Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][CH:23]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:21]=[C:22]([S:26]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6 isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmbrpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: COC(=O)C=CC=CCBr
Reactant: O=S([O-])c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C=CC=CCS(=O)(=O)c1ccccc1
Temperature: 20 °C
Yield: 73.2 %

Procedure:
A mixture of 6-bromohexa-2,4-dienoic acid methyl ester (0.41 g, 2.0 mmol), sodium benzene sulfinate (0.33 g, 2.0 mmol) and tetra-n-butylammonium iodide (37 mg, 0.1 mmol) was heated at reflux in dry THF (10 mL) under an atmosphere of nitrogen for 2 hours. The resulting slurry was allowed to cool to 20° C. and filtered. The filtrate was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). This solution was washed successively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), then with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (7:3 to 1:1 to 1:1 60-80° C. petroleum ether:diethyl ether) to give a solid that was recrystallised to give the title compound (0.39 g, 73%) as white crystals, mp 105° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][N:29]([CH3:37])[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:33]([CH2:32][CH2:31][CH2:30][N:29]([CH3:37])[CH3:28])(=[O:35])=[O:34])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCS(=O)(=O)Cl
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nnc2c(NC3CCN(S(=O)(=O)CCCN(C)C)CC3)cc(N(C)Cc3ccccc3)nn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol; purity 80%) was slurred up in 0.3 ml DMA. 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for 16 hours. Another portion of 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for additional 16 hours. The crude material was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2.C([SiH](CC)CC)C>ClCCl.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][CH:21]=2)=[CH:11][CH:10]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2[nH]cc(Cc3ccc(Br)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Add TFA (114.4 mmol) to a solution of 4-bromobenzaldehyde (76.2 mmol), 4-methylindole (76.2 mmol), and triethylsilane (228.4 mmol) in dichloromethane (10 mL) pre-cooled in an ice bath. Allow the mixture to warm to room temperature and stir for 2 hours. Add additional triethylsilane (228.4 mmol) and warm the mixture to 30° C. overnight in an oil bath. Dilute the reaction with water (100 mL) and extract with dichloromethane (2×100 mL). Separate and wash the organic phase with water (2×100 mL) and brine (100 mL). Dry the organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography over silica gel (120 g cartridge) eluting with 0-10% ethyl acetate in petroleum ether to yield the title compound (8 g, 26.6 mmol): MS (m/z): 301 (M+1)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:14])[C:12]#[N:13].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:14][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH3:15])[C:12]#[N:13]
Reactant: CC(C#N)c1ccc2ccccc2c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc2ccccc2c1
Temperature: -78 °C

Procedure:
To a stirred solution of naphth-2-ylpropionitrile (25 mmol, 4.52 g) in dry tetrahydrofuran (250 ml) at -78° C. was added n-butyl lithium (30 mmol, 18.75 ml; 1.6M solution in hexane) dropwise over a twenty minute period. After stirring the solution for twenty minutes at -78° C. methyl iodide (30 mmol, 4.26 g) was added in one portion. The reaction mixture was stirred for twenty minutes at -78° C. and the reaction was quenched with saturated NH4Cl (35 ml). The reaction mixture was warmed to room temperature, the volatiles were removed in vacuo, the residue diluted with water (200 ml) and extracted with diethyl ether (2×250 ml). The organic phase was washed with water (250 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative high pressure liquid chromatography (SiO2 :hexane/dichloromethane) to give α-methyl-naphth-2-ylpropionitrile as a white solid (3.21 g, 66 percent of theory).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C(Cl)Cl>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.05 g, 6.63 mmol), phenol (0.75 g, 7.95 mmol), triphenylphosphine (1.91 g, 7.29 mmol) in CH2Cl2 (20 mL) was added disopropyl azodicarboxylate (1.57 mL, 7.95 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was concentrated. The residue was flash chromatographed using 10:90 hexane-EtOAc to give 1.09 g of 8-phenoxy-1,4-dioxaspiro[4.5]decane. MS (EI) calcd: (M+H)+=235.1. Found: 235.0.
Reaction SMILES: C(C1C=CC=CC=1N[N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])(C)C.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])([CH3:19])[CH3:18].C(#N)CC#N.O.[NH2:33][NH2:34]>>[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][N:11]=[C:12]1[C:13]([NH2:14])=[N:34][N:33]=[C:15]1[NH2:16])([CH3:19])[CH3:18]
Reactant: NN
Reactant: CC(C)c1ccccc1N
Reactant: CC(C)c1ccccc1NN=C(C#N)C#N
Solvent: N#CCC#N
Solvent: O
Product: CC(C)c1ccccc1NN=C1C(N)=NN=C1N

Procedure:
4-[(2-isopropylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 106 mg (0.5 mmol) of 2-[(2-isopropylphenyl)hydrazono]malononitrile, which was derived from 2-isopropylaniline (142 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 90 mg (73%) of the compound as a greenish yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.Cl[CH:16]([C:21](=O)[CH3:22])[C:17]([O:19][CH3:20])=[O:18]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([CH3:22])[N:12]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Yield: 96.6 %

Procedure:
A solution of 4-(3-chloro-propoxy)-benzamide (0.5 g, 2.34 mmol, 1 eq) and methyl 2-chloro-3-oxobutanoate (0.7 ml, 5.62 mmol, 2.4 eq) in ethanol (5 ml) is heated at 110° C. in a sealed tube for 24 h. The mixture is concentrated, taken up in dichloromethane and washed with water. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography over silicagel (eluent: dichloromethane) to afford 0.7 g of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylate ax60 as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:18](=[O:21])[CH2:19]Cl)=[CH:13][N:12]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:46][CH2:47][CH2:48][OH:49]>C(#N)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:18](=[O:21])[CH2:19][NH:46][CH2:47][CH2:48][OH:49])=[CH:13][N:12]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CNCCO)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a solution of {(R)-2-[5-(2-chloro-acetylamino)-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (44 mg, 0.08 mmol) in acetonitrile (2 mL) were added triethylamine(30 μl, 0.22 mmol) and 2-amino-ethanol (60 μl, 0.96 mmol) in that order. The solution was stirred at 60° C. for 4 hrs, cooled to room temperature, and washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 10/1) and dried in a vacuum to afford 37 mg of the compound as a colorless oil (yield 80%).
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].P([O-])([O-])(O)=O.[NH4+].[NH4+].S1(CCCC1)(=O)=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: O=P([O-])([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 30.8 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol), diammonium hydrogen phosphate (0.99 g, 7.5 mmol) and dry sulfolane (40 ml) are placed in a glass-lined, stainless steel reactor. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (20 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to give 0.26 g (30%) picramide (Table 2, entry 1).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[C:14]#[N:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:12]=1[N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([F:1])=[C:3]([S:25]([Cl:24])(=[O:27])=[O:26])[CH:4]=[CH:5][C:6]1=2)#[N:15]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c(F)cccc21
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Cl)c2F
Temperature: 0 °C
Yield: 58 %

Procedure:
To a vial charged with 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.168 g, 0.521 mmol) was added DCM (2.085 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.139 ml, 2.085 mmol), faster than dropwise. After 30 mins the solution was added to ice water, and mixture was extracted 2× with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, then isocratic at 25%, 10% DCM throughout) providing product as a white foam, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.127 g, 0.302 mmol, 57.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-3.99 (m, 2 H) 4.52 (dd, J=5.14, 3.67 Hz, 2 H) 6.42 (dd, J=9.19, 1.66 Hz, 1 H) 7.34 (dd, J=9.19, 6.75 Hz, 1 H) 7.60 (d, J=8.51 Hz, 1 H) 7.95 (dd, J=8.56, 1.81 Hz, 1 H) 8.07 (d, J=2.15 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Product: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o tolyl-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as a colorless oil, MS (ESI+): m/z=394.08 ([M+H]+, 1 Br).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[CH2:20](I)[CH3:21]>>[CH2:20]([N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH3:21]
Reactant: CCI
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCn1nc(-c2ccc(OC)cc2)cc(C(=O)OC)c1=O
Yield: 79.4 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 79.4%.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+].[Na]>CO>[CH3:14][O:15][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1C(=O)O
Yield: 73 %

Procedure:
To 2-chloro-5-nitro-nicotinic acid (1.0 mmol) in methanol was added a solution of sodium methoxide in methanol (2.4 mmol, freshly prepared from sodium metal in methanol). The solution was refluxed for 2 h and the mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added 10% citric acid solution (20 ml) and the solution extracted with ethyl acetate (20 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was crystallised from water to give a yellow-white solid (73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([CH:15]([CH3:17])[CH3:16])[CH2:3]1.C(Cl)[Cl:19]>CO.Cl.O1CCOCC1>[ClH:19].[ClH:19].[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([CH:15]([CH3:17])[CH3:16])[CH2:3]1
Reactant: ClCCl
Reactant: CC(C)[C@H]1CN(C)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@H]1CN(C)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-4-methyl-2-(1-methylethyl)-1-piperazinecarboxylate (2.18 g crude, 8.76 assumed mmol) was dissolved in a mixture of MeOH (5 mL), CH2Cl2 (5 mL), and 4 N HCl in dioxane (8 mL). After stirring overnight at room temperature, another 8 mL of 4 N HCl in dioxane and 8 mL of MeOH were added, which dissolved the white precipitate that had formed and pushed the reaction to completion. Evaporation of the solvents in vacuo provided (3S)-1-methyl-3-(1-methylethyl)piperazine, dihydrochloride (1.97 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29](=O)[C:28]3[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=3[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:42][NH2:43]>CO>[CH3:12][N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:29]3=[N:42][NH:43][C:31](=[O:32])[C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=43)[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:19]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, 0.94 mmol) in hydrazine monohydrate (50 mL) and methanol (5 mL) was stirred at 40° C. for 24 hr. The mixture was cooled to room temperature and filtered to give the crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give benzyl methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate (80 mg, yield 16%). LC-MS (ESI) m/z: 517 (M+1)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[NH:11][NH2:12].[CH3:13][CH2:14][C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:11]([C:4]2[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=2[CH3:10])[N:12]=1)[CH3:13]
Reactant: Cc1cc(C)c(NN)c(C)c1
Reactant: CCC(=O)CC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Yield: 95 %

Procedure:
A solution of 7.46 g (0.04 mol) of 2,4,6-trimethylphenylhydrazine hydrochloride, 5.12 g (0.40 mol) of 3,5-heptanedione and 4.18 mL (0.60 mol) of triethylamine in 100 mL of absolute ethanol was refluxed overnight. The solvent was evaporated from the cooled reaction mixture and the residues were partitioned between water and ethyl acetate. The organic extracts were dried with brine and magnesium sulfate, and the solvent was evaporated to give the desired product in 95% yield. This compound was used in the subsequent reaction without further purification 1H-NMR (CDCl3): 11 (3H, t, J=7),1.24 (3H, t, J=7),1.90 (6H, s), 2.22 (2H, q, J-7), 2.28 (3H, 5.96 (1H, s), 6.86 (2H, s).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]3[O:17][CH2:18][O:19][C:14]3=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.C1CCC(C(O)=O)CC=1.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>O>[CH2:18]1[O:17][C:15]2=[CH:16][C:4]3[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=3[CH:13]=[C:14]2[O:19]1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Brc1oc2cc3c(cc2c1-c1ccccc1)OCO3
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2cc3c(cc2c1-c1ccccc1)OCO3

Procedure:
To a solution of 5.2 g. (0.016 mole) of 2-bromo-5,6-methylenedioxy-3-phenylbenzofuran in 225 ml. of acetic acid is added with stirring 5.0 g. (0.024 mole) of cyclohexene-4-carboxylic acid, then 2.2 g. (0.024 mole) of dinitrogen tetraoxide in 25 ml. of acetic acid. After about one hour the mixture is poured into cold water, and the yellow product is collected and washed with water. The product is dissolved in dichloromethane, and the solution is washed with cold 5 percent sodium hydroxide solution, water and saturated sodium chloride solution, then dried. The solution is concentrated to dryness to provide a yellow residue which is recrystallized from a benzene-hexane mixture, then from an isopropanol-benzene mixture to provide yellow needles of 5,6-methylenedioxy-2-nitro-3-phenylbenzofuran, m.p. 180°-183° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6](=[NH:28])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[NH:5][C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:26][CH:27]=3)=[N:11][CH:12]=2)=[N:28][CH:30]=1)[CH3:33]
Reactant: CCC(=O)CBr
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Solvent: CC(=O)O
Product: CCc1cnc(-c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)cc3)nc2)[nH]1
Yield: 101.3 %

Procedure:
By using methyl 3-(4-{5-[amino (imino)methyl]pyridin-2-yl) phenoxy)-2,2-dimethylpropanoate acetate (400 mg), and 1-bromobutan-2-one (234 mg), the procedure was carried out in the same manner as in Example 35(2) to obtain methyl 3-[4-[5-[5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (397 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.18 g, 75%). MS (ISN) 480.1 [(M−H)−]; mp 231° C.
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])([O-:9])=[O:8]>>[ClH:1].[N+:7]([C:10]1[CH:11]=[C:12]([C:13](=[NH:2])[NH2:14])[CH:15]=[CH:16][CH:17]=1)([O-:9])=[O:8]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[Al](C)C
Product: Cl
Product: N=C(N)c1cccc([N+](=O)[O-])c1

Procedure:
7.22 g (135 mmol) of ammonium chloride are reacted analogously to example 1A with 135 mmol of trimethylaluminum (67.5 ml of 2 M solution in hexane) and 10 g (67.51 mmol) of 3-nitrobenzonitrile.