Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cccc([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@H]3c3ccccc3)c2)CC1
Yield: 37.9 %

Procedure:
To a solution of rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone (500 mg, 0.899 mmol) in 5 mL dry toluene was added 1-methyl-piperazine (0.123 mL, 1.08 mmol), sodium tert.-butoxide (125 mg, 1.26 mmol), bis(dibenzylidenacetone)palladium (2.1 mg, 0.002 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.3 mg, 0.007 mmol) and than refluxed overnight. The reaction mixture was diluted with 10 mL water and extracted three times with 20 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 10:10:1 gave the desired product (196 mg, 38%), MS: m/e=576.1 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:21](N(CC)CC)[CH3:22].CS(Cl)(=O)=O>O1CCCC1>[C:18]([C:13]1[C:14]([CH2:16][O:17][CH2:21][CH3:22])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:20])=[CH:10][CH:9]=2)[CH:12]=1)#[N:19]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCc1cn(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 4-(3-cyano-4-hydroxymethylpyrrole-1-yl)benzoic acid ethyl ester (0.022 g) in tetrahydrofuran (1 mL) were added triethylamine (0.0082 g) and methane sulfonylchloride (0.0093 g) under ice-cooling. After warming to ambient temperature, this mixture was stirred for 30 minutes. The insoluble material of this reaction mixture was removed by filtration, and this filtrate was added to a mixture of ethanol (1.125 g) and sodium hydride (60%, 0.13 g), and this mixture was stirred for 5 hours. To this reaction mixture was added water, and this mixture was stirred at room temperature for 1 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (3 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=88/12−81/19) to give the title compound (0.010 g).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:10]1([C:2]2[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(-c2ccccc2)c[nH]1
Yield: 77 %

Procedure:
[step 1] 4-Iodo-2-propylimidazole obtained in Reference Example A16 was dissolved in dioxane/water (2 mL/1 mL), phenylboronic acid (0.108 g, 0.889 mmol), 1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064 mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give 4-phenyl-2-propylimidazole (0.091 g, 77%).
Reaction SMILES: O.NN.[OH-].[Na+].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=O)[CH2:14][N:15]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>C(O)COCCO>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: COc1ccc2c(ccn2CC(=O)c2ccccc2Br)n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc2c(ccn2CCc2ccccc2Br)n1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
140 μl (2.9 mmol) of hydrazine hydrate and 80 mg (2 mmol) of sodium hydroxide are added to a solution of 200 mg (0.6 mmol) of the compound obtained in Step B in 2 ml of diethylene glycol. After 24 hours' stirring at 160° C., the mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and then purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 7:3) to yield the title compound in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C(Cl)Cl.CO>[CH3:19][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCO)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCO)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid (1 g, 6 mmol) in 30 mL of CH2Cl2 and 5 mL of MeOH at rt was slowly added TMSCHN2 (10 mL), and the reaction mixture was left with stirring for 1 h. The solvent was remove under reduced pressure, and the resulting residue was diluted with water and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated to afford an oil (S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid methyl ester. MS [M+H]+ 262.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[N+:20]([O-])([OH:22])=[O:21].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(c2ncccc2C(=O)NCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2ncccc2C(=O)NCCO[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
To a solution of 1.27 g of compound 7 prepared in Examples 2-10 in 13 ml of acetonitrile was added dropwise a mixture of 2.0 g of fuming nitric acid and 1.4 g of acetic anhydride while maintaining the temperature below -10° C. The mixture was stirred for 4 hours, then poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to give N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide (compound 17). The product was dissolved in ethanol, and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 1.32 g of N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl) nicotinamide dihydrochloride (compound 18)(yield 66%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])[CH:17]=1
Reactant: Nc1cccnc1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Product: CC1CC(=O)c2c(C(=O)Nc3cccnc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 3-aminopyridine, General Procedure B provided the title compound:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[I:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:12][CH:13]=1
Reactant: C1=COCCC1
Reactant: OCCCc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(CCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
3,4-Dihydro-2H-pyran (2.5 mL, 27.4 mmol) and pyridinium p-toluenesulfonate (450 mg, 1.79 mmol) were added to a chloroform (50 mL) solution of 3-(4-iodophenyl)propan-1-ol (4.73 g, 18.0 mmol), and stirred overnight at room temperature. The reaction liquid was diluted with chloroform, washed with saturated saline, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (C-200, ethyl acetate:hexane=1:9 to 1:4) to obtain the entitled compound (6.22 g, 100%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](Cl)=[O:12])[CH3:9].CN(C1C=CC=CN=1)C.[Si]([O:30][C:31]1[CH:36]=[C:35]([O:37][Si](C(C)(C)C)(C)C)[CH:34]=[CH:33][C:32]=1[C@H:45]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]1)(C(C)(C)C)(C)C>ClCCl>[C:11](=[O:12])([O:10][CH2:8][CH3:9])[O:51][C@H:48]1[CH2:47][CH2:46][C@H:45]([C:32]2[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=2[OH:30])[CH2:50][CH2:49]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (0.5 ml), ethylchloroformate (0.5 ml) and dimethylaminopyridine (cat.) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dichloromethane (5 ml). After 72 hr at room temperature, the reaction mixture was partitioned between-ethyl-acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (5 ml) and was stirred with fluoride resin (500 mg) for 16 h at room temperature. The resin was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v), and then preparative HPLC to give the title compound (4 mg, 3%) as a cream solid. δH (CD3OD) 1.20-1.30 (3H, m), 1.40-1.60 (4H, m), 1.80-1.95 (2H, m), 2.00-2.20 (2H, m), 2.70-2.84 (1H, m), 4.06-4.20 (2H, m), 4.50-4.60 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d); m/z (ES−) 279 (M−H−).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.[Na].[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10]>C(O)(=O)C>[CH3:1][N:2]1[C:6]2=[N:7][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:15]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1nccc1N
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Product: Cn1ncc2cc([N+](=O)[O-])cnc21
Temperature: 108 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-5-amine (291 mg, 3.00 mmol) in acetic acid (3 mL) is added nitromalonaldehyde sodium salt (474 mg, 3.00 mmol) and reaction mixture is heated to 108° C. for 1 h. The reaction mixture is allowed to cool to room temperature and is stirred for 16 h. The solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography using a gradient of 0-100% ethyl acetate in heptane to afford the title compound as a solid (100 mg, 19%).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2>CN(C)C=O>[CH3:1][NH:2][C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CN
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC)nc3ccccc3n12
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Monomethylamine gas was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for 2 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 2 hours, and then poured over ice and stirred another 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (88% yield) of 4-methylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 271°-273° C. Mass spectrum: m/e, 227 (P).
Reaction SMILES: [NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].[Br:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O>>[Br:6][C:7]([F:13])([F:14])[C:8]([N:1]([CH2:4][CH3:5])[CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCNCC
Product: CCN(CC)C(=O)C(F)(F)Br
Reaction time: 1 h

Procedure:
Et2NH (7.9 g, 108 mmol) was added to ethyl bromodifluoroacetate (20.1 g, 99 mmol) at 30° C. The mixture was stirred for 60 min; then all volatiles were removed under reduced pressure. To the residue was added another 7.9 g of Et2NH and the mixture was stirred another 60 min.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C:22]([NH2:27])([CH2:25][CH3:26])[CH2:23][CH3:24]>>[CH3:19][O:20][C:21](=[O:28])[C:22]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Product: CCC(CC)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 2-amino-2-ethyl-butanoic acid methyl ester hydrochloride (1:1) (CAN 92398-54-4) as starting materials, and isolated (86 mg, 93%) as yellow oil; LC-MS (UV peak area, ESI) 100%, 362.2071 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[Cl:16][S:17]([C:14]1[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([CH2:1][CH3:2])[CH:15]=1)(=[O:19])=[O:18]
Reactant: CCOC(=O)COc1ccccc1CC
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a 250 ml round-bottom flask containing chlorosulfonic acid (30 ml) cooled to 0° C. was added ethyl (2-ethylphenoxy)acetate (7.2 g, 34.6 mmoles) dropwise. Once the addition was complete the ice-bath was removed and the reaction was allowed to warm to room temperature at which the reaction was stirred for 3 hours. The reaction was then slowly added to ice and, once the excess chlorosulfonic acid was quenched, the mixture was diluted with CH2Cl2 (200 ml). The phases were separated and the aqueous fraction was washed with CH2Cl2 twice. The combined organic fractions were dried over Na2SO4 and filtered and concentrated in vacuo to yield 7.2 g (70%) of crude product. The crude product was used with no purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCBr)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2-methoxybenzaldehyde, M.p. 78-79° C.
Reaction SMILES: [CH3:1][NH2:2].CO.O.[O:6]1[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7]1>>[CH3:1][NH:2][CH2:7][CH:8]([OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN
Reactant: CCCCCCCCCCC1CO1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCC(O)CNC
Reaction time: 24 h
Yield: 85.3 %

Procedure:
Two-thousand one-hundred and seventy grams of methylamine were introduced into 4550 ml of methanol at room temperature, whereupon there were dropped in 1288 grams of 1,2-epoxydodecane within 30 minutes at 20° C with stirring and water cooling and the mixture was allowed to stand for 24 hours with occasional stirring. After drawing off the excess methanol the residue was rectified. There were obtained 1284 grams (85.3% of theory) of N-methyl-N-(2-hydroxydodecyl) amine having a boiling point at 0.4 mm Hg of 130° C and a melting point of 67°-68° C.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 2-amino-3,6,7-trichloroquinoxaline (1.54 g, 6.20 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (2.01 g, 9.30 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.21 g of the titled compound (yield, 80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:32])[NH:11][CH2:12][CH2:13][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([NH2:24])=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1COCC1>C1COCC1.O>[C:25]([N:14]([CH2:13][CH2:12][NH:11][C:10]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:32])[C:15]([NH2:24])=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: COC(=O)c1ccc(C(=O)NCCN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(N)N(CCNC(=O)c1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
With continued reference to Scheme K, To Compound XXVII: 5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (2.2 g, 4.66 mmol) in 50% THF/H2O (50 ml) was added 1.5 eq. of LiOH (294 mg, 6.99 mmol) and the reaction mixture was left to stir at room temperature for 3 hours. 10% citric acid solution was added until acidic pH and THF was evaporated. The aqueous solution was then extracted with CH2Cl2 (3×70 ml). The organic phases were combined and washed with a solution of Brine, dried over MgSO4 and evaporated to give the desired product in 84% yield. 1H NMR (CD3OD, 400 MHz) δ 1.34-1.66 (m, 21H), 3.49-3.67 (m, 4H), 7.61-7.70 (dd, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[NH2:22][NH2:23].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[N:22][NH2:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=NN)n2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.1 %

Procedure:
In 2 ml of ethanol was dissolved 50 mg (0.17 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 26 mg (0.5 mmol)of hydrazine hydrate, and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was washed with n-hexane to precipitate the product, and 34 mg (yield 65%)of Compound I-11 was obtained by the filtration. mp 118-119° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[C:11]=2[CH:10]=[CH:9][C:8]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:21][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:17](=[C:16]([F:20])[CH:15]=[CH:14][CH:13]=3)[CH2:18][C:19]=2[C:7]=1[F:6])[CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc2c(c1F)Cc1c(F)cccc1-2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCOc1ccc2c(c1F)Cc1c(F)cccc1-2

Procedure:
56 mmol of 1-bromobutane are added to a mixture of 36 mmol of 1,8-difluorofluoren-2-ol and 109 mmol of anhydrous potassium carbonate in 250 ml of 2-butanone (methyl ethyl ketone) and the mixture is subsequently heated to reflux for 8 h. The still hot solution is then mixed with 50 ml of water. The phases are separated, the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed on a rotary evaporator. The purification is effected by filtration through aluminum oxide (neutral) using toluene as the eluent and recrystallization from heptane. 2-Butoxy-1,8-difluorofluorene is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C>[C].[Pd].O1CCCC1>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][O:2][CH3:1])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]2
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2n1COC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(N)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-nitro-1H-indole-2-carboxylate (2.35 g), 10% palladium-carbon (0.24 g), ethanol (4 ml) and tetrahydrofuran (10 ml) was stirred overnight at room temperature under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.92 g, yield 91%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).