Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][C:13]1([CH3:16])[CH2:15][O:14]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C([O-])(O)=O.[Na+]>[CH3:12][C:13]([OH:14])([CH3:16])[CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC1(C)CO1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 2-methyl-4-nitrophenol (5.50 g, 35.9 mmol), 2,2-dimethyloxirane (7.77 g, 108 mmol), K2CO3 (4.96 g, 35.9 mmol) and NaH2PO4 (4.31 g, 35.9 mmol) in MeCN (50 mL) and H2O (8.82 mL) was stirred at 140° C. in a steel bomb for 6 hours. After cooling to RT, the reaction was diluted with aq. saturated NaHCO3 (80 ml) prior to extraction with EtOAc (100 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 60% ethyl acetate) to elute 2-methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol (7.3 g, 32.4 mmol, 90% yield) as yellow oil. MS (M+1=226). 1H NMR (500 MHz, chloroform-d) δ ppm 8.00-8.15 (2H, m), 6.86 (1H, d, J=8.80 Hz), 3.90 (2H, s), 2.33 (3H, s), 1.40 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH3:22])[CH:9]=1)O)[CH3:2].S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:23][CH3:24])=[CH:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:10]([CH3:22])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(C)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)c(C)c1)OC

Procedure:
A mixture of 3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-propionic acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]1[O:6][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccccc1O
Product: Clc1ccc(Cl)c(-c2nc3ccccc3o2)c1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
2,5-Dichlorobenzoic acid (800 g, 4.2 mol), 2-aminophenol (415 g, 3.8 mol) and polyphosphoric acid (1600 g) were placed in a flask and heated at 180°-190° C. for 2 days. The viscous dark solution was poured onto ice while hot. The solid was collected by filtration and washed with water thoroughly. The solid cake was transferred into a large beaker and stirred with 2 liters of saturated aqueous sodium bicarbonate for 16 hours. The brownish suspension was filtered and washed with water and dried at 80° C. overnight to give 1 kg of crude product. The crude product was purified by recrystallization from cyclohexane twice to give 474 g of monomer as white crystals.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=1)=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
SOCl2 (10.84 mL, 148.5 mmol) was added to a suspension of 5-bromonicotinic acid (5 g, 24.75 mmol) in DCM (60 mL) and the RM was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (40 mL), the mixture was cooled to 0° C. under a nitrogen atmosphere, DIPEA (8.65 mL, 49.5 mmol) was added dropwise, followed with a solution of 4-trifluoromethoxyaniline (3.65 mL, 27.2 mmol) in DCM (20 mL). The RM was stirred for 2 h, treated with sat. aq. Na2CO3 (100 mL), and extracted EtOAc. The combined extracts were washed with sat. solution of KH2PO4 (pH=4), brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from n-heptane/EtOAc to afford the title compound as beige needles. UPLC-MS (Condition 1) tR=2.71 min, m/z=360.9-362.9 [M+H]+, m/z=358.9-361.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.3 Hz, 2H) 7.87 (d, 2H) 8.55 (t, J=2.1 Hz, 1H) 8.93 (d, J=2.2 Hz, 1H) 9.07 (d, J=1.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1.C(O)(=O)C>[Zn].CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate (1.58 g), zinc powder (1.5 g) and glacial acetic acid (1.5 ml) were added to anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour under ice-cooling. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (30 ml) and ethyl acetate (30 ml) and then extracted. The aqueous layer was further extracted twice with ethyl acetate (30 ml). The ethyl acetate layer was combined, and the combined solution was washed with 5% hydrochloric acid and water, and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, followed by filtration, and dried to give amorphous 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-caboxylic acid (1.0 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH:14][C:22](=[O:24])[CH3:23])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCC(N)C(=O)NCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13 (0.20 g, 0.98 mmol) in dry THF (2.0 mL) is added pyridine (0.086 g, 1.08 mmol), and then acetic anhydride (0.2 g, 1.96 mmol) is added dropwise. The reaction is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue purified by flash column chromatography to obtain the above compound as the R isomer.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:10]=[C:11]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:24])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:24][C:14]1[C:13]2[C:18](=[C:9]([NH:8][CH3:1])[CH:10]=[C:11]([CH2:25][N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:12]=2)[N:17]=[CH:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnc2c(N(C)Cc3ccccc3)cc(CN3CCOCC3)cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(NC)cc(CN3CCOCC3)cc2c1O
Yield: 70.5 %

Procedure:
A mixture of ethyl 8-[benzyl(methyl)amino]4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (500 mg, 1.15 mmol), 10% palladium charcoal (0.25 g) in ethanol (100 mL) is hydrogenated (50 psi initial hydrogen pressure) until HPLC shows that all the starting material has been reduced (2.5 h). The solution is filtered, the solvent removed, and the residual oil is applied in chloroform to a silica gel column which is eluted with 5-10% methanol/chloroform. After elution of a small amount of ethyl 4-hydroxy-8-(methylamino)-6-methyl-3-quinolinecarboxylate, the title compound (280 mg) is obtained.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6](N)[CH:5]=1.[OH:15]S(O)(=O)=O.N([O-])=O.[Na+].[NH4+].[OH-]>O>[OH:15][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)[C:3]([OH:2])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 39 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid methyl ester (Example 313, 1.96 g, 10 mmol) in 23 mL of H2O and 5 mL of con. H2SO4 at 0° C., was added a solution of NaNO2 (Aldrich, 900 mg, 13 mmol) in 9 mL of H2O. After 50 min stirring, the resulting diazonium salt was added to a solution of 17 mL of H2O and 17 mL of con. H2SO4 at 90° C. After stirred at 90° C. for 90 min, the mixture was cooled to room temperature and brought to pH 3 with con. NH4OH. The mixture was extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (5%-10% MeOH/CH2Cl2) to give 705 mg (39%) of product. 1H NMR (400 MHz, DMSO-d6) δ 13.64 (br s, 1H), 10.84 (s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.75 (t, J=2.2 Hz, 1H), 7.70 (dd, J=2.2, 1.3 Hz, 1H), 6.16 (s, 2H), 3.87 (s, 3H). MS (EI): m/z 184 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([NH2:14])=[O:13])[C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:15]1[CH2:20][CH2:19]S[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+].O[O:27][S:28]([O-:30])=O.[K+].C(Cl)Cl>COCCOC.O.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([NH2:14])=[O:13])[C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:15]1[CH2:20][CH2:19][S:28](=[O:30])(=[O:27])[CH2:17][CH2:16]1
Reactant: O=S([O-])OO
Reactant: NC(=O)c1c(F)c(Br)cc2c(C3CCSCC3)c[nH]c12
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: NC(=O)c1c(F)c(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 18.8 %

Procedure:
An aqueous solution of 0.0004 M Na2EDTA (0.882 mL, 0.353 μmol) was added to a solution of 5-Bromo-6-fluoro-3-(tetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (45 mg, 0.126 mmol) in DME (3 mL). In a separate flask, NaHCO3 (106 mg, 1.260 mmol) was added to a solution of Oxone (232 mg, 0.378 mmol) in water (1 mL). This mixture was then added in 3 portions over 3 min to the DME solution of 5-Bromo-6-fluoro-3-(tetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide. The reaction was stirred at room temperature for 17 h. Water (2 mL) and DCM (3 mL) were added, the layers were separated, and the aqueous layer was extracted with DCM (3×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), filtered, and concentrated under a stream of nitrogen at 50° C. The residue was dried under high vacuum, giving 9.2 mg (19%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].Cl>C(O)C>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of diphenylacetonitrile (28 g) in ethanol (100 ml) were added DBU (6 ml) and ethyl acrylate (30 ml), and the mixture was heated and stirred at 80° C. for 16 hours. After cooling, 2N-hydrochloric acid (200 ml) was added and the mixture was extracted with isopropyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude crystal crop was recrystallized from hexaneisopropyl ether to provide the title compound (34 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10](=[NH:16])[NH:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.[O-]CC.[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:16]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COCCNC(=N)c1cc(F)cc(F)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cc(F)cc(F)c2)n(CCOC)c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 3,5-difluoro-N-(2-methoxyethyl)benzenecarboximidamide hydrochloride (1:1 (i.e. the product from Example 9, Step B) (24.3 mmol) in ethanol (25 mL) was added diethyl ethoxymethylenemalonate (5.25 g, 24.3 mmol) followed by sodium ethoxide (21% soln) (9.1 mL, 24.3 mmol). The reaction mixture was heated and stirred at reflux for 24 h. The reaction mixture was cooled to room temperature concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (6.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2.C1COCC1.[NH4+].[Cl-].[NH4+].[OH-]>[Zn].CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Zinc (7.06 g, 108 mmol) was added to a stirred mixture of 20.0 g (71.2 mmol) of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 44 ml of THF, 20.1 g of NH4Cl and 90 ml of NH4OH that was cooled in an ice bath. The mixture was allowed to warm slowly to room temperature. After 5 hours reaction time, the zinc was removed by filtration. The phases were separated, and the aqueous layer was extracted three times with hexanes. The combined organic phase was washed twice with brine and dried over MgSO4. The MgSO4 was filtered off, and the solvent was removed under vacuum. Crude 6-bromo-1,2-difluoronaphthalene (16.4 g) containing 15% impurities (estimated) remained. The estimated yield of the crude 6-bromo-1,2-difluoronaphthalene was 85%. Recrystallization of the crude solid from methanol/water yielded light brown needles (13.6 g, 55.8 mmol, 77% yield).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:18][CH2:19][CH2:20][C:21]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:22]
Reactant: O=C(Cl)CCBr
Reactant: CCCCC(CC)CNCC(CC)CCCC
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)CCBr
Yield: 97 %

Procedure:
Step A is conducted using 2,2′-diethylhexylamine and 3-bromo-propanoyl chloride and leads to 3-bromo-N,N-bis(2-ethylhexyl)propanamide (Yield: 97%) for which the 1H and 13C NMR characterisations are given below:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
In a dry round-bottomed flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 25.2 mmol) was dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 1.22 g, 30.6 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min then cooled back to 0° C. and SEM-Cl (5.4 mL, 30.4 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with 50 mL water and extracted with 150 mL diethyl ether (2×). The combined organic layers were washed twice with 30 mL water and once with 30 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on ˜20 g SiO2 and chromatographed over 200 g SiO2 with EtOAc/Hexanes (gradient: 0-15% EtOAc). All fractions containing product were combined and concentrated to afford 6.61 g (80%) of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a pale yellow oil which gradually solidified. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.38 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H), 5.68 (s, 2H), 3.50-3.65 (m, 2H), 0.88-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1F)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Anhydrous piperazine was added to a THF solution of methyl 3,4-difluorobenzoate, and the mixture was stirred at 60° C. for 18 hours to obtain methyl 3-fluoro-4-piperazin-1-ylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Yield: 93.7 %

Procedure:
A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10% Pd—C (400 mg, 0.376 mmol) in ethanol (100 ml) and ethyl acetate (100 ml) is agitated under 1 atmosphere pressure of hydrogen overnight. The mixture is filtered and concentrated to give of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.87 g, 94% yield). MS (ESI) m/z 278 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][CH:31]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 57 %

Procedure:
The title compound was prepared in a yield of 57% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and α-(4-methoxyphenyl)benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.Cl[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1ncc([N+](=O)[O-])cc1C
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A yellow solution of 2-methoxy-3-methyl-5-nitropyridine (68.8 g, 409 mmol) and tert-butyl 2-chloroacetate (77.0 g, 511 mmol) in THF (1 L) was stirred and cooled to −20° C. in a dry ice/isopropanol bath. Potassium tert-butoxide (115 g, 1.02 mol) was added at a rate so that the reaction temperature was less than −10° C. The reaction mixture turned dark purple. When the addition was complete, the cooling bath was removed and the reaction was stirred for 30 min. The stirred reaction mixture was quenched with HCl (500 mL, 2.4 N). The purple solution turned pale yellow and the mixture separated into two layers. The organic layer was separated, washed three times with brine, and concentrated in vacuo. Hexane was added to the amber residue. The mixture was concentrated in vacuo and then dried under high vacuum for 1 hr to give tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.4 g, 72% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 4.09 (s, 2H), 4.02 (s, 2H), 2.21 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.81, 163.63, 147.88, 139.41, 135.19, 120.82, 81.66, 54.69, 44.48, 28.03, 15.27. An analytical sample was recrystallized from hexane to give white needles, mp 71-72.5° C. Anal. calcd. for C13H18N2O5: C, 55.31, H, 6.42, N, 9.92. Found: C, 55.52, H, 6.40, N, 9.84.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=O.Cl.[NH:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:14][C:9]1[CH:8]=[C:7]([C:5]2[N:23]=[C:18]3[NH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:3](=[O:15])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: N=C1NCCCN1
Reactant: COC(=O)CC(=O)c1ccc(C)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(=O)n3c(n2)NCCC3)cc1C

Procedure:
A suspension of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylideneamine hydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8 mmol) in ethanol (20 mL) was heated to reflux for 4 h. Water (5 mL) was added to the reaction at room temperature and tan solid was collected by filtration. M+1=256.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[CH:7][CH:6]=1)C=C.C([O-])(=O)/[CH:21]=[CH:22]/[C:23]([O-])=[O:24]>>[CH2:23]([O:24][C:10]1[CH:9]=[C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:7]=[CH:6][CH:5]=1)[CH:22]=[CH2:21]
Reactant: C=CCOc1ccc(-c2nc3cnccc3[nH]2)cc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: C=CCOc1cccc(-c2nc3cnccc3[nH]2)c1

Procedure:
2-(p-Allyloxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 215°.