temperature: 130 °C
Yield: 50 %

Procedure:
Conc. HCl (12 ml) was added to ethyl 5-acetyl-4-phenyl-7a-(pyrrolidin-1-yl)-3a,4,5,6,7,7a-hexahydroisoxazolo[4,5-c]pyridine-3-carboxylate (2 g) at 0° C., and the reaction mixture was heated to 130° C. for 5 h. The hydrochloric acid was evaporated under reduced pressure and the residue was dissolved in dichloromethane and basified with sodium carbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude compound which was used in the next step without further purification. Yield: 50%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])/[CH:6]=[CH:7]/[N+:8]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15])[CH2:6][CH2:7][NH2:8]
Reactant: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCN)cc(OC)c1OC

Procedure:
A solution of trans-3,4,5-trimethoxy-β-nitrostyrene (4.78 g, 20 mmol) in tetrahydrofuran (20 ml) was dropwise added to a suspension of lithium aluminum hydride (1.52 g) in tetrahydrofuran (20 ml) under ice-cooling and stirring. After stirring at room temperature for 3 hours, water (1.5 ml), 15% aqueous sodium hydroxide solution (1.5 ml), and water (4.5 ml) were sequentially added dropwise to the reaction mixture under ice-cooling and stirring. A small amount of potassium carbonate was added and stirred for a few minutes. Inorganic salts were filtered out and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2N hydrochloric acid and washed with dichloromethane. The aqueous layer was made basic with sodium hydroxide and the released oil material was extracted with dichloromethane. After washed with water, the extract was dried over potassium carbonate and the solvent was distilled out under reduced pressure to yield a crude oil of 3,4,5-trimethoxyphenethyl-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.[CH2:19]([NH:26][C:27](=[O:31])[C:28](O)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27](=[O:31])[C:28]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)C(=O)NCc1ccccc1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Yield: 90 %

Procedure:
The coupling of 4-(4-amino-2-fluorophenoxy)picolinamide to 2-(benzylamino)-2-oxoacetic acid was carried out in a manner similar to that which is described in Step C of Example 1 to give the title compound (90%) as a tan solid. 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 9.63 (t, 1H, J=6 Hz), 8.56 (d, 1H, J=5.6 Hz), 8.15 (br s, 1H), 8.02 (dd, 1H, J=12.8, 2 Hz), 7.82 (d, 1H, J=9.2 Hz), 7.75 (br s, 1H), 7.47 (t, 1H, J=8.8 Hz), 7.39-7.23 (m, 7H), 4.41 (d, 2H, J=6.4 Hz); MS(ESI+) m/z 409.22 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>[Pd].CO>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[CH3:1])=[CH:13][CH:12]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.8 %

Procedure:
A 250-mL flask was purged with nitrogen and charged with 151a (1.5 g, 4.6 mmol), 10% palladium on carbon (50% wet, 200 mg), and methanol (70 mL). It was evacuated, charged with hydrogen gas, and stirred at room temperature for 10 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 151b (1.1 g, 81%) as brown solid. MS-ESI: [M+H]+ 293
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:17])([N+:14]([O-])=O)[CH3:13].O.NN>[Ni+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:17])([CH3:13])[NH2:14]
Reactant: CC(C)(Cc1c[nH]c2ccc(Br)cc12)[N+](=O)[O-]
Agent: [Ni+2]
Agent: NN
Solvent: O
Product: CC(C)(N)Cc1c[nH]c2ccc(Br)cc12

Procedure:
5-Bromo-3-(2-methyl-2-nitropropyl)indole, 5.9 g. was reduced with Raney nichel and hydrazine hydrate according to the method of Procedure 67D. The crude product was purified by dissolving in 200 ml. of dilute hydrochloric acid, treatment with activated charcoal, filtering, and basification of the filtrate with 10% aqueous sodium hydroxide. Yield 3.8 g. of white powder, m.p. 150°-155° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].CCCCCC.CCOC(C)=O>CC#N>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH3:18]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
4-Phenylimidazole (1.884 g, 13 mmol) and KF/Al2O3 (0.113 g, 10 mol %) were dissolved in 30 mL of CH3CN, added with ethyl acrylate (1.301 g, 13 mmol) and stirred at room temperature. Initiation and termination of the reaction were confirmed by TLC (hexane:EtOAc=1:1). Upon completion of the reaction, KF/Al2O3 was filtrated under reduced pressure, water was added to the reaction mixture, and the aqueous phase was extracted with methylene chloride. The organic layer was dried with MgSO4, filtrated and then concentrated under reduced pressure to obtain the target compound.
Reaction SMILES: [Na+].[I-].C1(OC)C=CC=CC=1.C[Si](Cl)(C)C.[NH2:16][C:17]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][C:20]([CH2:21][C@H:22]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][C:18]=1[Cl:52]>C(#N)C>[NH2:16][C:17]1[C:47]([C:48]([F:50])([F:49])[F:51])=[CH:46][C:20]([CH2:21][C@H:22]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)[CH2:35][CH2:34]2)=[O:32])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[Cl:52]
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: COc1ccccc1
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
5.75 g (38.4 mmol) of NaI, 3 mL of anisol and 4.92 mL (38.4 mmol) of trimethylsilylchloride were added to the solution of 7.0 g (12.8 mmol) of tert. butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo-butanoate in 375 mL acetonitrile. The reaction mixture was stirred for 90 min at 40° C., combined with another 5.75 g (38.4 mmol) of NaI and 4.92 mL (38.4 mmol) of trimethylsilylchloride and stirred for a further 2 h at 40° C. The mixture was evaporated down i. vac. and further reacted as the crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[CH3:23])=[O:13].[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[C:15]=1[CH3:23])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(S(=O)(=O)c3ccccc3)c3ccccc23)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (0.15 g, 0.485 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.023 g, 0.582 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then benzenesulfonyl chloride (0.086 g, 0.485 mmol) was added to the mixture. The reaction was warmed to room temperature slowly and stirred for another 30 minutes. It was quenched by adding water (10 mL) slowly, and extracted by ethyl acetate (10 mL×3). The organic layer was dried and purified by Prep-HPLC to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(phenylsulfonyl)-1H-indole-3-carboxamide (9 mg 4.1% yield). LRMS (M+H+) m/z: calcd 449.14. found 450. HPLC Purity (215 nm): 97%. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=6.8 Hz, 1H), 7.81 (dd, J=8.4 Hz, J=0.8 Hz, 2H), 7.62-7.7.54 (m, 2H), 7.46-7.40 (m, 2H), 7.35-7.28 (m, 2H), 6.80 (t, J=6 Hz, 1H), 6.51 (s, 1H), 4.58 (d, J=4.6 Hz, 2H), 2.80 (s, 3H), 2.64 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[C:9]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=O)[NH:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[CH3:1][C@H:2]1[N:7]2[C:8]3[C:9]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[CH2:5][NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3cccc(OC(F)(F)F)c3n21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1CNCc2cc3cccc(OC(F)(F)F)c3n21
Yield: 50.7 %

Procedure:
A solution of (R)-4-methyl-6-trifluoromethoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (800 mg, 2.81 mmol) in tetrahydrofuran (4 ml.) was added to a suspension of lithium aluminium hydride (420 mg, 11.1 mmol) in tetrahydrofuran (4 mL) and the resulting mixture was heated to reflux for 90 min. After cooling the reaction mixture was slowly added to a cooled saturated aqueous sodium potassium tartrate solution. The resulting suspension was filtered on dicalite and the organics extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate to ethyl acetate/methanol gradient) to yield the title compound as a light yellow solid (385 mg, 51%). Mp: 58-60° C.; EI-MS: m/e=270.1 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]=1[Cl:18])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CO>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)CC1=C(Cl)CCc2ccc(OC)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
A mixture of [2-Chloro-7-methoxy-3,4-dihydro-2H-naphthalen-(1E/Z)-ylidene]-acetic acid ethyl ester and of (2-Chloro-7-methoxy-3,4-dihydro-naphthalen-1-yl)-acetic acid ethyl ester (26.82 g, 95.52 mmol) is dissolved under an atmosphere of argon in dioxane (280 ml). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ, 47.70 g, 210.16 mmol) is added, and the reaction mixture is refluxed for 2 h. TLC analysis indicates complete conversion of starting material. After cooling to RT, addition of MeOH renders the reaction mixture homogeneous. Silica gel (250 g) is added, and the solvent is removed by rotary evaporation. Purification by FCC (hexane/EtOAc 9:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.24 (t, J=8.8 Hz, 3H), 3.95 (s, 3H), 4.19 (q, J=8.8 Hz, 2H), 4.28 (s, 2H), 7.16-7.19 (m, 1H), 7.22 (s, 1H), 7.38 (d, J=10 Hz, 1H), 7.68 (d, J=10 Hz, 1H), 7.75 (d, J=10 Hz, 1H). ES+−MS: 279.2, 281.2 [M+H]+.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[S:19])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[C:21]([N:20]1[C:2](=[O:8])[C:3](=[O:5])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]#[N:10])=[CH:16][CH:15]=2)[C:18]1=[S:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)NC(=S)Nc1ccc(C#N)cc1
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(=O)N(c2ccc(C#N)cc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Ethyl chlorooxoacetate (1.15 mL, 10.29 mmol) was added dropwise to a stirring solution of 1-(4-cyanophenyl)-3-(tert-butyl)-thiourea (0.802 g, 3.25 mmol) in dichloromethane (40 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to afford a residue which was purified by flash column chromatography (50% ethyl acetate/hexanes) to afford 0.48 g (32%) of 4-[3-(tert-butyl)-4,5-dioxo-2-thioxo-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 200.4–201.3° C.; 1H NMR (DMSO-d6): δ 8.00 (d, 2H), 7.52 (d, 2H), 2.20 (q, 2H), 1.79 (s, 9H); IR (KBr) 3500, 2220, 1760 cm−1; MS (m/z) 287 (M+).
Reaction SMILES: [CH2:1]1[N:12](CC(O)=O)[CH2:11][CH2:10][N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH2:8][CH2:7][N:6]([CH2:21][C:22]([OH:24])=[O:23])[CH2:5][CH2:4][N:3]([CH2:25][C:26]([OH:28])=[O:27])[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:11]1[NH:12][CH2:1][CH2:2][N:3]([CH2:25][C:26]([OH:28])=[O:27])[CH2:4][CH2:5][N:6]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:8][N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10]1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.0 equivalents of DOTA mono acid was dissolved in NMP and treated with 8.0 equivalents of HBTU and 16.0 equivalents of DIEA. This solution was stirred for 15 min at RT and then transferred to the amine on the resin and the coupling was continued for 24 h at RT. The resin was then drained, washed and then the peptide was cleaved and purified.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1)#[N:2].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:14]([C:10]1[N:11]=[CH:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:15]
Reactant: CCOC(=O)c1ncoc1-c1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ocnc2C=O)cc1
Yield: 85.7 %

Procedure:
To a solution of ethyl 5-(4-cyanophenyl)oxazole-4-carboxylate (500 mg, 2.06 mmol, 1.00 equiv) in anhydrous THF (10 mL) maintained under nitrogen at −78° C. was added dropwise a 25% solution of DIBAL (2.5 mL) in toluene with stirring. The resulting solution was stirred at −40° C. for 3 h and then quenched by the addition of 10 mL of water. The mixture was extracted with 2×10 mL of ethyl acetate. The combined organic layers was washed with 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to yield 350 mg (86%) of 4-(4-formyloxazol-5-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 10.16 (s, 1H), 8.42 (d, J=8.4 Hz, 2H), 8.04 (s, 1H), 7.83 (d, J=8.4 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:34]([CH2:35][CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:33])[N:9]=[CH:10][C:5]=2[C:4](=[O:37])[C:3]=1[C:38](=[O:40])[NH2:39].[ClH:41].CCOCC>CO.O1CCOCC1>[ClH:41].[NH2:1][C:2]1[N:34]([CH2:35][CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:33])[N:9]=[CH:10][C:5]=2[C:4](=[O:37])[C:3]=1[C:38]([NH2:39])=[O:40]
Reactant: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3c(F)cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3OC)nc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3c(F)cc(N4CCNCC4)cc3OC)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.14 g (0.23 mmol) of the product prepared in step 10.4 is suspended in 4 mL of methanol, and 1.15 mL (4.61 mmol) of a 4N solution of hydrogen chloride in dioxane are added. The mixture is stirred at room temperature overnight, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 0.10 g of the expected product is obtained in the form of a grey powder, which is used as obtained in the following step. Yield (dihydrochloride)=95%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>C(C(C)=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Reactant: BrCC1CO1
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1

Procedure:
Methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g) anhydrous potassium carbonate (0.39 g), epibromohydrin (0.78 g) and dry methyl ethyl ketone (20 ml) were stirred and heated under reflux for 16 hours. The cooled reaction mixture was filtered, the filtrate evaporated under reduced pressure and the residual oil purified by elution from a silica column with chloroform/methanol. Methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate was obtained as an oil which solidified, (0.52 g, 57%, m.p. 84°-87°C; M+, 321, M 321).