Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([O:8][CH2:9][CH:10]=O)[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C.O>[CH:1]1([CH:4]([O:8][CH2:9][CH:10]=[N:18][OH:19])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1
Reactant: C=CCC(OCC=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(OCC=NO)C1CC1
Reaction time: 0.25 h

Procedure:
[(1-Cyclopropylbut-3-en-1-yl)oxy]acetaldehyde (C50) (3.63 g from the previous step, ≦13.0 mmol) was dissolved in a 2:1 mixture of ethanol and water (39 mL). Sodium acetate (5.32 g, 64.9 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 2.76 g, 38.9 mmol) was added. The reaction mixture was heated to 60° C. for 5 minutes, at which time water (4×1 mL) was added until a solution formed. After 1 hour at 60° C., the reaction mixture was cooled, concentrated under reduced pressure to remove ethanol, and diluted with saturated aqueous sodium chloride solution (100 mL). The mixture was extracted with diethyl ether (3×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptane) provided the product as a thick, opaque oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 1.771 g, 10.47 mmol, 81% over two steps. 1H NMR (400 MHz, CDCl3) δ [7.50 (dd, J=5.7, 5.6 Hz) and 6.92-6.99 (m), total 1H], 5.84-5.97 (m, 1H), 5.03-5.15 (m, 2H), {[4.53 (dd, half of ABX pattern, J=16.4, 3.5 Hz) and 4.41 (dd, half of ABX pattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=12.9, 5.5 Hz) and 4.16 (dd, half of ABX pattern, J=12.9, 5.8 Hz)], total 2H}, 2.65-2.74 (m, 1H), 2.37-2.44 (m, 2H), 0.81-0.91 (m, 1H), 0.59-0.68 (m, 1H), 0.47-0.56 (m, 1H), 0.35-0.44 (m, 1H), 0.07-0.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1ncnc2cc(F)ccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
7-Fluoroquinazolin-4-ol (1 g, 6.0 mmol) was dissolved in concentrated H2SO4 (3 mL) at 0° C. Concentrated HNO3 (3 mL) was added dropwise with stirring in 15 min. The mixture was stirred at 100° C. for 3 h and cooled to room temperature. The mixture was poured into ice-water with stirring. The precipitate was filtered and recrystallized in HOAc to give 0.60 g of 7-fluoro-6-nitroquinazolin-4-ol (38%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(OCC)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C=NCCCl
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: CCOCC
Product: O=C(NCCCl)Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 2 g of 2-aminofluorene in 125 mL of anhydrous ethyl ether is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution is stirred for 16 h at room temperature, cooled at -20° C., and filtered. A white solid separated and was recrystallized from ethanol (white flakes), yield 40%, mp 206°-208° C., IR (KBr pellet): 3300 (NH), 1730 (C=O, ester), and 1640 cm-1 (C=O, ureido); 1H NMR (DMSO-d6 : CDCl3): 8.08 ppm, 7.44 ppm, 7.35 ppm, 7.3 ppm, 7.27 ppm, 7.25 ppm, 7.16 ppm, 7.13 ppm, 7.02 ppm, 6.97 ppm, 6.96 ppm, 6.94 ppm, 6.93 ppm, 6.9 ppm, 6.87 ppm, 6.8 ppm, 3.5 ppm, 3.36 ppm, 3.33 ppm, 3.3 ppm, 3.25 ppm, 3.23 ppm, 3.2 ppm, 2.85 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[C:4]([O:17][CH3:18])[CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(F)ccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)ccc1-c1ccc(N)cc1

Procedure:
A mixture of 10 grams of 4'-fluoro-2'-methoxy-4-nitrobiphenyl in 250 ml. of ethanol is reduced by hydrogen at atmospheric pressure and at room temperature using 5% palladium-on-charcoal (0.5 gram) catalyst. After the required uptake of hydrogen, the mixture is filtered and the catalyst washed with fresh ethanol. The ethanol solution is then concentrated in vacuo, and the residue recrystallized from aqueous ethanol to yield 4-(4'-fluoro-2'-methoxyphenyl)-aniline.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:12][C:13]1[CH:14]=[N:15][N:16]([C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:17]=1
Reactant: COc1ccc(F)c(C=O)c1
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2cc(Cl)cn2)c(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-5-methoxybenzaldehyde (450 mg, 2.92 mmol) in DMSO (13 mL) are added 4-chloro-1H-pyrazole (450 mg, 4.39 mmol) and K2CO3 (810 mg, 5.84 mmol) at room temperature. The solution is heated to 100° C. for 1.5 hours. The solution is cooled down and is diluted with H2O (150 mL) and extracted with EtOAc (3×). The combined organic layers are dried with MgSO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 5-25% EtOAc in heptane as the eluent to afford 2-(4-chloro-pyrazol-1-yl)-5-methoxy-benzaldehyde which is used without further purification
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 92.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoic acid (0.425 g, 0.938 mmol) was dissolved in a mixed solution of acetonitrile (18 ml) and water (6 ml) and after adding thereto CAN (1.29 g, 2.35 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.376 g, 0.868 mmol, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reaction time: 2 h

Procedure:
12.7 g of 3-(4-bromophenyl)-1-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-imidazolidin-2-one, 300 ml of tetrahydrofuran, 100 ml of water and 23.6 ml of 4N sodium hydroxide solution are stirred overnight at ambient temperature. The precipitate is suction filtered, suspended in 1 litre of water, acidified with concentrated hydrochloric acid and stirred for 2 hours. It is then suction filtered, washed with water and dried at 60° C.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=1)[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]>S(=O)(=O)(O)O>[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]=1[N+:1]([O-:4])=[O:2])[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1)C(=O)OC2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1[N+](=O)[O-])C(=O)OC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Powdered potassium nitrate (0.51 g, 5 mmol) was added to a stirred solution of 3-ethoxalylamino-1,8-naphthalenedicarboxylic anhydride (1.57 g, 5 mmol) in 15 ml of conc. sulfuric acid at 0° C. Stirring was continued for 2 h at the same temperature, then the reaction mixture was poured into 150 ml of ice-water. The separated yellow solid was isolated by filtration and washed with water ethanol and ether. Trituration with a small amount of ethyl acetate afforded 1.38 g (77%) of the title compound. M.p. 221°-222° C.; 1H-NMR CDCl3 +DMSO-d6): 1.43 (t,J=7Hz, 3H, CH3), 4.37 (q,J=7Hz, 2H, CH2), 7.70-8.60 (m, 3H, ArH), 8.82 (s, 1H, H-2), 11.3 (broad s, 1H, NH).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][C:45]([CH3:50])([CH3:49])[C:46]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)=[O:47]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise trimethylacetyl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.384 g oil. Crystallization as the oxalate salt from 2-propanol provided 0.297 g colorless crystals. Mp 194° C. Mass spectrum, m+ =413. Anal (C25H37N5O6) theory C, 59.63; H, 7.41; N, 13.91; found C, 59.47; H, 7.62; N, 13.63.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:10]([CH2:11][C:12](=[O:27])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](OCC)=[O:29].[O-]CC.[Na+]>C1COCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:14]([CH2:13][C:12](=[O:27])[C:11]2=[CH:28][OH:29])[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (5.08 g, 12.2 mmol) was dissolved in THF/ethanol (40 mL, 1/1, v/v). Ethyl formate (9.84 mL, 122.4 mmol) was added followed by sodium ethoxide (12 mL of 21% solution in ethanol). The resulting mixture was stirred at room temperature for 30 minutes then heated to 60° C. for 30 minutes after which the solution was cooled back to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 5.43 g (quantitative) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.114, method [1], MS (ESI) 465.0 (M+Na).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][O:35][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:32][CH:33]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(CO)cc3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(COS(C)(=O)=O)cc3)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.3 %

Procedure:
Methanesulfonyl chloride (60 μL, 0.70 mmol) was added to a solution of 6-cyano-3-(4-hydroxymethyl-phenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid tert-butyl ester (224 mg, 0.60 mmol) and triethylamine (110 μL, 0.80 mmol) in DCM (20 mL). The mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as yellow oil (374 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:31])([F:30])I>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:10][C:5]2[NH:6][C:7]([S:9][C:28]([F:31])([F:30])[F:27])=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)I
Reactant: S=c1[nH]c2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Sc1nc2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Compound number 49 (i.e., 6-chloro-5-(2,3-dichlorophenoxy)-2-trifluoromethylthiobenzimidazole) was prepared as follows. A solution of 5-chloro-6-(2,3-dichlorophenoxy)-2,3-dihydro-1H-1,3-benzodiazole-2-thione (200 mg, 0.58 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) and potassium carbonate (120 mg, 0.87 mmol, 1.50 equiv) was placed into a 50-mL 3-necked round-bottom flask. The mixture was sustained by aeration with trifluoro(iodo)methane. The resulting solution was stirred for 2 h at 130° C. in an oil bath. The resulting solution was diluted with 50 ml of water. The resulting solution was extracted with 2×80 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA/PE (1:15). This resulted in 81.0 mg (34%) of 6-chloro-5-(2,3-dichlorophenoxy)-2-trifluoromethylthiobenzimidazole as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1.Br[CH:19]([OH:21])[CH3:20].C(=O)([O-])O.[Na+].C(C(C)=O)C>O>[OH:21][CH2:19][CH2:20][N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1
Reactant: CC(O)Br
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)C3)cc12
Yield: 43.1 %

Procedure:
To the obtained (−)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (3.0 g) were added bromoethanol (8.21 g), sodium hydrogen carbonate (5.6 g), methyl ethyl ketone (84 ml) and water (8.4 ml), and the mixture was stirred under reflux for 2 hr. The reaction mixture was concentrated, extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (methanol/ethyl acetate; 2/5) and crystallized from ethyl acetate to give (−)-3-[1-(2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (1.5425 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C1COCC1>[C:18]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: NCCCN1CCC(Cc2ccccc2)CC1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCCCN2CCC(Cc3ccccc3)CC2)c1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg, 1.29 mmol, 1 eq) was dissolved in THF at 25° C. under N2 then 3-cyanophenyl isocyanate (186 mg, 1.29 mmol, 1 eq) was added. TLC after 30 minutes shows the reaction complete. The solvent was removed in vacuo then the residue was purified over silica gel in 100% EtOAc to 8:2 chloroform/MeOH to yield 437 mg of an amber oil as product. NMR (300 MHz, DMSO-d6) δ 9.90-9.50 (m, 1H); 9.32 (s, 1H); 7.93 (s, 1H); 7.59 (d, 1H, J=7Hz); 7.43 (t, 1H, J=7Hz); 7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H); 6.68 (t, 1H, J=7 Hz); 3.50-3.25 (m, 2H); 3.25-3.07 (m, 2H); 3.07-2.90 (m, 2H); 2.90-2.60 (m, 2H); 2.60-2.40 (m, 2H); 2.00-1.60 (m, 5H); 1.60-1.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:20][C:21]#[CH:22]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:20][CH2:19][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and N-(3-butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was stirred at room temperature for 24 hours and then diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over potassium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 29.87 g of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione. A portion of the product was recrystallized from isopropyl alcohol and dried to provide an analytically pure sample as white crystals, mp 155.0-156.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:17]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOc2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Hydroxy-2,3-dihydro-4H-chromen-4-one (900 mg) was dissolved in DMF (10 mL), and tert-butyl(chloro)diphenylsilane (1.711 mL) and 1H-imidazole (448 mg) were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 80:20) to obtain 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.08 g) as a colorless transparent syrup.
Reaction SMILES: [S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+].[N+:9]([C:12]1[C:21]2[C:16](=[C:17]([N+:22]([O-])=O)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]>O.CO>[N+:9]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[C:17]2[NH2:22])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: Nc1cccc2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.2 %

Procedure:
A 70° C. solution of sodium sulfide (3.17 g, 32.97 mmol) and sodium bicarbonate in water (7 mL) was added dropwise to suspension of 1,5-dinitro naphthalene (2.0 g, 9.16 mmol) in methanol (30 mL) at reflux and the resultant mixture was stirred for 5 min. The mixture was cooled to 0° C., quenched with ice and stirred for a further 10 min followed by acidification with concentrated hydrochloric acid. The resulting mixture was stirred for 30 min then washed with ethyl acetate (2×50 mL). The aqueous layer was basified with aqueous ammonia and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulphate, filtrated and concentration in vacuo afforded of 5-nitronaphthalen-1-amine (710 mg, 42%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[CH:3]=[N:4]O.N.[H][H].O>CO.[Ni]>[CH:16]([CH:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][NH2:4])([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)CN
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
490 g (1.84 moles) of the 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime obtained according to Example 5 are dissolved in 2.4 liters of methanol and this solution is filled, together with about 200 g of liquid ammonia, with the addition of 150 g of Raney nickel, into a 6.3 liter steel autoclave. Hydrogen is then injected until the pressure is 100 bars and the mixture is heated to 100° C. with stirring. The mixture is hydrogenated forabout 5 hours under these conditions and cooled and the ammonia and excess hydrogen are then allowed to blow off. Subsequent distillation under a high vacuum yields 436 g (1.705 mols) of 1-isopropyl-10,10-dimethyl-1,11-diaminoundecane in the form of a colourless, water-clear liquid; boiling point 87° C./4 Pa; nD20 =1.46l9.