Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.C(O)C.[OH-].[Na+].[BH4-].[Na+]>O>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (50.0 g) was added ethanol (400 mL), and the mixture was stirred for 10 min. To this solution was added dropwise at 25° C. a solution separately prepared by dissolving sodium hydroxide (1.0 g) in water (125 mL) and adding sodium borohydride (3.28 g), and the wall-side of the titration equipment was washed with water (50 mL). The mixture was stirred at 25° C. for 1 hr, activated carbon (10.0 g) was added, and the mixture was stirred for 1 hr. The insoluble material was removed by filtration, and washed with a mixed solution (200 mL) of water.ethanol (1:4). 6M Hydrochloric acid was added to the filtrate at 25° C. to adjust the mixture to pH 3.0. Then, 1 mol/L aqueous sodium hydroxide solution was added to adjust the mixture to pH 7.0. The mixture was concentrated to 200 mL, the attachment on the wall was washed with a mixed solution (50 mL) of water-ethanol (1:4), and the mixture was stirred at 50° C. for 30 min. Water (50 mL) was added dropwise, and the mixture was stirred at 50° C. for 30 min. After stirring at 25° C. for 2 hr, water (450 mL) was added dropwise, and the mixture was stirred at 25° C. for 2 hr. The precipitated solid was collected by filtration, and the solid was washed with water (500 mL) and dried at 60° C. under reduced pressure to give {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (47.6 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CC(=O)CC>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][C:1]([OH:11])=[O:10])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: Br
Solvent: CCC(C)=O
Product: O=C(O)CC(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
A mixture of trans-cinnamic acid (2 g, 13 mmol) and HBr (30% solution in AcOH, 40 mL) was stirred at room temperature for 18 h and then evaporated to dryness. The resulting solid was taken upin 2-butanone (100 mL) and p-nitroaniline (5 g, 36 mmol) was added. The reaction mixture was refluxed for 18 h, allowed to cool and partitioned between CHCl3 and 1N HCl. The organic phase was dried and concentrated to a residue. This was purified by chromatography on silica gel (hexane: EtOAc, 50%), to afford the title compound as a yellow solid (0.78 g, 21%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=[N+:19]=[N-:20]
Reactant: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of intermediate 42, (2-(bromomethyl)-5-fluorophenyl)(morpholino)methanone, (1.0 g, 3.32 mmol) in dimethylformamide (10 mL) was added sodium azide (230 mg, 3.5 mmol) and the mixture stirred under a nitrogen atmosphere for 1 h. The solvent was evaporated in vacuo, and the residue dissolved in CH2Cl2, then washed with water. The organic phase was dried (Na2SO4), filtered, concentrated, and the residue purified by column chromatography (SiO2, CH2Cl2) to provide 770 mg (Yield 88%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.27 (2H, s) 3.51-3.65 (2H, m) 3.66-3.97 (4H, m) 4.38 (2H, brs) 6.92 (1H, dd, J=8.2, 2.7 Hz) 7.07 (1H, dt, J=8.5, 3 Hz) 7.34 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 265 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]>>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1ccccc1CCl
Agent: [Na]
Product: Cc1ccccc1CSc1cccc[n+]1[O-]
Yield: 85 %

Procedure:
The intermediate 2-(2-methylphenylmethylthio)pyridine N-oxide is prepared by the procedure described in Example 2 from α-chloro o-xylene and 2-mercaptopyridine N-oxide sodium salt. Melting point 134° -136° C. Yield 85% theory. Structure confirmed by IR and NMR.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[C:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(=O)c2ccccc2)cc1

Procedure:
10.00 g (41.3 mmol) of 4-(benzoyloxy)benzoic acid and one drop of N,N-dimethylformamide are refluxed in 40 ml of thionyl chloride with stirring until gas is no longer evolved. The excess thionyl chloride is very substantially removed by distillation under reduced pressure and co-distilled twice with petroleum ether (50/70) under reduced pressure from the remaining residue for complete removal. Purification is carried out by recrystallization from 150 ml of petroleum ether (50/70)/ethyl acetate 2:1, and the crystals are washed with 4 ml of petroleum ether (50/70)
Reaction SMILES: [C:1]([CH2:4][C:5]1[O:6][C:7]([SH:10])=[N:8][N:9]=1)([OH:3])=[O:2].CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:10][C:7]3[O:6][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[N:9][N:8]=3)[CH2:25][S:24][C@H:19]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cc1nnc(S)o1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reaction time: 3 h

Procedure:
A solution of 9.61 g (0.06 mol) of 2-carboxymethyl-1,3,4-oxadiazole-5-thiol in 120 ml of acetone is added to a warm (45°) solution of 10.9 g (0.04 mol) of 7-aminocephalosporanic acid in a mixture of 220 ml of water, 50 ml of acetone and 13.44 g (0.16 mol) of sodium bicarbonate. The temperature is raised to 65° and the pH maintained at 7.4-7.6 by addition of aqueous sodium carbonate solution. After 3 hours, the acetone is removed in vacuo and the reaction mixture is cooled to 10° and adjusted a pH 3.5 by addition of dilute hydrochloric acid. The product is collected, washed with water and then acetone to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[CH3:18]>C(O)CO>[NH:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[CH2:25][CH2:26]2)=[N:7][CH:6]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cn1
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3ccc(-c4nc5ccccc5[nH]4)cn3)CC2)ccc1OC
Yield: 9 %

Procedure:
A solution of 2-(6-chloro-pyridin-3-yl)-1H-benzoimidazole (23.0 mg, 0.10 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 220° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (9%) of the title compound. MS (ISP): 456.6 [M−H]−.
Reaction SMILES: Br[C@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)CC2CCCCC2)OC1=O
Agent: [Na+]
Product: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)N=[N+]=[N-])OC1=O
Temperature: 0 °C

Procedure:
42.5 g (0.135 mol) of 5(R)-bromo-6-cyclohexyl-2(S)-isopropyl-4(S)-hexanolide and 35 g (0.54 mol of NaN3 in 480 ml of N,N'-dimethyl-N,N'-propylene urea (DMPU) are stirred at room temperature for 72 hours and then poured onto 1 liter of ice-cold 0.1N HCl. The mixture is then extracted three times with ether, and the combined organic phases are washed twice with 0.1N HCl and three times with brine and dried with MgSO4. After concentrating the solvent by evaporation, the residue is recrystallised from hexane: m.p. 38.5°-39°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:15]1[C:19]2[CH:20]=[CH:21][C:22](/[C:24](/[CH2:43][CH3:44])=[CH:25]\[CH2:26][N:27]([O:35]C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[CH:23][C:18]=2[O:17][C:16]=1[CH2:45][CH3:46])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C:15]1[C:19]2[CH:20]=[CH:21][C:22](/[C:24](/[CH2:43][CH3:44])=[CH:25]\[CH2:26][NH:27][OH:35])=[CH:23][C:18]=2[O:17][C:16]=1[CH2:45][CH3:46])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC/C(=C/CN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C(=C/CNO)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of TFA (5 mL) in methylene chloride (10 mL) was added dropwise to the cold (ice bath) solution of tert-butyl (2Z)-3-(3-benzyl-2-ethyl-1-benzofuran-6-yl)pent-2-enyl[(tert-butoxycarbonyl)oxy]carbamate (4.0 g; 7.45 mmol) in methylene chloride (25 mL). The mixture was stirred at ° C. for 1 hour and at room temperature for 1 hour and solvent evaporated. The residue was extracted with ethyl acetate, washed with sodium bicarbonate solution, water, and evaporated to dryness. The residue was chromatographed on silica gel using 2% ethyl acetate in hexane as an eluent to give the title compound (1.8 g) as an oil. 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 2H, J=7.25 Hz), 1.05 (t, 3H, J=7.47 Hz), 1.2-1.25 (m, 6H), 2.35 (q, 2H, J=7.47 Hz), 2.85 (q, 3H, J=7.47 Hz), 3.95 (d, 2H, J=6.59 Hz), 3.96 (s, 2H), 5.55 (t, 1H, J=6.59 Hz), 6.05 (brs, 1H), 6.95 (dd, 1H, J=7.9, 1.32 Hz), 7.22-7.35 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C(O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[N:29]=[C:13]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9]
Reactant: CSc1c(F)cc(C(=O)CC(=O)C(F)(F)F)cc1F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CSc1c(F)cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[3,5-difluoro-4-(methylthio)phenyl]-4,4,4-trifluoro-butane-1,3-dione (1.09 g, 3.6 mmol) dissolved in ethanol (150 mL). One drop of concentrated hydrochloric acid was added and 4-fluorophenylhydrazine hydrochloride (0.69 g, 4.0 mmol). The reaction was stirred at ambient temperature for 72 hours. Solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL) extracted with water (2×100 mL), saturated ammonium chloride (2×150 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the 5-[3,5-difluoro-4-(methylthio)-phenyl]-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole was obtained by crystallization from ethyl acetate and hexanes (0.71 g, 50%). 1H NMR (CDCl3/300 MHz) 7.36-7.29 (m, 2H), 7.18-7.13 (m, 2H), 6.81-6.77 (m, 3H), 2.53 (s, 3H). ESHRMS m/z 389.0557 (M+H+, Calcd 389.0547). Anal. Calcd for C17H10F6N2S: C, 52.58; H, 2.34; N, 7.21. Found: C, 52.45; H, 2.34; N, 7.15.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([C:17](Br)([CH3:19])[CH3:18])=[O:16].CS(C)=O>O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([C:17]1[CH:19]=[CH:15][C:6]2[C:5](=[CH:14][CH:9]=[CH:8][CH:7]=2)[CH:18]=1)=[O:16]
Reactant: CC(C)(Br)C(=O)c1ccc2ccccc2c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Yield: 146.9 %

Procedure:
0.75 g of sodium azide was added to a mixture comprising 1.59 g of α-bromoisopropyl 2-naphthyl ketone and 40 ml of dimethyl sulfoxide, and the mixture was reacted at 50° C. for 1.5 hours. The reaction mixture was put into water and extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.19 g of oily α-azideisopropyl 2-naphthyl ketone.
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:3]([OH:5])=[O:4].[CH3:23]O.S(=O)(=O)(O)O>O>[F:1][C:2]([F:22])([C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])[C:3]([O:5][CH3:23])=[O:4]
Reactant: CO
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 87 %

Procedure:
A 2-1, four-necked, round-bottomed flask equipped with stirrer, addition funnel, thermometer and reflux condenser, is charged with 728 g (2 mol) of dried perfluoroheptanoic acid, 160 g (5 mol) of methanol. The mixture is stirred and added dropwise 50 ml concentrated sulfuric acid and then heated to reflux for 4 hr. At the end of the reflux period the mixture is cooled to room temperature and poured into 2 l cold water. After separation of the phases, the lower organic phase is washed with water till pH neutral and dried over CaCl2. Distillation of the crude gives 658 g (87%) of methyl perfluoroheptanoate, bp 139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:25][CH2:24][C:12]3([N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[CH:6][C:5]=1[O:26][CH:27]([CH3:29])[CH3:28])([O-])=O.O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:25][CH2:24][C:12]3([N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[CH:6][C:5]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1N
Yield: 98.5 %

Procedure:
A mixture of 400 mg of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate, 592 mg of hydrazine hydrate and 52.5 mg of 10% palladium-on-carbon in 10 ml of ethanol is refluxed for 1 h. The mixture is filtered and the filtrate is concentrated under reduced pressure, so as to obtain 365 mg of 2-methylpropan-2-yl 7-[4-amino-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in the form of a mauve gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[C@H:11]([CH3:18])[NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[NH:9][C:10](=[O:19])[CH:11]([CH3:18])[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]=2[CH:7]=1
Reactant: CC(C)CCN[C@@H](C)C(=O)Nc1cnc(Cl)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN1c2cc(Cl)ncc2NC(=O)C1C
Temperature: 125 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of N-(4,6-dichloropyridin-3-yl)-N2-(3-methylbutyl)alaninamide (350 mg, 1.15 mmol) in DMF (1.0 mL) was added tri-basic potassium phosphate (250 mg, 1.20 mmol). The reaction mixture was heated to 125° C. and stirred at the same temperature for 3 h. The reaction was then cooled to rt, diluted with water (5 mL) and the aqueous phase was extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with water, dried over Na2SO4 and evaporated to give desired product (Yield: 33%), which was used for next step without any further purifications. 1HNMR (CDCl3, 300 MHz) δ 0.90-1.01 (m, 6H), 1.33 (d, 3H), 1.52-1.75 (m, 2H), 1.80 (s, 1H), 3.10-3.19 (m, 1H), 3.31-3.42 (m, 1H), 4.07 (q, 1H), 6.51 (s, 1H), 7.65 (s, 1H), 9.41 (br s, 1H).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[CH:30]=[CH:29][C:28]2=[N:31][N:32]=[C:33]([C:34]([F:37])([F:36])[F:35])[N:27]2[N:26]=1>C(O)C>[F:36][C:34]([F:35])([F:37])[C:33]1[N:27]2[C:28]([CH:29]=[CH:30][C:25]([N:4]3[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]3)=[N:26]2)=[N:31][N:32]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (4.00 g, 20.0 mmol) was added to a mixture of diisopropylethylamine (4.11 mL, 23.7 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (4.0 g, 18.2 mmol) in ethanol (80 mL). The mixture was heated under reflux for 6 hours and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,4-diazepane-1-carboxylate (5.94 g, 85.4%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 1.15 (9H, d), 1.72-1.93 (2H, m), 3.27-3.39 (2H, m), 3.50-3.63 (2H, m), 3.66-3.75 (2H, m), 3.83 (2H, t), 7.46-7.56 (1H, m), 8.19-8.31 (1H, m); apparently as a mixture of rotamers; m/z 387 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C=O)C>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
4-[4-(4-Trifluoromethoxybenzyl)piperazin-1-yl]phenol (3.36 g, 9.54 mmol) was dissolved in of DMF (20 ml). To the solution, sodium hydride (420 mg, 10.5 mmol) was added at room temperature, and the solution was stirred for 15 minutes at 80° C. To the reaction mixture, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (2.18 g, 10.0 mmol) was added with cooling on ice-bath followed by stirring for further 15 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (2.0 g, yield 40%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added ethyl bromoacetate (326 mg), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as white powder crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19].O.[OH-].[Li+]>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#Cc1ccsc1N
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccsc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (3.87 g, 20.13 mmol), 2-aminothiophene-3-carbonitrile (2.50 g, 20.13 mmol), and DMSO (25.0 ml). Add lithium hydroxide monohydrate (1.69 g, 40.27 mmol) all at once and then stir the mixture at ambient temperature for 24 hours. Pour the mixture onto ice chips and stir it for 1.5 hours. Remove the resulting orange precipitate by vacuum filtration and then dry it under vacuum to give 4.85 g (86%) of the title compound: mass spectrum (ion spray): m/z=279.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C@H:11]([C:13]([NH:22][CH2:20][CH3:21])=[O:15])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(Cl)c1
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(cyclopropylmethyl)alanine and ethylamine: MS (ES) m/z 306 (M+1).