Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:33])([CH3:3])[CH3:2].Cl>C(O)(=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:33])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)n3c(=O)n(C(C)C)c4ccccc43)CC2)CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCCC3)CC2)c2ccccc21
Yield: 87.3 %

Procedure:
A mixture of Methyl 1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylate (1.33 g, 2.90 mmol, Step 4) in 4N-HCl (6 mL) and acetic acid (6 mL) was stirred at reflux for 18 h . After cooling, the reaction mixture was concentrated and basified with sat. NaHCO3 aq. (100 mL), extracted with CH2Cl2 (150 mL) for three times. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluted with MeOH/CH2Cl2 (1:10) to give 1.12 g (85%) of title compound as white solid. The crude compound was recrystallized from EtOAc×2 and dried in vacuo at 50° C. for 2 days to give 610 mg of title compound as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:15](=O)[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:10]12.[CH2:21]([Zn]CC)C.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:21])=[O:13]
Reactant: COc1ccccc1-n1c(=O)oc(=O)c2ccccc21
Reactant: CC[Zn]CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1Nc1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(2-Methoxyphenyl)isatoic anhydride (1 g, 0.00369 mole), 4 ml (0.00532 mole) of 1.33M diethylzinc in 4 ml of tetrahydrofuran, and 15 ml of tetrahydrofuran were combined at 0°-5° C. and then stirred at room temperature for two days. The reaction mixture was poured into water and extracted with ether. The ether extracts were washed with 20 ml of 1N potassium hydroxide, then dried over anhydrous magnesium sulfate and concentrated. The residue (1.12 g) was flash chromatographed on silica gel using 5% ethyl acetate/95% hexane as eluant to afford ethyl 2-(2-methoxyphenylamino)benzoate as a yellow viscous liquid, b.p. 284°-286° C. (760 mm).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:31]3[N:30]=[C:23]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[CH2:13][C@@H:12]1[OH:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.N1C=CC=CC=1>[C:25]([NH:24][C:23]1[NH:22][C:20](=[O:21])[C:19]2[N:18]=[CH:17][N:16]([C@@H:14]3[O:15][C@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:12]([OH:32])[CH2:13]3)[C:31]=2[N:30]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@@H](O)[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a suspension of 51 (5 g, 11.33 mmol) in anhydrous dichloromethane (200 mL) and anhydrous pyridine (30 mL) was added dropwise trifluoromethanesulfonic anhydride (5.8 mL, 33.99 mmol) at 0° C. After removal of the cooling bath, the reaction was stirred at room temperature for 30 min until the reaction mixture cleared up. Then water (20 mL) was added and the reaction was further stirred for 3 h at room temperature. The organic layer was separated and evaporated. The residual oil was then purified by column chromatography on silica gel eluting with CH2Cl2-MeOH (95:5) yielding the title compound 52 (0.5 g, 10%), together with N2-isobutyryl-9-(3-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)-guanine (53) (1.93 g, 39%) and N2-isobutyryl-9-(5-O-benzoyl-2,3-dideoxy-β-D-threo-pentofuranosyl)-(N3→3′)-cycloguanine (54) (0.89 g, 18%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([NH:34][CH:35]([CH:39](O)[CH3:40])[C:36]([O-:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:28]1([NH:34][CH:35]([CH:39]([Cl:1])[CH3:40])[C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(O)C(Nc1ccccc1)C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Cl)C(Nc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-chlorosuccinimide (1.24 g) and dry THF (60 ml), stirring at RT, is slowly added triphenylphosphine (2.43 g) in 50 ml of THF. Then th m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoate (3.5 g) in 30 ml of THF is added slowly. The reaction mixture is stirred overnight. The reaction is then concentrated under reduced pressure. The residue (oil) is taken up in ether, washed with water, dried over magnesium sulfate and evaporated to yield the m-phenoxybenzyl ester of 2-phenylamino-3-chloro-butanoic acid, MS m/e 395 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)CBr
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccc(Cl)cc1)S(=O)(=O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-chlorophenyl)-3-methoxy-benzenesulfonamide (900 mg, 3.02 mmol) in anhydrous THF (40 mL) was added sodium hydride (146 mg, 3.62 mmol) at 0-5° C. under nitrogen. The mixture was stirred at 25° C. for 30 minutes. Methyl bromoacetate (463 mg, 3.02 mmol) was then added, stirred for 1 h at 25° C. A further amount of methyl bromoacetate (232 mg, 1.51 mmol) was added, and stirring continued for another 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water, dried (Na2SO4), evaporated under reduced pressure to yield the title compound as oily compound, which was used as such in the next step. Yield: 1.03 g (92%).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (617 mg, 2.04 mmol), methylurea (302 mg, 4.07 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. %, 4.63 mL, 3.06 mmol) was heated at 100° C. for 8 h. After this time, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (50 mL), and then filtered through a pad of silica gel. The organics were then concentrated in vacuo to give the crude product. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionyl]-3-methyl-urea as a white solid: EI-HRMS m/e calcd for C15H18Cl2N2O3 (M+) 344.0694, found 344.0699.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8](=[O:14])[CH:7]1[CH3:15].[Br:16]Br.Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[CH:6]([CH3:5])[CH:7]([CH3:15])[C:8](=[O:14])[C:9]=2[S:10][CH:11]=1
Reactant: BrBr
Reactant: CC1C(=O)c2sccc2C1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1C(=O)c2scc(Br)c2C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 29.3 g (220 mmol) of AlCl3 in 40 ml of chloroform a solution of 16.4 g (100 mmol) of 4,5-dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 15 ml of chloroform was added while vigorously stirring for 30 min at 0° C. This mixture was stirred for 15 min; then, a solution of 5.48 ml (17.1 g, 107 mmol) of bromine in 10 ml of chloroform was added dropwise over 1 h at 0° C. The resulting mixture was stirred for 1.5 h at room temperature and then poured on 200 cm3 of ice. The mixture was acidified with 4 M HCl to pH 1. The organic layer was separated, and the aqueous layer was washed with 3×100 ml of dichloromethane. The combined organic fractions were dried over K2CO3 and evaporated to dryness. The product was isolated by vacuum distillation, bp 110-112° C./2 mm Hg. Yield 22.1 g (91%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Ca+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[CH:10]([CH:22]1[CH2:27][C:26](=[O:28])[O:25][C:23]1=O)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC>O.C(O)(C)C>[C:26]([O:25][CH:23]=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:28])[CH2:27][CH2:2][C:1]([O-:4])=[O:3].[Ca+2:5].[CH:23]([O:25][C:26](=[O:28])[CH2:27][CH2:7][C:6]([O-:9])=[O:8])=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: CC(=O)[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCC=COC(=O)CCC(=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 113.2 %

Procedure:
A solution of 313.5 g (1.98 mol) calcium acetate in 1000 ml water was added to a solution of 570 g (1.98 mol) dodecenyl succinic anhydride in 1000 ml isopropanol. The mixture was then heated to 90° C., left at that temperature for 1.5 h and then concentrated in a water jet vacuum. The residue was dried in vacuo in a drying cabinet at 100° C. 680 g of the calcium soap were obtained in the form of a colorless powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][C:18]=1[F:22])=[O:12]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.31 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in 1,3-difluorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.16 g of 6-bromo-1-(2,4-difluorophenyl)-1-hexanone.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+:7].[C:8]1(=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>CO.[Pd]>[Na+:7].[CH:8]1([NH:1][CH2:2][C:3]([O-:5])=[O:4])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=C1CCc2ccccc21
Reactant: NCC(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CNC1CCc2ccccc21
Reaction time: 24 h
Yield: 29.7 %

Procedure:
Glycine (5.1 g, 0.068 mole) was dissolved in a solution of NaOH (2.72 g, 0.068 mole) and methanol (125 ml). To this was added 1-indanone (10.0 g, 0.076 mole, 10% excess) and 5% Pd/C dry (2.0 g). This mixture was subjected to hydrogen at room temperature on a Parr shaker for 24 hours. The catalyst was removed by filtration and fresh 5% Pd/C dry (2.0 g) added. Hydrogenation was resumed for 20 hours. A total of 55 psi of H2 (68 psi theory) was taken up. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to an oily residue. This residue was dissolved in H2O (100 ml) and extracted with ethyl acetate (3×25 ml). The aqueous solution was cooled on an ice bath and a white solid precipitated. This solid was collected and air dried to give 5.0 g of crude product. A second crop was obtained by concentrating the filtrate under reduced pressure to a solid residue. This residue was recrystallized from 70% isopropanol/H2O (40 ml), collected and air dried to give 4.3 g of product. The two crops were combined, triturated in 80% isopropanol/H2O (50 ml), collected, air dried and dried in vacuo at 60° to give 6.8 g (0.037 mole, 47% yield), melting point 196°-200° (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16].[OH-].[K+].NN>C(O)CO>[CH3:19][O:18][CH:3]([O:2][CH3:1])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: COC(OC)c1ccsc1C(=O)c1ccccc1F
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: COC(OC)c1ccsc1Cc1ccccc1F
Temperature: 25 °C

Procedure:
To 2-(2-fluorobenzoyl)-3-thiophenecarboxaldehyde dimethylacetal (144 g), and ethylene glycol (500 ml) was added potassium hydroxide (115 g) and hydrazine.monohydrate (74.8 ml). The reaction mixture was warmed slowly in an oil bath to 70°-75° C.; 10-15 ml of distillate was collected. The temperature was slowly increased to 120°-125° C. and maintained at this temperature for 30 mins. The oil bath was removed, and the mixture allowed to cool to room temperature. Ether and water were added and the layers separated. The aqueous layer was extracted with ether-dichloromethane, and the combined organic layers washed with brine and dried over anhydrous potassium carbonate, filtered and concentrated. The residue in ethyl acetate was passed through a pad of silica gel and ethyl acetate. Concentration afforded 2-(2-fluorobenzyl)-3-thiophenecarboxaldehyde dimethylacetal.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].N1C=CC=CC=1.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][Si:17]([CH3:20])([CH3:19])[CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)OCCO[Si](C)(C)C
Yield: 91.4 %

Procedure:
In a three-neck flask having a capacity of 500 ml, 26 g (0.2 moles) of 2-hydroxyethyl methacrylate (abbreviated to HEMA) and 16 g of pyridine were dissolved in 200 ml of carbon tetrachloride. At room temperature, 107.5 g (0.2 moles) of trimethylchlorosilane was slowly dropped into the solution in the flask to complete the addition of the entire amount in 30 min. During this process precipitation of hydrochloric acid salt of pyridine took place. After filtration, carbon tetrachloride in the reaction liquid was distilled out by using an evaporater, and the remaining liquid was distilled under reduced pressure to obtain 37 g of 2-trimethylsiloxyethyl methacrylate (abbreviated to HEMA-Si).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid (6.1 g, 0.04 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was added, dropwise, bromoacetyl bromide (8.0 g, 3.5 mL, 100 mol %) while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~20 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice-water. The light precipitate which formed was filtered and then dried in a vacuum oven for 20 h at 40°-45° C., giving 7.8 g (72%) of the title compound: mp 213°-215.3° C.; 1H NMR (DMSO-d6) δ13.56 (bs, 1H, OH), 11.19 (s, 1H, NH), 9.68 (s, 1H, OH), 8.19 (d, 1H, J=8.8), 7.36 (d, 1H, J=3.2), 7.01 (dd, 1H, J=3.2, J=9.2), 4.19 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 164.32, 153.08, 131.69, 122.21, 120.79, 119.00, 116.60, 30.66; MS (EI, m/z) 273 (M+), 275 (M+2+). HRMS (EI) calcd for C9H8NO4Br 272.9637, found 272.9634.
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]2[CH2:12][CH2:13][CH2:14][C:4]=12.Br>CC(O)=O>[N+:9]([C:8]1[C:3]([OH:2])=[C:4]2[CH2:14][CH2:13][CH2:12][C:5]2=[N:6][CH:7]=1)([O-:11])=[O:10]
Reactant: COc1c([N+](=O)[O-])cnc2c1CCC2
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2c(c1O)CCC2
Temperature: 130 °C

Procedure:
A mixture of 4-methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (1.535 g, 7.905 mmol) in AcOH (2.6 mL) was treated 48% aq. HBr (2.6 mL, 23 mmol). The flask containing the mixture was sealed and heated at 130° C. for 40 min., then allowed to cool. The resulting mixture was concentrated under reduced pressure, the residue was neutralized to pH=7-8 using 50% NaOH with cooling. After further concentrating, the residue was diluted with MeOH and THF, dried, filtered and concentrated to give the crude sub-title compound as light brown powder, which was used without further purification. LCMS calc. for C8H9N2O3 (M+H)+: m/z=181.1. Found: 181.2.
Reaction SMILES: C(N(CC)CC)C.BrCC[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.Cl.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[NH2:27])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(N(N)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Triethylamine (5.2 mL 37.8 mmol) and (1-(2-Bromoethyl)-4-methoxybenzene (1.9 mL, 12.60 mmol) were added to a solution of p-tolylhydrazine hydrochloride (2 gm, 12.60 mmol) in ethanol (30 mL) and the resulting solution was stirred at RT for an 1 h after which it was heated at 90° C. for 2-3 h. The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3, and extracted in ethyl acetate. The combined organic layers was dried over Na2SO4 and concentrated to obtain (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g). (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g, 10.9 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.5 gm, 10.9 mmol) were taken in ethanolic HCl (30 mL), and stirred at RT for 15 min and the solvent was removed in vacuo. The residue was taken in ethanol (30 mL) and heated at 90° C. for 3. After completion of the reaction (the progress of the reaction was monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3. The product was extracted in ethyl acetate and the organic layers were separated, dried over Na2SO4 and concentrated. The resulting crude product was purified over neutral alumina (10% Me-OH in dichloromethane) to obtain the product as free base (500 mg). The NMR data for the compound is as follows: 1H NMR (DMSO)—7.40-7.35 (d, 1H), 7.25 (s, 1H), 6.90-6.85 (d, 1H), 6.85-6.80 (d, 2H), 6.80-6.75 (d, 2H), 4.25-4.10 (t, 2H), 3.85-3.75 (m, 1H), 3.65 (s, 3H), 3.00-2.80 (t, 2H), 2.65-2.55 (d, 2H), 2.30 (s, 3H), 2.20-2.00 (m, 1H), 1.95 (s, 3H), 1.45-1.40 (m, 2H), 1.40-1.35 (m, 2H).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:8](=[O:21])[N:9]([CH3:20])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][CH:11]=2)=[O:6])C>C(OC(=O)C)(=O)C>[OH:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][CH3:19])[N:9]([CH3:20])[C:8](=[O:21])[C:7]=1[C:5]([OH:6])=[O:4]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2c1c(O)c(C(=O)O)c(=O)n2C
Temperature: 80 °C
Yield: 76 %

Procedure:
While cooling, 10 ml of conc. hydrochloric acid was added to 30 ml of acetic anhydride. To this solution, 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (10.5 g, 38 mmol) was added and the mixture heated at 80° C. for 14 hours. The mixture was cooled to room temperature and the crystalline product was filtered off, washed with cold methanol and dried to yield the title compound (7.2 g), yield 77%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14](=O)[NH:13][N:12]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:12][N:13]=1
Reactant: COc1ccc(OC)c(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(OC)c(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(2,5-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:23]=2[O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cccc(CN)c1OC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1OC

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (160 mg, 0.43 mmol) and 2,3-dimethoxy benzylamine (87 mg, 0.52 mmol). The title compound was obtained as a solid (80 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.25 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 6.99 (2H, m), 6.82 (1H, m), 4.38 (2H, m), 3.78 (3H, s), 3.71 (3H, s). MS m/z: 498.29, 500.27 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[N:4][C:3]=1[CH3:25]>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[N:4][C:3]=1[CH3:25]
Reactant: Cc1nc(C)c2nc(/C=C/c3nc(N4CCCC4)nn3C)nn2c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc(C)c2nc(CCc3nc(N4CCCC4)nn3C)nn2c1C
Yield: 55.2 %

Procedure:
(E)-5,6,8-Trimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine (45 mg, 99.4%) and Pd/C (5 mg) were stirred in acetic acid (0.7 ml) under hydrogen for 1 h. The mixture was filtered and concentrated to give the product (25 mg) as a light brown solid. MS: m/z=341.2 (M+H+)