Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (3.0 g), benzylbromide (1.5 ml) and 1 N sodium hydroxide (30 ml) is stirred at room temperature for 6-7 hours. After cooling, the precipitated sodium 3-benzyloxy-5-nitro-4-phenylbenzoate is collected by filtration and washed with a small amount of icecold water. After drying, the sodium salt is dissolved in hot water (100 ml), and the 3-benzyloxy-5-nitro-4-phenylbenzoic acid is precipitated by addition of 4 N hydrochloric acid (10 ml). After cooling, the acid is collected by filtration, washed with water and dried. After recrystallization twice from isopropanol, it is obtained with a melting point of 188.5°-189.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39]
Reactant: O=C(Cl)C1CC1
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), cyclopropane carbonyl chloride (16 mg, 14 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-28 (66 mg, 93%). 1H NMR (600 MHz, CDCl3): δ 8.33 (s, 1H), 7.40 (t, J=6.1 Hz, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 6.40 (br s, 2H), 5.90 (s, 2H), 4.29 (t, J=6.2 Hz, 2H), 3.11 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.87-1.91 (m, 2H), 1.45-1.49 (m, 1H), 0.98-0.96 (m, 2H), 0.77-0.74 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 173.7, 154.9, 153.0, 151.8, 148.3, 147.5, 146.6, 144.7, 119.9, 119.5, 109.6, 102.5, 101.7, 45.3, 40.6, 35.3, 29.1, 14.9, 7.1 HRMS (ESI) m/z [M+H]+ calcd. for C21H26N7O3S, 456.1818. found 456.1812.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of commercial 4′-bromo-2,2,2-trifluoroacetophenone (100 mg) in 1.9 mL of methanol was added sodium borohydride (15 mg). The mixture was stirred at room temperature overnight. Water was added, extracted with methyl t-butyl ether (3×20 mL) washed with water and brine. It was dried with magnesium sulfate and the solvent removed under reduced pressure to yield the title compound and it was used as such for the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([OH:28])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:20]1[CH:19]=[CH:18][C:17]([CH3:16])=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1cc(C)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (113 mg), ethyl 5-methylsalicylate (632 mg), and 4-dimethylaminopyridine (435 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (64.1 mg, yield 35%).
Reaction SMILES: [C@@H:1]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:21]>C1COCC1>[C@@H:1]1([N:10]([CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(1S)-2,3-dihydro-1H-inden-1-ylcarbamate (1.82 g, 7.80 mmol) in THF (50.0 mL) under an atmosphere of argon at 0° C. was added 60% sodium hydride in mineral oil (968 mg, 24.2 mmol) and the suspension was allowed to warm to rt and stir for 30 min. Iodomethane (1.52 mL, 24.2 mmol) was added and the mixture was stirred overnight. The reaction was then quenched via addition of saturated ammonium chloride solution (10.0 mL) and was concentrated in vacuo. The mixture was then partitioned between water (20 mL) and DCM (50 mL) and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the title compound as a clear, colorless oil (1.84 g, 95%). LC/MS: Rt=2.21 min, ES+ 248 (AA standard).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(Cl)Cl>[C:39]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:27][CH3:28])[CH2:24][CH2:25]2)[CH2:9]1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C(C)=O)C3CCCCC3)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(ethyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]1[CH:25]([OH:26])[CH2:24][NH:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:23]1[CH2:22][CH2:21][CH:25]([OH:26])[CH2:24]1)=[O:13])[CH2:8]2
Reactant: OC1CCNC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)C1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and DL-3-pyrrolidinol (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(3-hydroxy-pyrrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (68 mg, 66%) as an off-white powder. ES-HRMS m/e calcd for C19H29N4O2 (M+H+) 345.2285, found 345.2281.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[O:22][N:21]=4)=[C:9]3[C:8]2=[O:28])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].O>FC(F)(F)C(O)=O>[N:1]([C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[O:22][N:21]=4)=[C:9]3[C:8]2=[O:28])=[CH:4][CH:3]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(4-aminobenzyl)-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline (0.1 g, 0.25 mmol) in trifluoroacetic acid (3 ml) at 0° C. was added sodium nitrite (0.1 g, 1.4 mmol). After 5 min. sodium azide (0.16 g, 2.5 mmol) was added. Stirring was continued for 1 h. Then water (20 ml) was added, and the mixture was extracted twice with dichloromethane (20 ml). The combined extracts were dried over sodium sulphate and evaporated to give the title compound as a pale yellow solid, m.p. 183°-184° C. (dec.). Chromatographic purification (SiO2)/CH2Cl2 -acetone 4:1) gave crystals with m.p. 194°-197° C. (dec.).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(I)ccc1OC1CCOCC1
Yield: 84.6 %

Procedure:
In a manner similar to the method described in Example 9, 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) and K2CO3 in N,N-dimethylformamide to give 5-iodo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 3.4 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OCCOc2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 62 %

Procedure:
A mixture of 64 g of methyl{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate and 37.4 g of N-bromosuccinimide in 800 ml of carbon tetrachloride is stirred and refluxed for 72 hours or until the reaction is complete. The solution is filtered and the filtrate passed through a silica gel column with carbon tetrachloride as eluent to give 49.4 g of white crystals, mp 76°-80° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[CH2:21]([SnH:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.[NH4+].[Cl-]>C1COCC1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Clc1ncccn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Prepare this compound according to the procedure described by Sandosham et al, Tetrahedron (1994), 50, 275-284). Prepare fresh LDA from diisopropyl amine (25 ml, 178 mmol) and n-BuLi (2.5 M, 70 ml, 175 mmol) in THF (230 ml). Treat the LDA solution with a solution of tributyltin hydride (142 ml, 156 mmol) in THF (30 ml) dropwise at 0° C. and stir for an additional 15 min after completion of addition. Cool the reaction mixture to −78° C., add a solution of 2-chloropyrimidine (15 g, 131 mmol) in THF (100 ml) dropwise and stir the reaction mixture for 3 h at −78° C., then allow the reaction mixture to warm to 0° C. over a period of 30 min. Pour the reaction mixture on saturated aqueous NH4Cl and extract with EtOAc. Combine the organic layers, dry and concentrate. Purify the residue by column chromatography to produce the desired compound as a light yellow oil. 1H NMR (CDCl3) δ8.65 (d, 2H), 7.1 (t, 1H), 1.6 (m, 6H), 1.3 (m, 6H), 1.1 (m, 6H), 0.85 (t, 9H).
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O[K])(C)(C)C.[CH:14](Br)([Br:16])[Br:15].CCCCCC>CCCCC>[Br:15][C:14]1([Br:16])[CH:7]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: BrC(Br)Br
Reactant: C1=CCCCCC1
Agent: CC(C)(C)O[K]
Solvent: CCCCC
Solvent: CCCCCC
Product: BrC1(Br)C2CCCCCC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of cycloheptene (500 mg, 5.20 mmol, 1 eq) in dry Pentane (52 ml) under Ar atmosphere, tBuOK (671 mg, 5.98 mmol, 1.15 eq) was added. Suspension was cooled to 0° C. and CHBr3 (466 μl, 5.20 mmol, 1 eq) was added in a time period of six hours. Then the solution was warmed to Room Temperature (RT) and the resulting dark-brown solution was stirred overnight at RT. Reaction was controlled by TLC (Hexane as eluent) and was quenched with water (10 ml) and concentrated HCl until neutralization. Layers were separated and the aqueous layer was extracted with pentane (3×50 ml). Combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to obtain product 8,8-dibromobicyclo[5.1.0]octane as a brown oil that was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 1-methyl-4-(4-nitrobenzyl)piperazine (4.0 g) in methanol (100 mL) at room temperature under nitrogen atmosphere was added Raney nickel (1.6 gm). The reaction mixture was stirred for 2 hr under hydrogen atmosphere. The progress of the reaction was monitored by TLC and upon completion of the reaction, the mixture was filtered under nitrogen atmosphere and the solvent was removed under reduced pressure to give 4-[(4-methylpiperazin-1-yl)methyl]aniline (3.2 g). 1H NMR (CDCl3, 200 MHz) δ: 7.13 (2H, d, J=8.4 Hz), 6.61 (2H, d, J=8.4 Hz), 3.41 (2H, s), 2.45 (8H, bm), 2.27 (3H, s); m/e=206 (M+1).
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)CC1.[CH3:18][O:19]CC(Cl)=O.C1(C(Cl)=O)CC1>>[CH3:18][O:19][CH2:1][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: COCC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: O=C(Cl)C1CC1
Product: COCC1NCCc2cc(OC)c(OC)cc21

Procedure:
1,2,3,4-Tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl- 6,7-dimethoxy-isoquinoline but substituting in the first step 2-methoxyacetyl chloride for cyclopropylcarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[N:4][C:5]([Br:10])=[C:6]([F:9])[C:7]=1[Br:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:10][C:5]1[C:6]([F:9])=[C:7]([Br:8])[C:2]([F:1])=[C:3]([C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[F:12])[N:4]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Fc1c(Br)nc(Br)c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 28.2 %

Procedure:
To a degassed mixture of 3,5-difluoro-2,4,6-tribromopyridine (4.26 g, 12.1 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.80 g, 10.4 mmol), aqueous sodium carbonate (10 ml of a 2M solution) and tetrahydrofuran (40 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.67 g). The mixture was then stirred at 55° C. for 48 h under an atmosphere of nitrogen. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was separated and evaporated and the residue chromatographed on silica gel eluting with isohexane on a gradient of dichloromethane (20-40%) to afford 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine as a solid (1.21 g): δH (400 Mdz, CDCl3) 7.37 (1H, t, J 9 Hz), 8.38 (1H, m), 8.55 (1H, dd, J 6, 3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl.C1COCC1>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NNc1ccc(Cl)nn1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloropyridazin-3-yl)hydrazine, 4-nitrobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and diethyl ether to obtain N′-(6-chloropyridazin-3-yl)-4-nitrobenzohydrazide. To this, acetic acid was added, and the mixture was stirred at 110° C. for 2 hours, the reaction solution was concentrated under reduced pressure, and the resultant crude crystal was washed with ethanol to obtain 6-chloro-3-(4-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine. Dat (F:276).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])C.[OH-].[Na+].O>C(O)C>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[C:8](=[O:10])[CH2:9][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)CC2C(=O)O)c(OC)c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5.80 g (0.020 mole) of ethyl-[1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylate] in 25 ml of ethanol a solution of 0.88 g (0.022 mole) of sodium hydroxide and 60 ml of water is added. The reaction solution is stirred for 2 hours and extracted three times with 20 ml of ether each. The aqueous layer is acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted three times with 20 ml of dichloromethane each. The united organic solutions are dried over anhydrous magnesium sulfate, filtered and from the filtrate the dichloromethane is distilled off. The residue is treated with ether, the yellowish-white crystalline product is filtered off and recrystallized from benzene. Thus 4.0 g of 1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylic acid are obtained. Yield: 75.4%. M.p.: 124°-125° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[CH:5]=1)=[O:3].BrBr.ClC1C=C(Cl)C=CC=1C(=O)C[Br:19].C(C1C=CC=CC=1C(=O)CBr)C.C(C1C=CC(C(=O)CBr)=CC=1)(C)C.C(C1C=C(C=CC=1)C(=O)CBr)C(C)C.CC1C=C(C=CC=1C)C(=O)CBr.C(OC1C=C(C=CC=1)C(=O)CBr)C.C(OC1C=CC(C(=O)CBr)=CC=1)(C)C.C(OC1C=C(C=CC=1OCC)C(=O)CBr)C.FC1C=CC(F)=CC=1C(=O)CBr>C(Cl)(Cl)Cl.C(O)(=O)C>[F:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[F:10])[C:2](=[O:3])[CH2:1][Br:19]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: BrBr
Agent: CC(C)Cc1cccc(C(=O)CBr)c1
Agent: CC(C)Oc1ccc(C(=O)CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(F)c(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 10.1 g. (0.065 mole) of 3,4-difluoroacetophenone in 100 ml. of glacial acetic acid was added 3.4 ml. (0.065 mole) of bromine dropwise. When the addition was complete the solution was stirred for 0.5 hr. and then stripped to dryness under reduced pressure. The residue was dissolved in chloroform and washed with aqueous sodium bicarbonate. Evaporation of the organic phase provided 14.8 g. (97%) of colorless liquid product. Similarly prepared were 2,4-dichlorophenacyl bromide, o-ethylphenacyl bromide, p-isopropylphenacyl bromide, m-isobutylphenacyl bromide, 3,4-dimethylphenacyl bromide, m-ethoxyphenacyl bromide, p-isopropoxyphenacyl bromide, 3,4-diethoxyphenacyl bromide, and 2,5-difluorophenacyl bromide.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClC(Cl)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
tert-Octylamine (51.7 g, 0.4 mol) and triethylamine (61.2 ml, 0.44 mol) in 260 ml of dichloroethane are introduced into a reactor. The mixture is heated to 70° C. and then 4-nitrobenzoyl chloride (77.9 g, 0.42 mol) is added in small portions in 50 minutes. The mixture is refluxed for 4 hours. The reaction mixture is poured into ice-cold water; the product is extracted with dichloromethane, drying is carried out, and the solvent is evaporated off. The beige precipitate obtained is recrystallized from a mixture of isopropyl ether and ethanol (10:1 ratio). After drying under vacuum, 84.6 g (yield: 76%) of 4-nitro-N-(tert-octyl)benzamide are obtained in the form of an off-white powder, which is used as it is in the following stage.