Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
3-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (12) (0.202 g; 0.42 mmol) is dissolved in methylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid (5 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×50 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.147 g) as an oil.
Reaction SMILES: C1([C:7](C2C=CC=CC=2)([O:13][Si](C)(C)C)[C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)C=CC=CC=1.S(N[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(C1C=CC(C)=CC=1)(=O)=O.C([O-])(=O)C.[Na+].C(=O)/C=C/CC>C(Cl)(Cl)Cl>[CH2:11]([C@@H:12]1[C@@H:8]([CH:7]=[O:13])[N:9]1[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH3:10]
Reactant: C[Si](C)(C)OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: CC/C=C/C=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a 500 mL round-bottom flask equipped with a stir bar was added (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (2.60 g, 8.00 mmol) and CHCl3 (200 mL). To the solution was added tert-butyl tosylcarbamate (10.9 g, 40.0 mmol). The flask was placed in a room temperature-water bath. To the stirred solution was added sodium acetate (9.84 g, 120 mmol), then (E)-pent-2-enal (4.04 g, 48.0 mmol). The mixture was stirred at room temperature for 40 minutes. The mixture was filtered, washing the filter cake with a small amount of CHCl3. The filtrate was concentrated in vacuo at 30° C. The resulting orange liquid was dissolved in Et2O (400 mL) and transfered to a 1 L separatory funnel. The solution was washed with water:aq. sat. NaHCO3 (200 mL:200 mL). The aqueous phase was extracted with Et2O (100 mL). The combined organics were washed with brine (200 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford (2R,3S)-tert-butyl 2-ethyl-3-formylaziridine-1-carboxylate as a pale orange liquid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH2:35])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH:35][C:46](=[O:47])[CH2:45][O:44][CH3:43])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)c1cn(C[C@@H](C2CCCCC2)N2Cc3cc(Oc4ccccc4)ncc3N=C2N)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@H](Cn1cc(C(C)(C)C)nn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound #152 (0.115 g, 0.24 mmol), prepared, for example, as described in Example 44 above, was taken up into DCM (5 mL) and then triethylamine (34 μL, 0.24 mmol) was added. Methoxy-acetyl chloride (22 μL, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using normal phase chromatography (heptanes:EtOAc) to yield the title compound as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]>N1C=CC=CC=1>[C:1]([NH:15][C:14]1[CH:16]=[CH:17][NH:10][C:11](=[O:12])[N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Benzoyl chloride (2.3 mL, 20 mmol) was added dropwise over 30 min to a stirred suspension of cytosine (1.1 g, 10 mmol) in dry pyridine, and stirring was continued at room temperature for a further 4 h at room temperature. The reaction was quenched by adding a small amount of methanol. The solid was filtered, washed with EtOH and dried in vacuo to give 1.92 g of the desired product 6 (90%).
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].[CH:7](=O)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:8]([CH:7]=[N+:5]([CH:2]([CH3:4])[CH3:3])[O-:6])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(C)NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[N+]([O-])=CC=Cc1ccccc1
Reaction time: 1 h

Procedure:
N-Isopropylhydroxylamine hydrochloride (5.04 grams, 45.2 millimoles, 1 molar equivalent; available from Acros Organics) was combined with trans-cinnamaldehyde (5.66 grams, 42.9 millimoles, 0.95 molar equivalent; available from Aldrich Chemical Company) in 16 milliliters of water. Initially, the mixture was an emulsion due to the low solubility of the trans-cinnamaldehyde. After being stirred rapidly for about one hour, the emulsion disappeared, and a homogeneous light yellow solution resulted. After being stirred for four hours, the reaction mixture was poured into methylene chloride and treated with 26 milliliters of saturated aqueous sodium carbonate solution until the pH was about 10.5. The phases were separated and the aqueous phase was extracted with additional methylene chloride. The combined organic phases were separated, dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue dried under vacuum overnight to produce 7.4 grams (91 percent of theory) of the desired product nitrone that was determined to be pure by liquid chromatography and further characterized by NMR spectroscopy. UV-visible spectrum of the product in absolute ethanol revealed an absorption maximum (λmax) at 330 nanometers. Exposure of this dilute solution to a 390 nanometer light source converted the nitrone to the corresponding oxaziridine with a shift of the absorption maximum to 256 nanometers. All sample manipulations were done in a dark room containing only red light to insure the stability of the nitrone product.
Reaction SMILES: ClC1C2C(=CC(OC)=[C:9]([O:12]C)C=2)C=C(Cl)N=1.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:31]([OH:33])=[O:32])[N:20]=1>>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:12][CH3:9])[CH:27]=2)[CH:22]=[C:21]([C:31]([OH:33])=[O:32])[N:20]=1
Reactant: COc1ccc2c(OC)nc(C(=O)O)cc2c1
Reactant: COc1cc2cc(Cl)nc(Cl)c2cc1OC
Product: COc1cc2cc(C(=O)O)nc(OC)c2cc1OC

Procedure:
This intermediate was prepared from 1,3-dichloro-6,7-dimethoxy-isoquinoline in three steps according to the preparation of 1,6-dimethoxy-isoquinoline-3-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=[N:14][OH:15]
Reactant: O=Cc1sccc1C1OCCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1sccc1C1OCCO1

Procedure:
3-(1,3-Dioxolan-2-yl)thiophene-2-carbaldehyde (13.1 g, 71.11 mmol), prepared by a method described by Hibino (S. Hibino et al., J. Org. Chem. 1984, 49, 5006), was dissolved in ethanol (80 ml). At room temperature a solution of hydroxylamine hydrochloride (two equivalents) and sodium hydrogencarbonate (one equivalent) in water (130 ml) was added and the resultant mixture stirred at this temperature for two hours. The ethanol was removed under reduced pressure and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation after filtration afforded 3-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde oxime as an off-white solid (quantitative). 1H NMR (2 isomers, 1:1) (CDCl3): δ 8.56 (1H, s), 8.45 (1H, s), 7.50 (1H, d, J 5.26), 7.25 (1H, d, J 5.2), 7.21 (1H, d, J 5.28), 7.12 (1H, d, J 5.2), 6.09 (1H, s), 5.99 (1H, s), 4.17–4.00 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Mg+2].[Cl-].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1cccc(Cl)c1F
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1F
Temperature: 95 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(3-chloro-2-fluorophenyl)-2-methylpropanoic acid (1.386 g, 6.40 mmol) and thionyl chloride (60.0 mL, 823 mmol) was stirred at 95° C. for 2 hours. The reaction was concentrated in vacuo, azeotroped using DCM (2×100 mL), and dried in vacuo to give the crude acid chloride. A solution of diethyl malonate (0.967 mL, 6.40 mmol) and MgCl2 (0.263 mL, 6.40 mmol) in ACN (40 mL) at 0° C., was treated dropwise with TEA (1.87 mL, 13.4 mmol), and the mixture was stirred at 25° C. for 3 hours. A solution of the acid chloride in ACN (35 mL) was added, and the mixture was stirred at 50° C. for 18 hours. The solution was concentrated in vacuo, diluted with 10% HCl(aq) (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (75 mL), dried over MgSO4, concentrated, and dried in vacuo. The residue was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give 1.56 g of the title compound. MS m/e=325 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>[OH-].[Na+].O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: OCC(O)CCl
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(O)CO)cc1C
Temperature: 140 °C
Yield: 57.4 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (2.00 g, 12.2 mmol, 1.0 equiv) and 3-chloropropane-1,2-diol (1.02 mL, 12.2 mmol, 1.0 equiv) in 50% aqueous NaOH solution (20.0 mL) was heated at 140° C. for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2,3-dihydroxypropoxy)-2,6-dimethylphenyl)ethanone (1.66 g, 7.0 mmol) as yellow oil in 57% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2 H), 4.10-4.11 (m, 1 H), 4.08-4.09 (m, 2 H), 4.01-4.02 (m, 1 H), 3.74-3.75 (m, 1 H), 2.58-2.59 (brs, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.05-2.10 (brs, 1 H); ESI-MS: m/z 239.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=1.[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[N:15]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=3)=[CH:23][CH:24]=2)=[N:15]1
Reactant: Cn1nnc(-c2ccc(O)cc2)n1
Reactant: CCc1ncc(CCCO)n1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(CCCOc2ccc(-c3nnn(C)n3)cc2)n1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89 mmol), 4-(2-methyl-tetrazol-5-yl)-phenol (172 mg, 0.98 mmol), and DEAD (171 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0° C. To the above solution was added triphenylphosphine (257 mg, 0.89 mmol) at 0° C. and the mixture was stirred for 2 h allowing the mixture to warm to 20° C. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-15/1) to afford 267 mg (92%) of 5-[3-[4-(2-methyl-tetrazol-5-yl)phenoxy]propyl]-1-methyl-2-ethylimidazole, as a white crystalline solid, m.p. 115°-117° C. (recrystallization from methylene chloride/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][N:18]=[C:19]=[O:20]>O1CCCC1>[CH3:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6]
Reactant: CN=C=O
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCOC1
Product: CNC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Methyl isocyanate (20 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by silica gel chromatography (5% 2M ammonia in methanol:methylene chloride). The solvent was evaporated to give 28.1 mg (89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1>CN(C1C=CN=CC=1)C>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:14](=[O:15])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:37]([F:42])[CH:36]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Reactant: COC(=O)c1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 9.6, [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (example 9.3) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid methyl ester (CAS Reg. No. 185629-32-7) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=538.3 [M+H+].
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11]([NH:24][NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:10]1=[O:31])C1C=CC=CC=1>CN(C)C=O.O.[Pd]>[CH2:29]([O:28][C:26]([NH:25][NH:24][C:11]1[C:10](=[O:31])[N:9]([OH:8])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(O)c1=O
Yield: 92.3 %

Procedure:
A solution of 4-benzyloxy-2-(2-ethoxycarbonylhydrazino)-6-(1H-imidazol-1-yl)-quinoxalin-3(4H)-one (10.9 g; ~25.9 mmol) in a mixture of 200 ml N,N-dimethylformamide and 100 ml water was hydrogenated at atmospheric pressure and room temperature by using 1 g 5% Pd-C as a catalyst. The catalyst was removed by filtration, and the residue was stirred with acetone to give the title compound (7.9 g; 92%). M.p. 216°-218° C. (decomp.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[C:32]([O:36][C:37]([NH:39][C:40](=[N:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])SC)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(O)C.[Hg]=O>[C:47]([O:46][C:44]([N:43]=[C:40]([NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1)=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=[Hg]
Solvent: CCO
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (300 mg) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (203 mg) in ethanol (20 mL) was added mercury(II) oxide (152 mg). The mixture was stirred for 2 hours at ambient temperature. The resultant precipitates were removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 2% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give 2-{trans-4-[2,3-bis(tert-butoxycarbonyl)guanidino]cyclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellow powders (432 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH2:3]1.[I:20]N1C(=O)CCC1=O.O>C(Cl)Cl>[I:20][C:16]1[NH:15][C:14]([C@@H:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]2[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])=[N:18][C:17]=1[CH3:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c[nH]c([C@@H]2CC(C)CN2C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of tert-butyl (2S)-4-methyl-2-(4-methyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (307 mg, 1.013 mmol) in CH2Cl2 (15 mL) is added N-iodosuccinimide (240 mg, 1.013 mmol) at 5° C. The reaction mixture is stirred for one hour and water (2 mL) is added. The organic layer is separated, dried over Na2SO4, and evaporated to dryness. The residue is purified by flash column chromatography on silica gel (12 to 100% EtOAc in Hexanes) to give tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (246 mg, 62%).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:15]([OH:28])[CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C:6]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>CO>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:15]([OH:28])[CH2:16][NH:37][CH3:36])[C:6]1=[O:35])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2c(=O)n(C(C)(C)C)c3ccccc32)cc1
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1c(=O)n(C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a cold 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester. To a solution of (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester (0.8 g, 1.6 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (4 mL, 8 mmol) and the reaction mixture stirred for 12 hours at room temperature in a sealed tube. Upon completion, the reaction was partitioned between a saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica, 20% MeOH in dichloromethane) to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-methylamino-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with diethyl ether/dichloromethane to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a white solid. HRMS: calcd for C21H27N3O2+H+, 354.21760. Found (ESI, [M+H]+), 354.2179.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Product: CN1CCN(c2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-methylpiperazin-1-yl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.