Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[S:17][C:18]4[C:19]([N:24]=3)=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[CH:4]([OH:5])=[O:3].[S:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:24]=[C:16]1[O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][O:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Product: O=CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-carboxylic acid ethyl ester (200 mg, 0.59 mmol) in THF (6 mL) was added 4 N LiOH (0.15 mL, 0.59 mmol). Two additional aliquots of 4 N LiOH (each 0.30 mL) were added over 2 h. The mixture was stirred (rt, 24 h). The reaction mixture was partially concentrated in vacuo. The remaining aqueous solution was purified by reverse phase HPLC to provide the title compound as a white solid (92 mg, 44%). MS (ESI): mass calcd. for C15H8N2O4S, 312.02; m/z found, 312.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.53 (dd, J=4.8, 1.7, 1H), 8.43 (dd, J=8.0, 1.7, 1H), 8.09 (d, J=8.6, 1H), 8.04 (d, J=2.1, 1H), 7.56-7.50 (m, 1H), 7.41-7.32 (m, 1H). The remaining proton was not detected and is believed to be hidden in the solvent peak.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][CH2:15]Cl)=[O:13])[C:7]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[I-:25].[Na+]>CC(C)=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][CH2:15][I:25])=[O:13])[C:7]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCCl)CC1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCI)CC1=O

Procedure:
1-(n-Butyl)-3-(3,5-dichlorophenyl)-4-(chloromethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one was treated with sodium iodide in acetone as described in Folkmann, M.; Lund, F. J. Synthesis 1990, 1159 to give 1-(n-butyl)-3-(3,5-dichlorophenyl)-4-(iodomethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=O.F[B-](F)(F)F.C[O+](C)C.[NH:20]([C:22](OC)=[O:23])[NH2:21]>C(Cl)Cl>[CH3:9][O:8][C:6]([CH:5]1[N:1]2[C:2](=[N:21][NH:20][C:22]2=[O:23])[CH2:3][CH2:4]1)=[O:7]
Reactant: COC(=O)NN
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCc2n[nH]c(=O)n21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A portion of (S)-methyl 2-pyrrolidone-5-carboylate (3.00 g, 0.021 mol) was dissolved in DCM (105 mL) and treated with trimethyloxonium tetrafluoroborate (3.10 g, 0.021 mol). The mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. The oil was dissolved in DMF (100 mL). Methyl hydrazinocarboxylate (2.00 g, 0.022 mol) was added and the solution was heated to reflux using a Dean-Stark trap for 24 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (silica gel, using a gradient of DCM:MeOH 95:5 to 90:10) to provide 3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 4.68-4.72 (m, 1H), 3.82 (s, 3H), 2.75-2.99 (m, 4H); MS (ES+) 184.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[CH:5]=[C:6]([O:8][CH3:18])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cc(-c2ccc3nonc3c2)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Br)cc(-c2ccc3nonc3c2)c1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 5-(3-bromo-5-hydroxyphenyl)benzofurazan (8.70 g, 30 mmol), potassium carbonate (14.42 g. 90 mmol) and methyl iodide (2.83 mL, 45 mmol) in dimethylformamide (100 mL) is stirred at 18° C. for 16 h. The mixture is then treated with water (600 mL) and extracted with ethyl acetate (3×150 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from t-butylmethyl ether-hexane to give 5-(3-bromo-5-methoxyphenyl)benzofurazan as a beige crystalline solid. m.p. 135-137° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60](O)=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:61])[CH3:59])=[O:56])([CH3:52])([CH3:53])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 79%. [α]D =+12.1° (c=0.87, tetrahydrofuran).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.72-7.75 (m, 2H), 7.60-7.62 (m, 2H), 3.80-3.83 (m, 6H), 3.03-3.14 (m, 4H); MS (ESI−) M/Z 431 (M−H)−.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH2:7][C:8]#[N:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[C:8]([CH2:7][NH:6][C:13](=[O:14])[O:15][CH2:16][CH3:17])#[N:9]
Reactant: N#CCN
Reactant: CCOC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCC#N
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Aminoacetonitrile sulfate (H2NCH2CN.1/2H2SO4, 121.5 g, 1.156mole) was dissolved in water (230.9 g) and the solution was cooled to 0° to 5° C. and adjusted to pH 5 to 7 by the addition of a small amount of 30% aqueous sodium hydroxide solution. Ethyl chloroformate (108.5 g, 1.00 mole) and 30% aqueous sodium hydroxide solution were concurrently added dropwise with stirring and keeping pH at 5 to 7 at 0° to 5° C. over 2 hours and the mixture was stirred at the same temperature for additional 2 hours while keeping the same pH by dropping, if necessary, 30% aqueous sodium hydroxide solution. The total amount of 30% aqueous sodium hydroxide solution was 294.3 g. The reaction mixture was extracted three times with toluene (485 ml). The toluene layer was dried over anhydrous magnesium sulfate, toluene was evaporated and the residue was cooled to room temperature to give crystals (124.7 g, 0.968 mole) of ethyl N-cyanomethylcarbamate.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[OH:16].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:16][C:9]1[C:8]([CH3:7])=[CH:13][C:12]([Br:14])=[CH:11][C:10]=1[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
39.9 g (286 mmol) K2CO3 were added to a solution of 50.0 g (249 mmol) 2,6-dimethyl-4-bromophenol in 500 mL DMF and stirred for 20 min. Then 34.0 mL (286 mmol) benzylchloride were slowly added dropwise and the reaction mixture was stirred for 3 h at 100° C. bath temperature. After the reaction had ended the mixture was poured onto 500 mL water and exhaustively extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and evaporated down i. vac.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].S(=O)(=O)(O)[OH:19]>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]([NH2:13])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1Oc1cn[nH]c(=O)c1Cl
Product: NC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 2-(5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (43.1 g, 0.17 mol) in concentrated sulfuric acid (150 mL) was stirred at 110° C. for 1 h and was then allowed to cool to 25° C. The reaction was added dropwise to ice water. The resulting precipitate was collected by filtration, washed with cold water and dried in vacuo to afford 2-(5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzamide (44.5 g, 96%) as a white solid; ESI-MS 266 [M+H+]; HPLC: >97% (purity). 1H-NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 7.81 (s, 2H), 7.62-7.65 (m, 1H), 7.47-7.55 (m, 2H), 7.33-7.38 (m, 1H), 7.24-7.27 (m, 1H).
Reaction SMILES: [ClH:1].N[C:3]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH2:10][CH3:11])[N:4]=1.N([O-])=O.[Na+]>Cl.[Cu]Cl>[Cl:1][C:3]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH2:10][CH3:11])[N:4]=1
Reactant: CCn1cc(C#N)c(N)n1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCn1cc(C#N)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.00 g (7.34 mmol) of 3-amino-1-ethyl-1H-pyrazole-4-carbonitrile hydrochloride was dissolved in semi-concentrated hydrochloric acid (50 ml), the mixture was cooled to 0° C. and sodium nitrite (532 mg, 7.71 mmol) was added. The mixture formed was stirred at 0° C. for 45 minutes and then added dropwise to a solution, pre-heated to 60° C., of copper(I) chloride (727 mg, 7.34 mmol) in semiconcentrated hydrochloric acid, with evolution of gas. The reaction mixture was stirred at 60° C. for 2 hours, cooled to RT and extracted with CH2Cl2 (3×50 ml). The combined organic phases were dried over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel using the mobile phase dichloromethane/methanol. This gave 630 mg (55%) of 3-chloro-1-ethyl-1H-pyrazole-4-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[F:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:29]=1)[C:24](O)=[O:25].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C)C=O>[F:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)=[O:25]
Reactant: O=C(O)c1cc(OCc2ccccc2F)cc(OCc2ccccc2F)c1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cccc(NC(=O)c3cc(OCc4ccccc4F)cc(OCc4ccccc4F)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (210 mg), 3,5-bis[(2-fluorobenzyl)oxy]benzoic acid (380 mg), ethyldiisopropylamine (0.47 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (510 mg) and N,N-dimethylformamide (8 mL) was stirred at 60° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane and dissolved in ethyl acetate (50 mL). Activated carbon was added, and the mixture was stirred at 60° C. for 30 min. The activated carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (284 mg, yield 50%) as colorless crystals. melting point 157-158° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[N:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[N:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)n1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (656 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][S:9]C(=O)C.[S-2].[Na+].[Na+].Cl>CO.O>[CH2:13]([CH:7]([CH2:8][SH:9])[C:6]([N:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:4][C:3]([OH:28])=[O:2])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CN(C(=O)C(CSC(C)=O)Cc1ccccc1)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: O=C(O)CN(C(=O)C(CS)Cc1ccccc1)c1ccccc1F
Reaction time: 1 h

Procedure:
A solution of the N-(S-acetyl-2'-benzyl-3'-mercaptopropionyl)-2-fluorophenylglycine methyl ester of Example 19b (0.2 mmol) in methanol (2 ml) was degassed with argon for 20 minutes then treated with a solution of sodium sulphide (1 mmol) in degassed water (2 ml). After 30-90 minutes, 0.25M aq. HCl (20 ml) was introduced and the mixture extracted with ethyl acetate (3×20 ml). The dried (MgSO4) organic phases were evaporated to give the title compound as a clear oil, an approximately equimolar mixture of diastereoisomers.
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cl
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
To a suspension of 50 mol of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.97 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. After 5 minutes, there was added 2.68 g (10.0 mmol) of N-(3-bromopropyl)phthalimide and the mixture was refluxed for 33 hours. This was cooled to room temperature, then poured into 200 ml of saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated and was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 1.03 g of N-(3-chloropropyl)phthalimide and further development with chloroform resulted in 1.21 g (yield: 53%) of white crystals of N-[3-(N-methoxy-N-methylamino)propyl]-phthalimide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]=O.[H][H]>C(O)C.[Pt]=O>[CH3:11][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: C=O
Reactant: Nc1ccccc1C(=O)O
Agent: O=[Pt]
Solvent: CCO
Product: CNc1ccccc1C(=O)O

Procedure:
A solution of 2-aminobenzoic acid (25 g) in ethanol (300 ml) reacted with an excess of paraformaldehyde and then reduced with hydrogen gas at 60 psi over platinum oxide (25 g) catalyst. After hydrogen uptake ceased, the mixture was filtered and the solvent removed on a rotary evaporator. The product was purified by chromatography on silica gel and the structure confirmed by nmr and infrared analysis.
Reaction SMILES: C([N:3](CC)CC)C.[N+]([O-])(O)=O.[CH3:12][C:13]1[CH:17]=[C:16](C)[N:15]([C:19]([NH2:21])=[NH:20])N=1.C1C=C2C(C(O)(O)[C:31](=O)[C:25]2=CC=1)=O.[ClH:35]>O>[ClH:35].[ClH:35].[NH:15]([CH2:16][CH2:17][CH2:13][CH:12]([NH2:3])[C:31]#[CH:25])[C:19]([NH2:21])=[NH:20]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])O
Product: C#CC(N)CCCNC(=N)N
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Triethylamine (4.5 ml, 30 mmoles) is added to a solution of 1,4-diamine-5-hexyne dihydrochloride (1.85 g, 10 mmoles) in water (50 ml) at -10° C. To this solution 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.3 g, 10.5 mmoles) is slowly added (in small portions) and the resulting mixture is stirred 2 h at -10° C., and for 3 days at room temperature after all starting materials have reacted (this is controlled by electrophoresis and ninhydrin colorimetric analysis). Then, the mixture is acidified (pH 5-6) with a 1 M solution of HCl and washed with dichloromethane (2×100 ml). The aqueous layer is concentrated under reduced pressure to a volume of 5 ml. This concentrated mixture is purified by ion exchange chromatography. (DOWEX 50W-X8, 100-200 mesch, H+Form) which is eluted by using a gradient of solution of HCl (0 to 4 N). The eluted fractions are checked by electrophoresis on silica gel plates and colorimetric analysis (ninhydrin and Sakaguchi reagent). The fractions containing the guanidino material are concentrated together under reduced pressure to give the title compound (1.7 g) as a colorless oil. NMR(1H) δ ppm. 1.76 (m, 4H); 2.96 (d,1H,J=1H2); 3.16 (m, 2H) 4.2 (m, 1H). M/Z: MH+ 155; MH± NH3 : 138; MH± NH2 --CNHNH2 =98.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[Cl-].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[C:22]([C:29](O)=[O:30])[CH:21]=2)[CH:15]=1.Cl>C(#N)C.O.C(N(CC)CC)C>[CH3:9][O:8][C:6]([CH:5]([C:29](=[O:30])[C:22]1[CH:21]=[C:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[N:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C(=O)OC)C(=O)c1cc(-c2cccnc2)n2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.8 cm3 of triethylamine are added dropwise to a suspension of 1.4 g of magnesium chloride in 16 cm3 of acetonitrile under argon, followed, after 5 minutes, by 2.9 cm3 of dimethyl malonate. The resulting white suspension is then stirred at ambient temperature under argon for 1 hour. To this suspension is then added, via a cannula, a suspension, prepared beforehand from 6.3 g of the chloride of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid in 36 cm3 of acetonitrile under argon, to which 2.8 cm3 of triethylamine has been added. The resulting brick-red suspension is stirred at ambient temperature under argon for 18 hours and is then cooled to 0° C. and treated dropwise with 7 cm3 of concentrated hydrochloric acid. The resulting mixture is diluted with 15 cm3 of distilled water and separated and then the aqueous phase is extracted 6 times with 50 cm3 of dichloromethane. The organic extracts are combined and dried over magnesium sulphate and then concentrated at reduced pressure (2.7 kPa). 8.1 g of methyl 2-(methoxycarbonyl)-3-oxo-3-[3-(3-pyridyl)-5,6,7,8-tetrahydro-1-indolizinyl]propionate are thus obtained in the form of a beige crystalline solid melting at 146-150° C. (Rf=0.65; thin layer chromatography on silica gel; eluent: 10/90 by volume mixture of methanol and of dichloromethane).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]3[N:13]([N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]=3[C:17]([NH2:19])=[O:18])[C:7]=2[CH2:6]1)(=[O:4])[CH:2]=C.[CH3:33][O-].[Na+].Cl.[CH3:37][NH:38][CH3:39]>CO>[CH3:37][N:38]([CH3:33])[CH2:39][CH2:2][C:1]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]3[N:14]=[C:15]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][CH:25]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:13][C:7]=2[CH2:6]1)=[O:4]
Reactant: C=CC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Reactant: C[O-]
Reactant: CNC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)CCC(=O)N1CCc2c([nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn23)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of 7-acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (6 mg, 0.014 mmol) in 5 mL of MeOH at RT was added NaOMe (15 mg, 0.28 mmol) followed by dimethylamine hydrochloride (12 mg, 014 mmol), then the mixture was stirred at 50° C. overnight. After cooling down to RT, the mixture was concentrated. The residue was purified by pre-HPLC eluting from 0% to 60% CH3CN in H2O. Fractions containing the desired product were combined and lyophilized overnight to give 2.5 mg (35%) of 6-(3-(dimethylamino)propanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.84-11.82 (m, 1H), 9.55 (s, 1H), 7.69-7.66 (m, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.04 (m, 4H), 4.75-4.72 (m, 2H), 3.87-3.82 (m, 2H), 3.02-3.00 (m, 2H), 2.84-2.78 (m, 2H), 2.77 (s, 6H), 2.71-2.68 (m, 2H). MS (ESI) m/e [M+1]+ 472.9.