Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][NH:10][CH2:11][C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([C:61](O)=[O:62])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][N:10]([CH2:11][C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:61]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[O:62])[CH2:6][CH2:7]1
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)N2CCC(F)(F)CC2)cc2ccccc21
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c(CN(CC(c2ccccc2)N2CCC(F)(F)CC2)C(=O)C2CCCCC2)cc2ccccc21
Temperature: 50 °C

Procedure:
3-({[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]amino}methyl)-1-methylquinolin-2(1H)-one (52 mg, 0.126 mmol), HATU (57.7 mg, 0.152 mmol), cyclohexanecarboxylic acid (0.019 ml, 0.152 mmol), and DIEA (0.026 ml, 0.152 mmol) were combined in DMF (1.5 ml) and the reaction heated at 50° C. for 0.75 hours. The mixture was purified directly by reversed-phase chromatography (15-95% ACN in water (with 0.5 ml/l NH4OH) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Fractions containing desired material were concentrated in vacuo and repurified by reversed-phase chromatography (5-50% ACN (with 0.1% TFA) in water (with 0.1% TFA) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Desired fractions were free-based via Phenomenex Strata X-C cartridge. HRMS [M+H] 1+ 522.2936. 1H NMR (400 MHz, CDCl3): δ 7.60-7.55 (m, 1 H), 7.53-7.49 (m, 1 H), 7.39 (d, J=8.52 Hz, 1 H), 7.35-7.28 (m, 4 H), 7.25-7.19 (m, 3 H), 4.50-4.35 (m, 2 H), 4.16-4.07 (m, 1 H), 3.88 (t, J=7.6 Hz, 1 H), 3.76 (s, 3 H), 3.31 (dd, J=7.38 Hz, 13.42 Hz, 1 H), 2.69-2.65 (m, 2 H), 2.53-2.43 (m, 2 H), 2.28-2.20 (m, 1 H), 2.01-1.88 (m, 4 H), 1.74-1.34 (m, 7 H), 1.25-1.05 (m, 3 H). 29.8 mg, 45%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:17][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C@H:27]2[C:33]3[N:34]=[CH:35][S:36][C:32]=3[C@@H:31]([NH:37]C(OC(C)(C)C)=O)[C@H:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[CH2:29][CH2:28]2)=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[O:8]=[C:9]1[NH:17][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]1[CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C@H:27]2[C:33]3[N:34]=[CH:35][S:36][C:32]=3[C@@H:31]([NH2:37])[C@H:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
A mixture of trifluoroacetic acid (0.986 mL, 12.80 mmol) and (4R,7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (16.4 mg, 0.026 mmol) in methylene chloride (10 mL) was stirred at rt from for 2.5 h. The solvent was removed under vacuum and the crude product was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (13 mg, 89%) as a white solid: LCMS (M+H=541.40); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.98 (1H, br. s), 8.64 (1H, s), 8.08 (1H, d, J=4.8 Hz), 7.31-7.64 (1H, m), 6.94-7.19 (4H, m), 6.11-6.21 (1H, m), 4.42 (4H, m), 3.23-3.43 (1H, m), 2.85-3.16 (2H, m), 2.24 (6H, m), 1.83-1.98 (2H, m), 1.56 (2H, br.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4].[NH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:16]([C:21](O)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:16]([C:21]([NH:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The HCl salt of H-Ala-OBzl (43 g, 200 mmol) was dissolved in DMF (500 ml) and stirred with Boc-Asn-OH (46.5 g, 200 mmol), NMM (27 ml), HOBt (54 g), and DCC (45 g) at 0° C for 1.5 hr and 25° C for 17 hr. The reaction mixture was worked up as in Example 11 to a solid which was crystallized from tetrahydrofuran and minimum petroleum ether: 62.5 g (79.4%); mp 140°-141° C; [α]D25 -31.1° (c 1, MeOH). Anal. Calcd for C19H27N3O6 (393.44): C, 58.00; H, 6.92; N, 10.68. Found: C, 57.77; H, 7.09; N, 10.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccncc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A mixture of 4-methoxy-3-nitroaniline (168 mg, 1 mmol) and Isonicotinoyl chloride hydrogen chloride (267 mg, 0.2 M in 1.5 mmol) in pyridine (1 mL) is sealed in a microwave reactor and heated at 100° C. under microwave radiation for 5 mins. Then 1N NaOH aqueous solution is added to the reaction mixture. After stirring at room temperature for several minutes, the mixture is filtered. The solid is washed with H2O and air dried to give 263 mg of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:10]=1)=[O:4].Br.[C:26]1([CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:10]=1)[CH2:2][N:42]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: c1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Agent: Br
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(C(O)CN(CCCCCCOCCCc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of ethyl N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]carbamate (0.58 g), N-[6-(3-phenylpropoxy)hexyl]benzenemethanamine hydrobromide (0.66 g) and DEA (0.48 g) in dichloromethane (15 ml) was stirred at room temperature under nitrogen for 26 h. Dichloromethane (50 ml) was added, the solution washed successively with 2N hydrochloric acid (50 ml), water (50 ml), 8% sodium bicarbonate solution (50 ml), dried and evaporated in vacuo. The residual brown oil (1.02 g) in absolute ethanol (20 ml) at 0° was treated with sodium borohydride (0.15 g), and the mixture was allowed to warm up to room temperature and stirred under nitrogen for 18 h. 2N Hydrochloric acid (5 ml) was cautiously added, the mixture stirred at room temperature for 5 min and evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate solution (10 ml) and EA (20 ml) and the organic phase dried and evaporated in vacuo to give a yellow oil. Purification by FCC on triethylamine deactivated silica (40 g) eluting with ER-CX (7:3) gave the title compound as a colourless oil (0.84 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][NH2:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].[OH-].[Na+].[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[C:22]([O:21][C:19]([NH:15][CH2:14][C:6]1[CH:7]=[C:8]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
A solution of methyl 5-nitro-3-aminomethybenzoate (1980 mg, 9.4 mmol) in 1N NaOH (28 mL, 28 mmol) and tert-BuOH (20 mL) was stirred at r.t. for 10 hours and then added BOC2O (4100 mg, 18.8 mmol) and stirred for 17 hours. The reaction mixture was added hexanes (50 mL) and water (50 mL). The aqueous layer was acidified with 5% citric acid aq. and extracted with CH2 Cl2 (2×70 mL). The CH2Cl2 layers were combined and washed with water (50 mL). The organic layer was evaporated to give the desired compound (2450 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 13.725 (s, 1H), 8.476 (s, 1H), 8.307 (s, 1H), 8.216 (s, 1H), 7.639 (t, J=5.7 Hz, 1H), 4.398 (d, J=5.7 Hz, 2H), 1.385 (s, 9H); 13C NMR (300 MHz, DMSO-d6) δ 165.5, 155.9, 147.9, 143.5, 133.6, 132.5, 125.4, 122.2, 78.3, 42.6, 28.2.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[NH:20]1[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:21]2=[O:27])=[CH:14][CH:15]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=c1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and pyrimidine-2,4(1H,3H)-dione. M/e+ 353 for C18H14ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.33 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.39 (td, J=6.9, 1.1 Hz, 1H), 7.00 (td, J=6.9, 1.1 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 1H), 5.45 (s, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])[C:9]([O:11]CC)=O)([O-:3])=[O:2].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[C:9]([C:8]([NH:7][C:6]1[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:14])=[O:11]
Reactant: CCOC(=O)C(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)C(=O)C(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A solution of 11.91 gm. (0.05 mole) of ethyl 3-nitro-oxanilate in 500 ml. of methylene chloride is cooled to 5° in an ice bath. There is added slowly, 25 ml. of dimethylamine and the mixture stirred for two hours in an ice-bath. The ice-bath is removed and the mixture allowed to stand at room temperature overnight.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.C[Sn](C)(C)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][N:5]=1
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: CSc1nsc(Cl)n1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To 30 ml of toluene were added 500 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 794 mg of trimethylphenyltin and 346 mg of tetrakistriphenylphosphine palladium, and the mixture was heated under reflux for 8 hours in a nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature, and a 20% aqueous potassium fluoride solution was added to the reaction mixture, followed by stirring. This mixture was filtered through Celite, and the filtrate was concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 455 mg of 3-methylthio-5-phenyl-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:11]
Reactant: NCCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 54.9 %

Procedure:
A solution of 18.95 g (0.25 mo.) of 3-aminopropanol and 37.0 g (0.25 mol) of phthalic anhydride in 25 ml of dry toluene was refluxed for three hours using a Dean-Stark apparatus. The mixture was cooled, concentrated in vacuo, dissolved in dichloromethane and washed with water. The evaporated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 183°-184° C. (0.1 mm Hg) to give 28.18 g (55%) of a white solid; m.p. 75°-77° C.; NMR: (CDCl3) δ 1.9 (2H,q), 3.65 (5H,m), 7.6 (4H,s).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN1CCOCC1.ClC(OCC)=O.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1.Cl[Si](C)(C)C>C(#N)C.C(C1C=CC(CNC(=O)CCCC2C=CC=CC=2)=CC=1)(O)=O.C(N(CC)CC)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:29][CH:28]=1)([OH:32])=[O:31]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
Hexanoic acid (3.06 g) in 20 mL acetonitrile is treated with N-methylmorpholine (2.9 mL) and the mixture cooled to -20° C. with stirring. Ethyl chloroformate (2.8 mL) is then added dropwise, keeping the temperature below or at -20° C. After stirring for an additional 40 min at that temperature, the solution is transferred to a cooled (-15° C.) solution of alpha-amino-p-toluic acid (2.0 g), triethylamine (15 mL), a chlorotrimethylsilane (5.0 mL) in methylene chloride (60 mL; prepared as described in Example 7). After the addition is complete, the mixture is stirred at 5° C. for 4 hrs, followed by overnight stirring at room temperature. After removal of the solvents by evaporation, the residue is redissolved in methylene chloride (100 mL) and extracted with 1N HCl (2×50 mL) and brine (2×50 mL). The organic layer is dried over magnesium sulfate and evaporated, leaving N-(4-carboxybenzyl)hexanamide as an off-white solid. The N-(4-carboxybenzyl)hexanamide product is crystallized from methanol/2N HCl, m.p. 178°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.O.CO.CCOC(C)=O.C(Cl)CCl.C(N(CC)CC)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=4)=[O:31])[CH2:19][CH2:18]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: O=c1[nH]nc2c(NC3CCNCC3)nc3ccc(F)cc3n12
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCC(Nc3nc4ccc(F)cc4n4c(=O)[nH]nc34)CC2)n1
Reaction time: 18 h

Procedure:
To a slurry of 98 mg of 8-fluoro-4-(piperidin-4-ylamino)-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 33 mg of 6-methyl-picolinic acid, and 32 mg of HOBT in DMF (1.4 mL) was added 109 mg of triethylamine, followed by 47 mg of EDC and the mixture was stirred for 18 hrs. To this mixture was added 15 mg of 6-methyl-picolinic acid and 57 mg of benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate, and stirring was continued for 30 min. The reaction mixture was diluted with water, and extracted with methylene chloride, and the organic extracts were washed with 50% saturated sodium bicarbonate and water, and then concentrated. The residue was separated using silica gel chromatography to provide a material that was dissolved in 10% MeOH/EtOAc, and washed with water. The organic extract was dried over sodium sulfate, filtered, and concentrated to provide the title compound as a white solid. MS (M+H)+=422.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:11]1[CH:18]=[CH:17][C:14](C#N)=[CH:13][CH:12]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2.[F:24][C:25]([F:37])([F:36])[O:26]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:11]1[CH:18]=[CH:17][C:14]([O:26][C:25]([F:37])([F:36])[F:24])=[CH:13][CH:12]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Yield: 68.2 %

Procedure:
The title compound was prepared by treatment of Step 2 intermediate, Intermediate 22 (2.0 g, 5.845 mmol) with 4-trifluoromethoxyphenylboronic acid (1.684 g, 8.183 mmol) in the presence of Pd[(C6H5)3P]4 (270 mg, 0.233 mmol) and sodium carbonate (3.11 g, 35.07 mmol) in a mixture of toluene, ethanol and water to afford 1.5 g of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.02 (s, 3H), 7.41-7.59 (m, 3H), 7.53-7.56 (m, 3H), 8.03-8.07 (m, 1H), 8.84-8.87 (m, 1H); ESI-MS (m/z) 377.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11](O)[N:12]1[CH:15]([CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:32])=O>C1COCC1>[CH2:1]([O:8][C:9]([CH:11]([Cl:32])[N:12]1[CH:15]([CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCC1CC(=O)N1C(O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCCC1CC(=O)N1C(Cl)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
1-(Benzyloxycarbonyl hydroxymethyl)-4-(2-acetoxyethyl)-2-azetidinone (1.8 g) is dissolved in 30 ml THF under N2 and cooled to -20° C. Pyridine 0.45 ml is added and then thionylchloride (0.390 ml in 4 ml THF) is added dropwise over 2 minutes. The reaction mixture is stirred at -20° C., for 5 minutes. The cooling bath is removed and the reaction mixture is stirred for another 25 minutes. The reaction mixture is diluted with 30 ml benzene and filtered. The filtrate is evaporated under reduced pressure at 5° C. The residue is 1-(benzyloxycarbonylchloromethyl)-4-(2-acetoxyethyl)-2-azetidinone which is used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=[C:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:22]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Cl:1][C:2]1[C:3]([CH:12]=[C:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:4]([S:8]([NH:11][C:30]([NH:29][C:23]2[N:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)=[O:31])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1cccc(Cl)c1C=C1CCOC1=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc(Cl)c2C=C2CCOC2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 0.15 g (0.0005 mol) of the product of Example 7 and 0.21 g (0.0008 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.12 mL (0.12 g, 0.0008 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 1 hour and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.2 g (83%) of the title compound: m.p. 212°-216° (dec); IR (nujol) 3410, 1765, 1730, 1605, 1365, 1340, 1155 cm-1 ; NMR (CDCl3, 200 MHz) δ 2.7-2.8 (2H, m), 3.94 (6H, s), 4.1-4.2 (2H, m), 5.84 (1H, s), 7.2-7.8 (3H, m), 8.25 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[BrH:22].CC(O)=O>>[Br:22][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CN1CCn2nc(Nc3cc(Cl)nn4ccnc34)cc2C1
Reactant: Br
Solvent: CC(=O)O
Product: CN1CCn2nc(Nc3cc(Br)nn4ccnc34)cc2C1
Temperature: 150 °C

Procedure:
To an autoclave was charged 124f (800 mg, 2.6 mmol)) and HBr/AcOH (60 mL). It was heated at 150° C. for 18 h. The reaction mixture was concentrated under reduced pressure to give black oil. The oil was recrystallized from methanol (30 mL)/dichloromethane (30 mL)/petroleum ether (90 mL) to 124g as a yellow solid (600 mg, 66%). MS-ESI: [M+H]+ 348.1
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][OH:30]>>[OH:30][CH2:29][C@@H:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)[C@H](N)CO
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CC(C)[C@@H](CO)NC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and (S)-(+)-2-amino-3-methyl-1-butanol in a manner similar to that described in Example 11.