Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'carbonyldiimidazole (2.69 g, 0.0166 mole), and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylene in tetrahydrofuran (33 ml of a 3.03M solution, 0.996 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, charcoaled, and filtered while hot. Water was added to the cloud point, and upon cooling, solid precipitated. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 3.21 g (62%) of title compound, mp 217°-218° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[CH2:13]2.P(Br)(Br)([Br:30])=O.N1C=CN=C1>ClCCCl>[Br:30][C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[C:11]([N+:20]([O-:22])=[O:21])[C:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:4][C:3]=1[O:2][CH3:1])=[CH:18][CH:17]=2
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(c2[N+](=O)[O-])CC(=O)N3)c(OC)c1
Reactant: O=P(Br)(Br)Br
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(Br)cc3c2[N+](=O)[O-])c(OC)c1
Temperature: 90 °C

Procedure:
To a solution of methyl 2-(3-methoxy-4-(4-nitro-2-oxoindolin-5-yloxy)phenyl)acetate (0.177 g, 0.476 mmol) in DCE (10 mL), phosphoryl tribromide (0.273 g, 0.952 mmol) was added dropwise at room temperature. The mixture was heated at 90° C. for 1 h, and then imidazole (0.049 g, 0.714 mmol) was added and heated for another 2 h. The reaction was quenched with ice, adjusted PH to 8 and diluted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. MS ESI (pos.) m/z: 435.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([NH:21][C:22](=[O:43])[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:25][C:24]=4[NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:55]([O:57][CH2:58][CH3:59])=[O:56]>C1COCC1.O>[CH2:58]([O:57][C:55]([N:18]1[C:15]2[CH2:16][CH2:17][N:12]([S:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][C:14]=2[C:20]([NH:21][C:22](=[O:43])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[NH:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:19]1)=[O:56])[CH3:59]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)CC4)c(NC3CCOCC3)c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2NC2CCOCC2)c2c1CCN(S(=O)(=O)c1cc(F)cc(F)c1)C2
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
To a solution of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (1.38 g, 2.24 mmol) in anhydrous THF (150 mL), cooled to −40° C., under argon, was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.35 mL, 2.35 mmol). The mixture was stirred for 5 min. then ethyl chloroformate (0.225 mL, 2.35 mmol) was added. The reaction was stirred at −40° C. for 1 h, then was poured in water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried with sodium sulfate. After filtration and evaporation the crude was triturated with ether to give the title compound as white solid (1.32 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.N1C=CN=C1>O1CCOCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:6]2[C:5](=[O:15])[C:4]3[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=3)[C:7]2=[O:14])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)CC1
Temperature: 140 °C
Yield: 53.5 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g, 12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 72 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (320:10:1) afforded the title compound (2.09 g, 54%). 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.73 (m, 2H), 2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34 (s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1)=[O:4].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[CH2:15]([N:12]1[CH2:13][CH2:14][C:6]2[C:5]([C:3]([NH:29][CH2:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:4])=[N:10][CH:9]=[N:8][C:7]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: NCC1CCCCC1
Solvent: CO
Product: O=C(NCC1CCCCC1)c1ncnc2c1CCN(Cc1ccccc1)C2

Procedure:
Into a 50 ml round bottom flask was combined 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic acid methyl ester (0.125 g, 0.411 mmol), C-cyclohexyl-methylamine (0.010 g, 0.88 mmol), and methanol (10 ml). The mixture was heated at reflux for 24 hrs. The mixture was allowed to cool, reduced in vacuo, and purified by flash chromatography using a methylene chloride:methanol gradient (0-10%). The combined fractions were reduced in vacuo to yield the title compound. (0.0177 g, 10.9%).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32].[CH3:33][NH2:34].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32]
Reactant: CN
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CI)C(O)C3O)c2n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CNC)C(O)C3O)c2n1
Reaction time: 18 h

Procedure:
A solution of the product from step (c) (0.25 g) in dimethylsulphoxide (3mil) was treated with a 40% solution of aqueous methylamine (1 ml). The reaction mixture was allowed to stand for 18 hours at room temperature then poured into ethyl acetate (200 ml), washed with a saturated solution of aqueous brine (3×100 ml), dried and concentrated. Purification (SiO2, methanol:chloroform 1:4 as eluant) afforded the subtitle compound (0.27 g).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)[Br:24].Br>C(Cl)Cl>[BrH:24].[CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc([C@@H]2CNC[C@H]2Cc2ccccc2)cc1OC
Agent: Br
Solvent: ClCCl
Product: Oc1ccc([C@@H]2CNC[C@H]2Cc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
0.37 g (1.24 mmol) of trans-3-benzyl-4-(3,4-dimethoxyphenyl)pyrrolidine was dissolved in methylene chloride, and 10 ml of a solution of 1M boron tribromide in methylene chloride was added to the resultant solution. The solution was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo. Further, methylene chloride was added to the concentrate and methanol (3 ml) was dropwise added thereto. The mixture was again concentrated in vacuo. This procedure was repeated several times, and a precipitated crystal was recovered by filtration to prepare 70 mg of a hydrobromide as an intended product (yield: 16%).
Reaction SMILES: [CH:1]1([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH3:23])=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20][C:19]3=[O:28])=[CH:13][CH:12]=2)[C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH3:23])=[C:21]([CH2:24][CH:25]([CH3:26])[CH3:27])[S:20][C:19]3=[O:28])=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(c1ccc(Cn2c(C)c(CC(C)C)sc2=O)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(C)C)sc(=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.01 g (2.515 mmol) of methyl cyclopentyl(4-{[4-methyl-5-(2-methylpropyl)-2-oxo-1,3-thiazol-3(2H)-yl]methyl}phenyl)acetate were dissolved in 30 ml of THF, and 10 ml of methanol and 10 ml of 1 N aqueous sodium hydroxide solution were added. The reaction solution was stirred at room temperature for 2 days. A further 5 ml of 1 N aqueous sodium hydroxide solution were then added, and the mixture was stirred at RT for another 2 days. 20 ml of 1 N hydrochloric acid were then added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. This gave 956 mg (2.47 mmol, 98% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[C:1](=[N:14][OH:15])([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cc2ccccc2cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cc2ccccc2cn1
Yield: 89 %

Procedure:
A solution of 3-acetyl-isoquinoline (0.65 g), hydroxylamine (0.29 g) and sodium acetate (0.47 g) in a mixture of methanol (20 ml) and water (3 ml) was heated to reflux for 1.5 hours. The reaction was then poured into water and extracted with ethyl acetate. The combined extracts were dried, concentrated and triturated with hexane to give 3-acetyl-isoquinoline oxime (0.63, 89% yield) as a white crystalline solid m.p. 135°-142° C.; 1H NMR: 2.50(3H,s); 7.61(1H,t); 7.70(1H,t); 7.87(1H,d); 7.99(1H,d); 8.11(1H,s); 9.28(1H,s) ppm.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:40])(=[O:39])[NH:34]C(C)(C)C)=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:39])(=[O:40])[NH2:34])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 94 %

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-(3-nitrophenyl)-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 13, Step B, and was obtained in 94% yield as a pale yellow solid after flash chromatography, mp 73°-76° C., homogenous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 508 (M+1)+.
Reaction SMILES: [CH2:1]1[C@@H:8]2[C@@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]1=[O:10].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]1[C@H:8]2[C@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]21[O:13][CH2:12][CH2:11][O:10]2
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Yield: 30.6 %

Procedure:
cis-Tetrahydropentalene-2,5(1H,3H)-dione (5 g, 36 mmol) and ethylene glycol (2.3 g, 36 mmol) were dissolved in toluene. To the resulting solution was added PTSA (684 mg, 3.6 mmol). The reaction mixture was refluxed for 12 h meanwhile the resulting water was removed away. Direct chromatography on silica gel gave 2.0 g (11 mmol, yield: 31%) of the desired product, (3a′R,6a′S)-tetrahydro-1′H-spiro[1,3-dioxolane-2,2′-pentalen]-5′(3H)-one: MS (m/e): 183 (M+1)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][N:14](C)[CH:15]=[O:16]>>[C:1]1(=[O:11])[N:5]([CH2:3][CH:7]2[O:16][C:15]3=[N:14][CH:13]=[CH:1][CH:2]=[C:10]3[CH2:9][CH2:8]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CC1CCc2cccnc2O1
Reaction time: 20 h

Procedure:
15.0 g (70 mmol) of a mixture of the compounds from Example V and VI (ratio 12:5) are heated at 100° C. with 16.0 g (86 mmol) of potassium phthalimide in 150 ml of dimethylformamide under nitrogen with stirring for 20 hours. Dimethylformamide is then distilled off in vacuo and the residue is partitioned between dichloromethane and water. 24.0 g of crystals having a melting range of 152°-158° C. are obtained.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH3:8].[OH:9][C:10]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]>C(O)C>[OH:9][C:10]1[C:17]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:16][C:13]([CH:14]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH3:8])=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Cc1nccn1N
Agent: Cl
Solvent: CCO
Product: Cc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.35 g of 1-amino-2-methylimidazole hydrochloride are dissolved in 300 ml of ethanol, whereupon 9.3 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added. The mixture is stirred at room temperature for 1 hour and then evaporated in a vacuum. 150 ml of ice-water and 200 ml of methylene chloride are added to the residue and the mixture is neutralized (pH=7) with saturated sodium bicarbonate solution. The methylene chloride phase is separated and the aqueous phase is extracted with 100 ml of methylene chloride. The combined methylene chloride phases are dried and evaporated. The residue is stirred with ether and filtered. The filter residue is dried at 80° in a vacuum and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-methylimidazole of m.p. 206°-207°.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: O=C1N(CCN2CCCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 245° C. and MS: m/e=481.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 1-(2-chloroethyl)piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=O)[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=[N:33][NH:32][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NN=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3)c1cccnc1

Procedure:
Next, 0.33 g of 5,6,7,8-tetrahydro-2-(3-nitrophenyl)-3-formylimidazo[2,1-b]benzothiazol, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, water was added and the desired substance was obtained in an amount of 0.21 g (yield of 46.7%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][N:24]1[C:23](=[O:27])[CH:22]=[N:21][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=3)[CH2:15][CH2:14]2)[C:25]1=[O:26]
Reactant: O=c1cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)[nH]1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c1=O

Procedure:
The compound 1 (3.77 g; 0.009 mol is added dropwise to a 60% suspension of sodium hydride in paraffin oil (0.77 g; 0.019 mol) in DMF (50 ml), followed, after stirring for 2 hours at room temperature, by iodomethane (1.4 g; 0.01 mol). After leaving overnight at room temperature, the mixture is concentrated to dryness under vacuum and then the residue is taken up in water (100 ml) and extracted with ethyl ether (2×50 ml). The dried organic phases (Na2SO4) are concentrated to dryness under vacuum to give an oil which crystallizes slowly.
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]([NH:34][NH2:35])=O)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:35][N:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (500 mg) was added acetic acid (3 ml), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.02 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.CC[O:33]CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:33]
Reactant: N#Cc1cc2c(cc1I)CCC2
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cc2c(cc1I)CCC2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-iodoindane-5-carbonitrile (36.5 mg, 0.136 mmol) in CH2Cl2 (1.0 mL) under N2 at −78° C. was added a solution of 1N diisobutyl aluminum hydride in toluene (272 μL, 0.272 mmol) dropwise. The reaction was stirred at −78° C. for 15 min. Keeping the temperature at −78° C., another two portions of diisobutyl aluminum hydride (100 μL each) were added until the starting material disappeared by TLC. The reaction mixture was poured into 2N HCl (45 mL) and diluted with Et2O. The mixture was stirred for 0.5 h. The Et2O layer was separated. The aqueous layer was extracted with Et2O (2×). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford 6-iodoindane-5-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H,), 2.19-2.13 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:8](=[O:9])[O:7][C:6](=[O:10])[CH:5]2[CH2:11][C:12]=1[CH3:13].BrBr>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[O:9])[O:7][C:6](=[O:10])[C:5]2=[CH:11][C:12]=1[CH3:13]
Reactant: CC1=C(C)CC2C(=O)OC(=O)C2C1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C)C(=O)OC2=O
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a solution of above-mentioned (a) (9.5 g, 53 mmol) in acetic acid (28 ml) was added dropwise a solution of bromine (6.1 ml, 0.12 mol) in acetic acid (28 ml) at 115° C. over a period of 45 minutes, and heated under reflux for 1 hr. The reaction solution was left overnight, and the precipitated crystals were collected by filtration, washed with diethyl ether, followed by drying to give 3.5 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1.[OH-].[K+]>CO>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:24])=[O:2])=[CH:11][CH:10]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)COc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
A solution of [4-(4-tert-butoxycarbonylaminobutyl)phenoxy]acetic acid methyl ester 32 (1.28 g, 3.78 mmol) in methanol (80 mL) was added with crushed potassium hydroxide (2.50 g, 85%, 37.8 mmol) and the mixture was stirred at room temperature for 5 h. Solvent was removed by rotary evaporation. The residue was taken up in water and acidified to pH ˜1 with 6N aqueous HCl, and extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4, and concentrated to complete dryness to afford the desired product 33 as a white solid (1.19 g, 97% yield). 1H NMR (300 MHz, CD3OD) δ 1.41 (s, 9H), 1.42-1.70 (m, 4H), 2.45-2.60 (m, 2H), 3.00-3.20 (m, 2H), 4.60 (s, 2H), 6.80 (d, 2H), 7.08 (d, 2H). m/z (ESI): 322 [C17H25NO5−H]−.