Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[N+:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C-:25].C(O)(=O)C>CN(C=O)C>[O:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]3[CH:25]=[N:24][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:8]3[N:17]=2)[CH2:19][CH2:20]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Clc1nc(N2CCOCC2)c2ccccc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of potassium t-butoxide (2.1 g, 19 mmol) in dry DMF (15 ml) was added during 15 min. at 0°-5° C. to a stirred solution of 2-chloro-4-morpholino-quinazoline (3.0 g, 12 mmol) and ethyl isocyanoacetate (2.1 g, 19 mmol) in dry DMF (40 ml). The mixture was stirred at room temperature for 2 hours. Then glacial acetic acid (2 ml) was added and the solvent was evaporated in vacuo. The residue was triturated with a mixture of water (50 ml) and ethyl acetate (10 ml) giving the title compound as a pale yellow precipitate. The product was collected by filtration and rinsed with water and ethyl acetate and dried. Yield 3.6 g (91%), m.p. approx. 165° C., resolidifies to give crystals melting at 195.5°-196.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([CH3:20])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:20])([CH3:21])[CH:5]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:8][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a stirred solution in DMF (50 mL) of 2,2-dimethyl-3,3-bis(4-hydroxy-phenyl)propionic acid methyl ester (1.1 g, 3.7 mmol), prepared as in step 1, was added Cs2CO3 (2.5 g, 7.7 mmol) and the mixture stirred 0.5 hours at room temperature. 2-Chloromethyquinoline (1.37g, 7.7 mmol) was added as a solid in small portions. The reaction mixture was stirred overnight at room temperature. The mixture was poured into 300 mnL of water and extracted with ether (2×200 mL). Brine was added to the aqueous layer and it was extracted twice with ether. The combined ether extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a light yellow oil. Chromatography on silica gel (40% ethyl acetate/hexanes) gave 1.68 g (78%) of 2,2-dimethyl-3,3-bis(4-(2-quinolyl-methoxy)phenyl)propionic acid methyl ester as a white foam.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-])=O)=[C:9]([CH:12]=1)[CH:10]=O.O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:17]([CH3:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ccc2nc1C
Temperature: 70 °C
Yield: 54.5 %

Procedure:
A 2.2 M solution of zinc(II)chloride (9.88 mL, 21.74 mmol) in diethyl ether was added to tin(II)chloride (4.12 g, 21.74 mmol) and activated 4 Å molecular sieve pellets (1.00 g) in ethanol (10 mL) under argon. Then, 5-bromo-2-nitro-benzaldehyde (1.00 g, 4.35 mmol) and ethyl 3-oxobutanoate (594.0 mg, 4.56 mmol) in ethanol (12 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 697.9 mg (55%) of ethyl 6-bromo-2-methyl-3-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.84 (s, 1H), 8.42 (d, J=2 Hz, 1H), 7.95 (dd, J=9, 2 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 4.38 (q, J=7 Hz, 2H), 2.84 (s, 3H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]([C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:28])=[C:12]([Cl:31])[CH:11]=1)C)=O)(C)(C)C.[ClH:32]>ClCCl>[ClH:31].[ClH:32].[Cl:31][C:12]1[CH:11]=[C:10]([NH:8][CH3:6])[CH:30]=[CH:29][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1[CH3:28]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OC(C)(C)C)cc3Cl)c2n1
Agent: Cl
Solvent: ClCCl
Product: CNc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (234 mg) was dissolved in dichloromethane (3 ml) and 4N hydrochloric acid (ethyl acetate solution) (2 ml) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added. The precipitated crystals were collected by filtration and concentrated under reduced pressure with heating to give methyl 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate dihydrochloride (215 mg) as pale-red crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:7].CN(C)[CH:21]=[O:22]>>[CH2:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:21]=[O:22])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:7]
Reactant: CCc1cc2cc(OC)ccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1[nH]c2ccc(OC)cc2c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dimethylformamide (1 mL) was cooled to 0° C. Phosphorus oxychloride (0.25 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-ethyl-5-methoxyindole (226 mg, 1.7 mmol) in dimethylformamide (2 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (25 mL) and stirred for 10 minutes. The precipitate was collected, washed with cold water and dried overnight in a vacuum desiccator set at 40° C. equipped to an oil driven vacuum pump yielding a white solid (213 mg, 62%): TLC Rf 0.55 in 4:1 ethyl acetate/hexanes. Melting point=211-212° C. 1H NMR (600 MHz, CDCl3) δ 11.84 (s, 1H), 10.04 (s, 1H), 7.58 (d, 1H, J=2.4 Hz), 7.30-7.28 (d, 1H, J=9 Hz), 6.81-6.79 (dd, 1H, J1=9 Hz, J2=2.4 Hz), 3.77 (s, 3H), 3.08-3.04 (q, 2H, J=7.8 Hz), 1.33-1.28 (t, 3H, J=7.8 Hz). 13C NMR (150 MHz, CDCl3) δ 183.86, 155.48, 153.86, 130.09, 126.33, 112.68, 112.20, 111.95, 102.41, 55.25, 18.92, 14.54. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.92; H, 6.97; N, 6.34.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:7]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[CH:7]2
Reactant: OC1c2cccc(F)c2CCC1CCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc2c1CCC(CCN1CCCC1)=C2
Yield: 67.6 %

Procedure:
To a solution of 5-fluoro-1,2,3,4-tetrahydro-2-[2-(1-pyrrolidinyl)ethyl]-1-naphthalenol (20.0 g) in toluene (250 ml) was added p-toluenesulfonic acid. monohydrate (16.2 g), and the mixture was refluxed overnight. After cooling, the reaction solution was washed successively with 1N aqueous sodium hydroxide solution, water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=5:1), and the fractions containing the desired compound were combined, concentrated under reduced pressure to give the desired compound (12.6 g), as an oily product.
Reaction SMILES: CC1(C)CC(=O)CC(=O)C1.C(OC([O:17][C@@H:18]([C@H:20]1[C:35](=[O:36])[N:22]2[C:23]([C:29]([O:31]CC=C)=[O:30])=[C:24]([CH2:27]O)[C@H:25]([CH3:26])[C@H:21]12)[CH3:19])=O)C=C.C(OC([NH:43][CH2:44][CH2:45][NH:46][C:47]([C:49]1[N:50]2[CH:56]=[N:55][CH:54]=[C:51]2[S:52][CH:53]=1)=[O:48])=O)C=C>>[OH:17][C@@H:18]([C@H:20]1[C:35](=[O:36])[N:22]2[C:23]([C:29]([O-:31])=[O:30])=[C:24]([CH2:27][N:55]3[CH:54]=[C:51]4[S:52][CH:53]=[C:49]([C:47](=[O:48])[NH:46][CH2:45][CH2:44][NH2:43])[N+:50]4=[CH:56]3)[C@H:25]([CH3:26])[C@H:21]12)[CH3:19]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: C=CCOC(=O)NCCNC(=O)c1csc2cncn12
Agent: CC1(C)CC(=O)CC(=O)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(=O)NCCN)[n+]4c3)[C@H](C)[C@H]12
Yield: 5.4 %

Procedure:
The same procedure as in Example 1 was repeated except that dimedone was used as a trapping agent in a deprotective reaction, and 145 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 340 mg of 3-[N-(2-allyloxycarbonylaminoethyl)carbamoyl]imidazo[5,1-b]thiazole were used, thereby obtaining 9.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17]C(N)=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.IC.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O.[CH3:42][N:43]([CH:45]=O)[CH3:44]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:14]=[CH:15][C:45]([N:43]([CH3:42])[CH3:44])=[CH:17][CH:18]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
(2R)-2-[N-(4-Chlorobenzene-sulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (Example 48, 0.10 g, 0.22 mmol) was dissolved in DMF (5 mL). To this solution was added iodomethane (62 mg, 0.44 mmol), and cesium carbonate (220 mg, 0.66 mmol). The reaction was then stirred at 40° C. for 18 h. The reaction was poured into EtOAc and water. The organic was collected, dried over MgSO4, and concentrated to an oily residue. The residue was further purified (Biotage 40S, loaded in CH2Cl2, eluted in 25% EtOAc/hexanes) to yield a yellow powder (15 mg, 16%). MS (ESI), (M+H)+ 438.1; 1H NMR (DMSO-d6, 500 MHz) δ 7.74 (dd, 2H, J=1.9, 6.7), 7.54 (dd, 2H, J=1.9, 6.8), 7.43 (s, 1H), 7.16 (d, 2H, J=8.6), 7.01 (s, 1H), 6.61 (d, 2H, J=8.8), 4.59 (q, 2H, J=16, 25), 4.34 (dd, 1H, J=5.0, 9.3), 2.85 (s, 6H), 1.27-1.47 (m, 3H), 0.80 (d, 3H, J=5.9), 0.52 (d, 3H, J=6.1).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31](COC)[N:32]=4)[CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)(=O)C>CO>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][N:31]=[CH:30]4)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(C[C@@H](OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)C(=O)OC)cc(C)c2n1
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reaction time: 1 h

Procedure:
To a solution of (R)-1-methoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (1.20 g, 2.25 mmol) in methanol (20 mL) was added acetyl chloride (0.40 mL, 5.62 mmol). The reaction was warmed to reflux and held there for 1 h. The reaction was concentrated by rotary evaporation under high vacuum and purified by column chromatography (5% methanol/dichloromethane) to give 1.09 g (99%) as a white foam solid. Mass spec.: 489.29 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[Br-].[Cl:27]C1C=C(C=CC=1Cl)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[C:22]([Cl:27])[CH:23]=1
Reactant: O=C(CCCCCCCCCc1ccc(Cl)cc1)C1=C(O)COC1=O
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl
Agent: [Br-]
Product: O=C(CCCCCCCCCc1ccc(Cl)c(Cl)c1)C1=C(O)COC1=O

Procedure:
Using the procedure of Example 41 for the synthesis of 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodecyl]-2(5H)-furanone above, but using 3,4-dichlorobenzyltriphenylphosphonium bromide in place of 4-chlorobenzyltriphenylphosphonium chloride, there is obtained the title compound.
Reaction SMILES: [CH2:1]([C:3]1([C:13](=[O:15])[CH3:14])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH3:12])[CH3:2].[Br:16]Br>C(Cl)Cl>[Br:16][CH2:14][C:13]([C:3]1([CH2:1][CH3:2])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH3:12])=[O:15]
Reactant: BrBr
Reactant: CCC1(C(C)=O)Cc2ccccc2C1C
Solvent: ClCCl
Product: CCC1(C(=O)CBr)Cc2ccccc2C1C
Yield: 65 %

Procedure:
2-Bromo-1-(2,3-dihydro-2-ethyl-1-methyl-1H-inden-2-yl)ethanone is prepared from 1-(2,3-dihydro-2-ethyl-1-methyl-1H-inden-2-yl)ethanone (21.6 g) by treatment with bromine (17.6 g) in methylene chloride (300 ml). Yield 65%.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:37]1([NH:36][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=2)[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1cn(C)c2ccccc12
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)Nc1ccccc1)Cc1cn(C)c2ccccc12
Reaction time: 16 h

Procedure:
A mixture consisting of 43.2 mg of 4-[N'-methyl-N'-(3,5-bis-trifluoromethyl-benzoyl)-amino]-5-(1-methyl-indol-3-yl)-pentanoic acid, 8.9 mg of aniline, 36.65 mg of propanephosphonic acid anhydride, 60 μl of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 16 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.547 (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-])=O>COCCOC.C(Cl)(Cl)Cl.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1])[C:6]([OH:8])=[O:7]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1N
Reaction time: 15 h
Yield: 113.6 %

Procedure:
To a solution of 4-amino-3,5-dinitrobenzoic acid (10 g, 44 mmol, 1 equiv) in DME (100 ml) and CHCl3 (10 ml) under nitrogen was added 10% palladium on charcoal (50% wet, 1 g, 5% w/w) and the resulting suspension was stirred under an atmosphere of nitrogen (35 psi) for 15 h. 10% Palladium on charcoal (50% wet, 1 g, 5% w/w) was added and the resulting suspension was stirred under an atmosphere of hydrogen (35 psi) for another 15 h. The catalyst was filtered off through a pad of celite and the solution was concentrated in vacuo to give 3,4-diamino-5-nitrobenzoic acid (D244) (9.85 g, 113%) as a red solid which was used in the next step without further purification. [M−H]−=196.1, RT=2.15 min
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>CCOCC.O>[ClH:29].[CH3:21][O:20][CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:15]=1
Reactant: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (12 mg, 0.03 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 301 (M−Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH:20]=2)[CH:7]=1)=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]([CH3:46])[C@@H:34]([CH3:45])[C:35]([NH:37][C@@H:38]([CH:42]([CH3:44])[CH3:43])[C:39](O)=[O:40])=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:39](=[O:40])[C@@H:38]([NH:37][C:35](=[O:36])[C@@H:34]([N:33]([C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:32])[CH3:46])[CH3:45])[CH:42]([CH3:44])[CH3:43])[CH:20]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)c1cn(-c2cncc([C@@H]3CCCN3)c2)c2ccccc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cncc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of 1-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl ester (I-2A-2b: 0.25 g, 0.75 mmol) and (S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoic acid (0.26 g, 0.86 mmol, prepared from (S)-2-amino-3-methyl-butyric acid methyl ester and (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid via amide coupling followed ester hydrolysis) in THF (41 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (0.25 g, 0.89 mmol). The mixture was warmed to room temperature, stirred for 3 hours, then quenched with water (20 mL) and concentrated under reduced pressure to remove THF. The remaining mixture was extracted with EtOAc (3×40 mL) and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography using 90-100% EtOAc/heptane to give the titled compound as a white solid (0.30 g, 65%).
Reaction SMILES: C([O:5]O)(C)(C)C.C([Li])CCC.[CH:12]1([NH:15][C:16](=[O:22])/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[CH:12]1([NH:15][C:16]([CH:17]2[CH:18]([CH2:19][CH2:20][CH3:21])[O:5]2)=[O:22])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OO
Reactant: CCC/C=C/C(=O)NC1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1OC1C(=O)NC1CC1
Temperature: -20 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with tert-butyl hydrogen peroxide (TBHP; 95 mL, 5.5 M, 522 mmol) and tetrahydrofuran (THF; 200 mL). The reaction was cooled to −20±5° C. and n-butyl lithium (n-BuLi; 235 mL, 2.5 M, 587 mmol) was charged to the addition funnel and slowly added, keeping the reaction temperature below −5±5° C. Upon completion of addition the reaction was warmed to 0±5° C. and the amide of Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. and the reaction stirred for 12 hours. After this time IPAc (200 mL) and saturated aqueous sodium hydrosulfite (200 mL) were added and the reaction stirred for 60 min. The layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Cl>COCCOC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:26]([C:21]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:28])=[O:27])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Sodium hydride (oil free; 0.053 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.151 g) in DME (5 ml). The solution was stirred for 10 minutes and then a solution of 4'-methyl-2-biphenylsulphonyl chloride (0.198 g) in DME (2 ml) was added. The solution was allowed to stand for 1 hour and then water (25 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted eith ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.12 g) m.p. 204-206° C.; 1H NMR (d6 -DMSO): 2.4 (s,3H), 3.85(s,3H), 7.05-7.2(m,4H), 7.3(dd,1H), 7.55-7.7(m,2H), 7.8(s,1H), 8.1(dd,1H); mass spectrum (+ve FAB, methanol/NBA): 436 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:20])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[CH2:18]([N:15]([CH2:16][CH3:17])[C:11]1[CH:10]=[C:9]([CH3:20])[C:8]([NH2:7])=[CH:13][C:12]=1[CH3:14])[CH3:19].[C:24]([OH:26])([C:23]([F:28])([F:27])[F:22])=[O:25]
Reactant: CCN(CC)c1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1cc(C)c(N)cc1C
Reaction time: 2 h

Procedure:
To a solution of 41 in 2 mL dichoromethane, trifloroacetic acid (1 mL) was added. The reaction mixture was stirred for 2 h. At this point, LC-MS showed the reaction to be complete. The reaction was concentrated to remove the solvent and most of the TFA. The residue was then dried further in a high vacuum oven over 24 h to give the title compound 42 as TFA salt (100% yield).