Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccccc3)c2CC1

Procedure:
To a solution of 2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) was added lithium aluminum hydride (100 mg). The mixture was heated at reflux for 4 h. Water (1 mL) was added, the mixture was filtered, and the filtrate was concentrated. After purification (SiO2, EtOAc/hexanes), 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. The intermediate was diluted with CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated to obtain the title compound (0.018 g). MS (ESI): exact mass calculated for C20H21N3, 303.17. found, m/z 304.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.38-7.35 (m, 3H), 7.19-7.18 (m, 3H), 7.12-7.10 (m, 2H), 5.13 (s, 2H), 3.35-3.21 (br m, 6H), 3.34-3.30 (br m, 2H), 2.81-2.79 (br m, 2H).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH:6]([C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:10]=1[NH2:11])([CH3:8])[CH3:7].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[CH3:17][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]([CH:6]([CH3:8])[CH3:7])[C:10]=1[NH:11][C:3](=[O:4])[CH2:2][NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: NCc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCc1ccccc1
Reaction time: 8 h
Yield: 96 %

Procedure:
Bromoacetylbromide (4.5 mL) was added portionwise to a mixture of 8.85 g 2,6-diisopropylaniline and 7.0 mL triethylamine in 300 mL EtoAc at 0° C. Upon completing the addition, excess triethylamine and 5.4 g benzylamine were added and the entire mixture was heated on the steambath for 30 minutes. The reaction mixture was allowed to sit overnight at room temperature, and was then filtered, concentrated, and filtered through silica gel (70-230 mesh) using hexane/EtoAc, 1/1, as eluant. A total of 15.62 g (96%) of the title product was obtained.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P([O-])([O-])([O-])=O.CCOCC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol) in THF (100 mL) at 0° C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0° C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL), dried (Na2SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5 g).
Reaction SMILES: FC(F)(C)[C:3](F)(F)[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[OH:8]>FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>[F:15][C:4]([F:16])([CH3:3])[C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[OH:8]
Reactant: CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(O)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CC(F)(F)C(F)(F)C(F)(F)C(O)(F)F

Procedure:
A 1.0 mL portion of dodecafluoroheptanol (PCR) was added to 1.0 mL of dodecafluoropentane to form a clear, homogenous solution. The same quantity of octafluoropentanol in dodecafluoropentane yielded two clear, non-mixing phases. The addition of 2.0 to 4.0 mL water to the dodecafluoroheptanol-dodecafluoropentane yielded two non-mixing phases. Upon cooling to 4° C. the two clear phases changed to three clear phases.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH3:23])[CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.[Cl-].[Na+]>CN(C=O)C>[S:34]1[CH:35]=[CH:36][N:37]=[C:33]1[NH:32][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:13]([CH3:23])[CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21]
Reactant: Nc1nccs1
Reactant: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1nccs1
Temperature: -23 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid (123 mg, 0.396 mmol) is dissolved in 1 mL of DMF and cooled to −23° C. TEA (51 μL, 0.37 mmol) is added followed by isobutyl chloroformate (48 μL, 0.37 mmol). After 40 min, 2-aminothiazole is added and the reaction mixture is allowed to come to 25° C. over 18 h. The reaction mixture is added to half-saturated aqueous sodium chloride and extracted with EtOAc. The combined organic layers are washed with 1N HCl, 5% sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo and purification by chromatography on silica gel (elution with hexanes-EtOAc 1:5 then EtOAc) provides (2S,3R)-2-tert-butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide as a foam (101 mg, 66%).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[S:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([N:23](CC)CC)C.N>ClCCl.O>[CH:5]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[S:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCN(CC)CC
Reactant: OC(=S)c1ccc(C2CCCCCC2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=S)c1ccc(C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Add thionyl chloride (1.35 mL, 18.4 mmol) to a mixture of 4-cycloheptylthio-benzoic acid (984 mg, 3.93 mmol) in dichloromethane (15 mL) at 0° C. Heat the mixture to reflux for 1 h. Cool the mixture to room temperature and concentrate in vacuo. Dissolve the residue in dichloromethane (20 mL) and cool to 0° C. Add triethylamine (1.1 mL, 7.86 mmol) and bubble ammonia gas through the solution. Warm the mixture to room temperature and stir for 1 h. Dilute with water (20 mL) and extract the aqueous phase with dichloromethane (3×20 mL). Wash the combined organic extracts with saturated aqueous NaHCO3 (20 mL). Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an off-white solid (976 mg, 99%). MS (APCI) m/z: 250 (M+H)+.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([CH:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[S:15][C@H:16]2[N:19]([CH2:20]O)[C:18](=[O:22])[C@H:17]2[NH:23][C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]1=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.S(Cl)(Cl)=O>O1CCCC1>[CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([C@@:14]2([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[S:15][C@H:16]3[N:19]([C:18](=[O:22])[C@H:17]3[NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20]2)[C:10]1=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N(CO)[C@@H]1SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(N=Cc2ccccc2)C1=O
Solvent: Cc1cccc(C)n1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
In 420 ml of anhydrous tetrahydrofuran was dissolved 30.00 g of (3R,4R)-4-[1-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-1-(p-nitrobenzyloxycarbonyl)methylthio]-1-hydroxymethyl-3-phenylacetamidoazetidin-2-one. To the solution were added, with ice cooling, 6.72 ml of 2,6-lutidine and 3.95 ml of thionyl chloride in this order. The mixture was stirred at room temperature for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 600 ml of anhydrous tetrahydrofuran. To the solution was added 13.6 ml of N,O-bis(trimethylsilyl)acetamide. The mixture was stirred at room temperature for 15 minutes and cooled to -60° C. To the reaction mixture were added, at 40° C. or below, 40.4 ml of hexamethylphosphoric triamide and 69.6 ml of tetrahydrofuran solution lithium bis(trimethylsilyl)amide (0.8 mmol/ml), in this order. The temperature of the mixture was elevated to -15° C. in 1 hour. To the reaction mixture was added 3.16 ml of acetic acid while maintaining the temperature at -15° C. The mixture was added to a mixed solvent consisting of 500 ml of water and 500 ml of ethyl acetate. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with diluted hydrochloric acid of pH 2.0, mixed with 200 ml of water, and adjusted to pH 7.0 with an aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 2/1) to obtain 13.32 g (yield: 45.7%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia- 1-azabicyclo[3.2.0]heptane.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH:13](=[O:17])C(C)C.C(O)(=O)C(O)=O>O1CCCC1>[CH2:9](/[C:10](=[CH:11]\[CH:5]([CH3:6])[CH3:7])/[CH:13]=[O:17])[CH3:8]
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Reactant: CC(C)C=O
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CC/C(C=O)=C\C(C)C
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (40.5 g) in tetrahydrofuran (160 ml) at -10° C. was added a solution of n-butyllithium (1.66M in hexane solution, 241 ml) under nitrogen atmosphere. The mixture was stirred for 20 minutes and then 1-(N-tert-butyl)butylimine (50.9 g) was added at the same temperature. Stirring was continued for 20 minutes and then cooled to -65° C. A solution of isobutanal (28.8 g) in tetrahydrofuran (120 ml) was added to the solution. The reaction mixture was kept at -65° C. for 90 minutes, then warmed slowly to room temperature and stirred overnight. The resultant mixture was poured into a saturated aqueous oxalic acid solution (1.5 l) and the mixture was stirred for one hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (300 ml×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was distilled to give (E)-2-ethyl-4-methyl-2-pentenal (35.7 g) : bP 30°~55° C. at 1.0~10 mmHg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[I:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15]>CCOCC>[I-:8].[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1)(=[O:16])[CH3:15]
Reactant: Cc1ccncc1
Reactant: CC(=O)OCCCCI
Solvent: CCOCC
Product: CC(=O)OCCCC[n+]1ccc(C)cc1
Product: [I-]

Procedure:
10 mmol (0.93 g) γ-picoline and 10 mmol (2.42 g) 4-iodobutylacetate are heated 4 h at 120° C. and after cooling repeatedly stirred with ether, decanted a finally dried in vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1OC1C=CC=CC=1)([O-:3])=[O:2].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>O1CCCC1>[O:10]([C:7]1[CH:6]=[C:5]([C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[NH:27][CH2:24][CH:25]=[CH2:26])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1Oc1ccccc1
Solvent: C1CCOC1
Product: C=CCNc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 10 gm of 4-nitro-1,3-diphenoxy-benzene, 30 ml of tetrahydrofuran and 10 l ml of allylamine was refluxed for 8 hours. Thereafter, the reaction mixture was worked up as in Example 3, and the reaction product was recrystallized from ethanol, yielding 6.1 gm (69% of theory) of the thin-layer chromatographically (cyclohexane/toluene=1:1) uniform title compound, m.p. 67°-68° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][OH:27].I[C:29]1[N:30]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[C:32]([CH3:34])[N:33]=1.C([Mg]Br)C.[CH3:58][N:59]([CH3:72])[C:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:63]([CH:70]=[O:71])=[CH:62][CH:61]=1>ClCCl.CO>[CH3:31][N:30]([CH3:29])[C:35]1[C:42]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:52]([CH:26]([C:3]2[N:4]=[CH:5][N:6]([C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])[OH:27])=[CH:53][CH:48]=1.[CH3:58][N:59]([CH3:72])[C:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:63]([CH:70]([C:31]2[N:30]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:29]=[N:33][C:32]=2[CH3:34])[OH:71])=[CH:62][CH:61]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Reactant: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Mg]Br
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(O)c2ccc(N(C)C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1ccc(N(C)C)c2ccccc12
Reaction time: 1 h
Yield: 87 %

Procedure:
(4-Dimethylamino)naphthalen-1-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methanol and (4-(dimethylamino)naphthalen-1-yl)-4-methyl-1-trityl-1H-imidazol-5-yl)methanol (4): A solution of (2) (5.1 g, 11.3 mmol) in dichloromethane (70 ml) was added ethyl magnesium bromide (3.0 M in diethyl ether, 3.8 mL, 11.4 mmol) drop wise at rt. The mixture was stirred for 1 h and a solution of 4-(dimethylamino)-1-naphthaldehyde (3) (1.15 g, 7.35 mmol) in dichloromethane (30 mL) was added drop wise via addition funnel. The reaction mixture was stirred at room temperature (n) overnight. The reaction mixture was quenched with ammonium chloride (aq). The resulting aqueous layer was extracted twice with dichloromethane (300 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 1 to 2% saturated ammonia methanol in dichloromethane to give a crude (4-(dimethylamino)naphthalen-1-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methanol and (4-(dimethylamino)naphthalen-1-yl)(4-methyl-1-trityl-1H-imidazol-5-yl)methanol (4) (3.35 g, 6.40 mmol, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (400 mg, 1.37 mmol) was dissolved in pyridine (4 mL) and to this was added 4-(dimethylamino)pyridine (17.3 mg, 142 μmol), and then cooled to 0° C. To this was added phenylacetyl chloride (540 μL, 4.08 mmol) and stirred for 3.5 h after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, dichloromethane/ethyl acetate=15/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-(phenylacetylamino)pyrazine (c-16) as a pale yellow solid (540 mg, 96.2%). Rf=0.25 (dichloromethane/ethyl acetate=15/1). Mp. 197.5-202° C. UV (MeOH) λmax (log ε) 330 (4.20), 293 (4.20), 274 (4.18). UV (pH 7.4 PB, 1% DMSO) λmax (log ε) 333.5 (3.73), 280.5 (3.85). 1H NMR (400 MHz, DMSO-d6) δ 3.68 (s, 2H), 3.81 (s, 3H), 4.03 (s, 2H), 7.01-7.08 (m, 4H), 7.11-7.24 (m, 3H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 4H), 8.01-8.06 (AA′BB′, 2H), 8.88 (s, 1H), 10.52 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6/CD3OD=2/1) δ 40.2, 42.9, 55.5, 114.8 (2C), 126.7, 127.2, 128.4 (2C), 128.6, 128.7 (2C), 128.8 (2C), 129.4 (2C), 129.7 (2C), 136.0, 137.5, 138.7, 143.9, 149.0, 151.2, 161.3, 170.6. IR (KBr, cm−1) 706, 837, 1034, 1179, 1248, 1296, 1413, 1439, 1449, 1497, 1545, 1574, 1609, 1670, 3281, 3381. HRMS (FAB+) m/z 410.1876 (M+H, C26H24N3O2 requires 410.1869).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:37]=[CH:36][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]#[N:35])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]([NH2:35])=[O:39])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:36][CH:37]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile (0.070 g, 0.145 mmol) in DMSO (1.0 mL). To this was added potassium carbonate (0.024 g, 0.174 mmol) and hydrogen peroxide (0.445 mL, 14.5 mmol) and the mixture was stirred at 20° C. for 3 days and quenched with water. The product was extracted into EtOAc, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was purified using a Gilson reverse phase liquid chromatography system. The product fractions were extracted into CH2Cl2. The organic layers were washed organics 1× saturated NaHCO3, 1×H2O, dried with Na2SO4, filtered through fritted funnel and concentrated to yield 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide as light yellow solid. MS m/z=500 [M+1]+. Calc'd for C29H21N7O2: 499.52.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([OH:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl>[CH2:38]([NH:40][C:41](=[O:42])[O:30][CH:28]1[CH2:27][N:26]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:29]1)[CH3:39]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(O)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)OC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-ol (100 mg, 0.23 mmol) in 2 mL of dry dichloromethane was added triethylamine (3 uL, 0.023 mmol) and ethyl isocyanate (0.11 mL, 1.4 mmol), respectively. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 100 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.00 (t, J=7.23 Hz, 3 H), 1.48-1.57 (m, 2 H), 1.59 (s, 9 H), 1.63-1.83 (m, 4 H), 2.04 (d, J=26.56 Hz, 2 H), 2.18-2.31 (m, 1 H), 3.00 (q, J=7.23 Hz, 2 H), 3.63 (dd, J=9.18, 5.08 Hz, 2H), 4.01-4.09 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 7.70-7.75 (m, 1 H), 7.79-7.84 (m, 1 H), 8.10 (s, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.1 TFA: C, 49.32; H, 5.54; N, 8.78. Found: C, 49.31; H, 5.42; N, 8.59.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH:16](O)([CH3:18])[CH3:17]>O>[CH:16]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 3-bromo benzoic acid (Aldrich, 2.4 g, 11.9 mmol) in isopropanol (20 mL) was treated with 1 mL of concentrated sulfuric acid and the resulting reaction mixture was refluxed overnight. The reaction mixture was then cooled to ambient temperature and diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (2.54 g, 88%).