Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[C:12]([O-])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NNc1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
A solution of 5 g of 4-cyanophenylhydrazine hydrochloride in 40 ml of acetic acid is admixed with 2.7 g of sodium acetate and then heated at 80° C. for 20 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated under vacuum. The residue is triturated in a PE/AcOEt mixture (90/10; v/v) and the precipitate formed is filtered off with suction. This gives 4.8 g of the expected compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([CH2:23][OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:17][C@H:18]([CH2:23][OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](CO)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.4 %

Procedure:
To a suspension of N-tert-butyloxycarbonyl-L-tert-butylglycine 8 (2.43 g, 10.5 mmol), L-leucinol 9 (1.23 g, 10.5 mmol) and TBTU (3.44 g, 11.5 mmol) in acetonitrile (30 mL) at 0° (ice bath) was added N-methyl morpholine (1.3 mL, 11.5 mmol). The resulting mixture was stirred 19 h (allowing the ice bath to warm to room temperature) and the white solid was collected on a filter (486 mg, 14% yield). The mother liquors were purified by flash chromatography (SiO2, 25-35% EtOAc-hexane) affording N-tert-butyloxycarbonyl-L-tert-butylglycyl-L-leucinol 10 (2.79 g, 80% yield) as a white solid (including the filtered solid).
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:37]=[CH:36][C:12]([CH:13]=[CH:14][C:15]2[C:24]([CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)([O-])=O.Cl>[Fe].O>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]=[CH:25][C:24]2[C:15]([CH:14]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]([NH2:6])=[CH:37][CH:36]=3)=[N:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:23]=2)=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc(N)cc2)cc1
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
In a solution of 40 ml of N,N-dimethylformamide and 10 ml of water, 10 g of iron powders and 5.2 g of 2,3-bis(4-nitrostyryl)quinoxaline were dispersed. While stirring, 2.4 ml of hydrochloric acid was dropwise added to the dispersion at room temperature. Stirring was continued for 15 minutes at the same temperature and then for 30 minutes on a steam bath at 70° C. The reaction liquid was transferred to a Soxhlet's extractor and extracted for 3 hours using 300 ml of acetone. The acetone extracts were poured into 500 ml of water to adjust the pH of the liquid to 9 to 10 with an aqueous sodium carbonate solution. The resulting crystals were filtered and dried to obtain 4.3 g (yield 98%) of the product having a melting point of 227° to 228° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=O.Cl.O>CO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=[C:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8]1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(OC)c(C=C2Oc3cc(O)ccc3C2=O)c1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 2,5-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, water 400 ml was added and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.21 g.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH2:37][CH2:38][C:39]1[O:40][CH:41]=[CH:42][CH:43]=1>>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][NH:37][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: NCc1ccco1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccco4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-aminomethylfuran according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ4.51 (d, J=5.5 Hz, 2H), 6.31 (d, J=3 Hz, 1H), 6.44 (d, J=3 Hz), 7.02 (d, J=8.3, 1H), 7.30 (s, 2H), 7.66 (m, 3H), 7.88 (m, 3H), 8.18 (s, 1H), 9.02 (br t, J=5.5 Hz, 1H), 11.4 (s, 1H), 12.8 (s, 1H); APCI−MS m/z438 (M−H)−; Anal. Calcd for C20H17N5O5S.1/2H2O: C, 53.57; H, 4.05; N, 15.62; S, 7.15. Found: C, 53.91; H, 4.01; N, 15.13; S, 6.78.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C1(C)C(C)=CC=CC=1>[CH:16]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH2:18][CH3:19])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCC(C)N
Solvent: Cc1ccccc1C
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
A mixture of 4-chloro-3,5-dinitro-o-xylene (140 grams, 0.61 mole), sec-butylamine (184 ml, 1.82 moles), and xylene (1400 ml) is brought to reflux. After refluxing overnight, the reaction mixture is cooled and filtered. The precipitate is washed with petroleum ether. The filtrate and washings are combined, washed with 500 ml. of 10% hydrochloric acid, and finally with 2 liters of water. The organic layer is separated and dried. Removal of the drying agent and the solvent leaves an orange oil which crystallizes with the addition of petroleum ether. A yellow orange solid (150.6 grams, 86.5%) with melting point 42° C. to 43° C. is collected.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1S(C)(=O)=O
Temperature: 25 °C

Procedure:
10-Methoxyharmalan (646 mg, 3 mmol) is dissolved in dry dichloromethane (40 ml). Triethylamine (1 ml, 7.2 mmol) and then, dropwise, mesyl chloride (0.25 ml, 3.2 mmol) are successively added with stirring at room temperature under a nitrogen atmosphere. The mixture is stirred for 4 hours at room temperature. Subsequently, after removal of the dichloromethane, the residue is subjected to flash chromatography on a silica column (AcOEt/PE, 50/50). 1-Methylene-2-mesyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is thus obtained (350 mg, Y=40%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].CC1C=C(CC2OC2)C=CC=1C=O>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([O:15][CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCC1CO1
Reactant: Cc1cc(O)ccc1C=O
Agent: Cc1cc(CC2CO2)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm Hg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(S(C)(=O)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step B, Example GJM10; 0.10 g, 0.32 mmol) in dichloromethane (3 mL) under a nitrogen atmosphere was added triethylamine (0.13 mL, 0.89 mmol) and neopentyl carbonochloridate (0.08 mL, 0.57 mmol). The resulting solution was stirred for 2 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (20 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 50% EtOAc in hexanes) provided the title compound as an off white semi-solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (m, 1 h), 8.03 (m, 1H), 6.84 (m, 1H), 4.49 (m, 2H), 4.14 (m, 2H), 3.77 (s, 2H), 3.07 (s, 3H), 2.75 (m, 2H), 2.11 (m, 1H), 1.82-1.71 (m, 2H) 1.59-1.47 (m, 1H), 1.39-1.25 (m, 2H), 1.04-0.85 (m, 11H), 0.73-0.54 (m, 2H), −0.11 (q, J=4.8 Hz, 1H); MS (ESI) m/z 439 [M+H]+. GPR119 Human EC50: 2 nM
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([N:43]=[N+:44]=[N-:45])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(N=[N+]=[N-])c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Compound 2 (0.600 g, 1.61 mmol) was dissolved in toluene (15 mL), and diphenylphosphoryl azide (0.696 mL, 3.23 mmol) and DBU (0.483 mL, 3.22 mmol) was added to the solution, followed by stirring at 60° C. for 4 hours. The reaction mixture was diluted with toluene, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain [4-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]phenylmethylazide (0.590 g, yield 92%).
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]([F:42])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:9][NH:10][C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:27]([CH3:29])=[CH:28][C:12]1=2.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:42][C:5]([F:4])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1)[CH2:9][N:10]([C:2]#[N:1])[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:31])[F:32])[C:27]([CH3:29])=[CH:28][C:12]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
Add cyanogen bromide (1.21 mL, 6.04 mmol, 5 M solution in acetonitrile) to a solution of (S)-tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.30 g, 4.03 mmol) and diisopropylethylamine (1.05 mL, 6.04 mmol) in tetrahydrofuran (50 mL) at room temperature under nitrogen and heat the mixture at 50° C. for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (2:3), to provide the title compound as a colorless oil (2.10 g, >99%), which is used in the next step without further purification: APCI MS m/z 496 (M+H−Boc)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(OCc2cccc(Cl)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(Cl)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (71 mg, 0.40 mmol) was reacted with the product from Example 144a (143 mg, 0.41 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (122 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.16 (s, 2H) 6.25 (d, J=6.98 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.07-7.25 (m, J=8.46 Hz, 5H) 7.38-7.53 (m, 3H) 7.80 (d, J=8.45 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.83 HZ, 1H) 9.79 (s, 1H) 11.02 (br s, 1H) 14.38 (br s, 1H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)on1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)on1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-methylisoxazol-5-yl)acetamide (0.036 g, 0.09 mmol) and ethanol (4 ml) was added 4-dimethylaminobenzaldehyde (0.018 g, 0.11 mmol) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.36 ml, 0.36 mmol). The reaction mixture was stirred at 70° C. for 4.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was triturated with water (4 ml); the brown precipitate was collected by filtration, washed with water (3×2 ml), ethanol (3×2 ml) and diethyl ether (2×5 ml). This solid was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.007 g, 16%). 1H-NMR (500 MHz, DMSO-d6) 2.19 (s, 3H, isoxazole CH3), 2.73 (s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.31 (s, 2H, NCH2CO), 3.71 (s, 4H, piperazine N(CH2)2), 6.18 (s, 1H, isoxazole C—H), 6.82 (d, J=8.9 Hz, 2H) and 8.01 (d, J=8.9 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4NMe2), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.45 (br s, 1H, CONH), 13.15 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1/[CH:23]=[CH:24]/[C:25](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:19]3[S:20][CH:21]=[CH:22][C:18]=3[CH3:17])=[N:16][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: Cc1ccsc1/C=C/C(=O)Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1sccc1C)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl MeOH/n-hexane yielded the titled compound. MW: 437.48; mp: 192.5-193.5° C.; 1H-NMR (DMSO) δ: 8.65 (1H, dd, J=4.9, 1.8 Hz), 8.07 (1H, td, J=7.8, 1.9 Hz), 7.87 (1H, d, J=15.6 Hz), 7.62 (1H, d, J=8.1 Hz), 7.52 (1H, dd, J=7.4, 4.9 Hz), 7.37 (1H, d, J=5.1 Hz), 7.24 (1H, d, J=8.9 Hz), 7.16 (1H, d, J=2.3 Hz), 6.86 (1H, d, J=4.9 Hz), 6.79 (1H, dd, J=8.9,2.5 Hz), 6.67 (1H, d, J=15.6 Hz), 3.72 (3H, s), 2.22 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:35].[K+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:35])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Reactant: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 85 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea, 0.74 g of potassium chloride, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-80° C. for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with three 40 ml portions of brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to yield 1.5 g of a brown oil. The oil was purified by chromatography to yield 1.5 g of the desired product as a light yellow oil in 86% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]2[C@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:47]1([CH2:53][CH2:54][CH:55]=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([C@@H:55]([OH:56])[CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:8]([N:10]2[C@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCc1ccccc1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H](CC1CCCC1)[C@@H](O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of acyloxazolidinone 2 (1.57 g, 5.00 mmol) in 20 mL of dichloromethane, cooled to −78° C. under nitrogen atmosphere, dibutylboron triflate (1.40 mL, 5.50 mmol) was added dropwise, followed by the addition of triethylamine. The mixture was warmed slowly to 0° C. and was stirred at 0° C. for an additional hour. The resultant boryl enolate solution was then cooled to −78° C., and 3-phenylpropanal (0.80 mL, 5.5 mmol) was added over a 5-min period time. The solution was stirred for 1 h at −78° C., then for 1 h at 0° C. The reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 10° C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary evaporator. The resulting slurry was extracted with three 20 mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (25% ethyl acetate-hexane) provided 1.11 g (56%) of aldol 3 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, 10H), 4.72 (m, 1H), 4.12-4.28 (m, 3H), 3.85 (m, 1H), 3.34 (1H, dd, J=13.4, 3.1 Hz), 2.80-2.95 (1H, m), 2.60-2.78 (2H, m), 1.95-2.05 (1H, m), 1.40-1.90 (10H, m), 1.10 (2H, m).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[ClH:5].[S:6]1(=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8](N)[CH2:7]1>>[ClH:5].[OH:2][CH2:1][CH2:3][NH:4][CH:8]1[CH2:9][CH2:10][S:6](=[O:13])(=[O:12])[CH2:7]1
Reactant: NCCO
Reactant: NC1CCS(=O)(=O)C1
Agent: Cl
Product: O=S1(=O)CCC(NCCO)C1

Procedure:
The procedure of Example 1 was repeated substituting 95 percent monoethanolamine (28.6 parts) for the ammonium hydroxide of Example 1. A sticky solid was filtered after treatment with hydrochloric acid, and upon drying in vacuo over P2O5 weighed 59.6 g. (78.5 percent of theory) m.p. 122°-124° C.