Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@H:38]1[CH2:41][C@@H:40]([C:42]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:51])[CH3:50].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@H:38]4[CH2:41][C@@H:40]([C:42]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:51])[CH3:50])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) (COCl)2 (0.69 ml, 8.03 mmol) in DCM (4 ml) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-1-yl)methanone (Intermediate 12, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; δ 5.94 (d, 1H, J=7.8 Hz), 4.74 (s, 1H), 4.59 (s, 1H), 4.54-4.41 (m, 1H), 4.17-4.05 (m, 1H), 3.74-3.62 (m, 1H), 3.37 (brs, 2H), 3.18-3.07 (m, 1H), 2.89 (t, 1H, 7.8 Hz), 2.51-2.40 (m, 1H), 2.39-2.28 (m, 2H), 2.04 (s, 3H), 2.01-1.84 (m, 2H), 1.81-1.75 (m, 1H), 1.74-1.45 (m, 7H), 1.44-1.21 (m, 15H), 1.21-1.09 (m, 2H), 0.95, 0.93 (s, 9H), 0.83-0.82 (m, 12H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm−1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192, 1024, 979, 881, 853.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[N:19]/[NH:20][C:21](=[NH:23])[NH2:22])=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[N:19]/[N:20]2[CH:2]=[C:3]([C:5]3[S:6][C:7]([Cl:10])=[CH:8][CH:9]=3)[N:22]=[C:21]2[NH2:23])=[CH:16][CH:17]=1
Reactant: N=C(N)N/N=C/c1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)s1
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)s2)cn1/N=C/c1ccc(Cl)cc1
Reaction time: 10 h
Yield: 72 %

Procedure:
A solution of 2-bromo-1-(5-chloro-2-thienyl)-1-ethanone (1.07 g, 4.49 mmol), 2-[(E)-1-(4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide (1.77 g, 8.98 mmol) was heated in ethanol (10 mL) for 2 h, then the mixture was left at room temperature for additional 10 h. The precipitate filtered, washed with hot water, and recrystallized from ethanol to give N1-[(E)-1-(4-chlorophenyl)methylidene]-4-(5-chloro-2-thienyl)-1H-1,2-imidazolediamine 2 (1.09 g, 72%) as a brown solid.
Reaction SMILES: ClCC[CH2:4][CH:5]([O:11]C(=O)C)CCCCC.C(Br)CCCC.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31].ClCCCC(O)CCCCC(F)(F)F>>[Cl:21][CH2:22][CH2:23][CH2:24][CH:25]([O:34][C:5](=[O:11])[CH3:4])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: O=C(CCCCl)CCCCC(F)(F)F
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: OC(CCCCl)CCCCC(F)(F)F
Solvent: CCCCCBr
Product: CC(=O)OC(CCCCl)CCCCC(F)(F)F

Procedure:
By following the procedure described for 1-chloro-4-acetoxynonane (Example A) but substituting 1-bromo-5,5,5-trifluoropentane for amyl bromide, there is obtained in succession: 1-chloro-9,9,9-trifluoro-4-nonanone, 1-chloro-9,9,9-trifluoro-4-nonanol, and 1-chloro-4-acetoxy-9,9,9-trifluoronane.
Reaction SMILES: [C:1]([CH2:3][O:4]/[N:5]=[C:6](/[C:23]1[N:24]=[C:25]([NH:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:26][CH:27]=1)\[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])#[N:2].O>C(O)=O>[NH2:28][C:25]1[S:26][CH:27]=[C:23](/[C:6](=[N:5]/[O:4][CH2:3][C:1]#[N:2])/[C:7]([OH:9])=[O:8])[N:24]=1
Reactant: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1

Procedure:
Diphenylmethyl (Z)-2-cyanomethoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (lg) was dissolved in formic acid (98%, 40 ml) and water (10 ml) at room temperature and stirred for 12 h. The solvent was removed in vacuo and the residue triturated with ether to give the title compound as an off-white solid (0.39 g). The product was sufficiently pure for the next step; νmax (nujol) 3700-2500, 1605 (broad), 1465 and 1380 cm-1 ; δH inter alia 5.09 (2H, s), 7.04 (1H, s). [Mass spectrum: EI M+ (226)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
4-[2-(4-Fluoro-phenyl)-pyrrolidin-1-yl]-pyridin-2-ylamine (61 mg, 0.24 mmol) and benzoyl isocynate (52 mg, 0.36 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (49 mg, 0.36 mmol). The mixture is then heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by re-crystallization from DCM/heptane affords 40 mg of the titled product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(#N)C.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1)[CH3:13]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(C(N)=O)cc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) were added to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide (686 mg), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, water (45 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried to obtain ethyl[4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:16]([N:13]1[CH2:12][CH:11]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(/C=C/c2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (18.75 g, 94.2 mmol) in dimethylformamide (30 ml) at 90° C. was added benzyl bromide (11.9 ml, 100 mmol) and the reaction stirred at 90° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethanol (400 ml) and sodium borohydride (4 g, 105 mmol) added in portions. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated to a slurry. Methanol was added, and the resultant solid filtered and dried to yield (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (12 g, 44%) as a white solid. δH (CDCl3) 2.41 (2H, br s, tetrahydropyridinyl CH2), 2.68 (2H, t, J 5.8 Hz, tetrahydropyridinyl CH2), 3.14 (2H, br s, tetrahydropyridinyl CH2), 3.63 (2H, s, NCH2Ar), 5.80 (1H, br s, tetrahydropyridinyl 5-CH), 6.40 (1H, d, J 16.2 Hz, ArCHCHC), 6.69 (2H, d, J 16.2 Hz, ArCHCHC), 6.96-7.02 (2H, m, ArH) and 7.25-7.39 (7H, m, ArH).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])O[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8]([O:11][CH2:14][CH3:15])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC1=CCC(NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.7 g. of 4-acetamidocyclohexanone [prepared by the method of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970)], in 150 ml. of anhydrous ethanol were added 25 ml. of ethyl orthoformate containing a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred at ambient temperature for about 16 hours, after which time the volatile constituents were removed by evaporation in vacuo. The residue comprising the diethylketal was dissolved in 200 ml. of toluene and the toluene was removed by distillation under a nitrogen atmosphere, until all of the diethylketal had been converted to the 1-ethoxycyclohexene derivative. The solution was cooled, washed with aqueous sodium bicarbonate and dried. Evaporation of the toluene yielded a residue comprising 4-acetamido-1-ethoxycyclohexene melting at 100°-102° C. after recrystallization from an ether-hexane solvent mixture; yield=6.2 g.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18][NH2:19])=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[CH:23]=[CH:22][N:21]=1.C(O)(=O)C>C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18]/[N:19]=[CH:30]/[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][N:21]=[CH:20]4)=[O:17])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc2cnccc12
Reactant: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(N/N=C/c1cccc2cnccc12)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a room temperature solution of 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) in ethanol (20 mL), was added isoquinoline-5-carbaldehyde (122 mg, 0.77 mmol) and acetic acid (0.5 mL). The reaction mixture was then heated at 80° C. for 3 h, concentrated in vacuo and the residue diluted with water and extracted with EtOAc (2×20 mL). The layers were separated and then the combined organic layers were washed with a saturated NaHCO3 solution, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via column chromatography eluting with 2% MeOH in dichloromethane to afford (E)-2-(4-cyclohexylphenyl)-N′-(isoquinolin-5-ylmethylene)cyclopropanecarbohydrazide (100 mg, 33%) as a white solid.
Reaction SMILES: O=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](OCCC)=[O:5].O.[NH2:17][NH2:18]>C(O)C>[C:10]1([C:2]2[CH2:3][C:4](=[O:5])[NH:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: CCCOC(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
To a solution of propyl 3-oxo-3-phenylpropanoate (10 g, 48.5 mmol) in ethanol (100 mL) was added hydrazine hydrate (9.71 g, 194 mmol) at room temperature. The reaction was heated to 80° C. for 2 h, cooled to room temperature and concentrated. The residue was crystallized from 20% ethyl acetate/hexane to give the title compound (6.58 g). LCMS m/z=161.08 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.32 (br, 2H), 7.32-7.78 (m, 5H), 12.1 (s, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][CH:7]=2)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>ClCCl.Cl[Ti](Cl)(Cl)Cl>[N:13]1([CH2:12][CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:6]([C:5]3[S:1][C:2]4[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=4[C:4]=3[C:29]([C:28]3[CH:32]=[CH:33][C:25]([Br:24])=[CH:26][CH:27]=3)=[O:30])=[CH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a solution of 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (650 mg, 2.0 mmol) and 4-bromobenzoyl chloride (657 mg, 1.5 equiv) in dichloromethane (25 mL) at 0° C. in dark was added TiCl4 (1.0 mL, neat) slowly under argon. The resulting mixture was stirred at ambient temperature for 4 h before being transferred carefully to a stirring solution of saturated aqueous NaHCO3 (100 mL). After stirring for 30 min, the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (4:4:92) afforded the product (940 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>C(O)C.CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CC(c1cccnc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1cccnc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 13 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)pyridin-2-amine (300 mg, 0.73 mmol), DMF (4.4 mL), ethanol (0.6 mL), 1M Na2S2O4 (3 eq, 2.19 mmol, 2.19 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.81 mmol, 121 mg). After 16 h, concentration in vacuo and column chromatography (EtOAc-DCM-MeOH, 50:50:2) gave the product (49 mg, 13%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.39 (d, J=6.6 Hz, 3H, CHCH3), 2.51-2.67 (2 m, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.58-3.66 (m, 5H, piperazine N(CH2)2 & CHCH3), 6.81 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.39 (dd, J=7.6, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.00 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.13 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.48 (d, br, J=4.4 Hz, 1H, pyridine H-6), 8.58 (br s, 1H, pyridine H-2), 13.11 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[C:1]=[S:2]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A solution of carbon disulphide (4.2 g) in dry acetone (8 ml) was added dropwise to a solution of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (10.71 g) in dry acetone (30 ml) during 15 minutes at -10° to 0°. To the stirred solution at -15° was added dropwise a solution of mercuric chloride (13.6 g) in dry acetone (20 ml) during 45 minutes. The solution was warmed to 0° and triethylamine (11.5 g) was added dropwise with stirring during 15 minutes. The mixture was refluxed for 45 minutes, the suspension filtered and the filtrate evaporated to dryness. The oily residue was dissolved in ether (150 ml), decolourising charcoal and excess anhydrous sodium sulphate were added and the suspension filtered after 2 hours. The filtrate was evaporated to dryness, the oily residue dissolved in ether and the solution chromatographed (alumina deactivated with water, 72.5 ml/kg/ether). The appropriate eluate was evaporated to give the title compound (5.05 g) as a brown oil.
Reaction SMILES: Cl.O.[C:3]([C:10]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=1[OH:12])(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Zn].C1(C)C=CC=CC=1>[CH2:3]([C:10]1[C:11]([OH:12])=[CH:13][CH:14]=[CH:15][C:16]=1[OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Subsequently, 30.0 g of zinc powder was mixed with 2.50 g of mercuric chloride, 1.5 ml of concentrated hydrochloric acid and 38 ml of water and shaken for 5 minutes, followed by decantation to discard the aqueous phase. Thereafter, 20 ml of water, 45 ml of concentrated hydrochloric acid, 25 ml of toluene and 14.6 g of the previously obtained n-hexanoyl resorcinol were added in this order, followed by refluxing under heating conditions for 30 hours. During the refluxing, 12.5 ml of concentrated hydrochloric acid was added four times every 6 hours in order to keep the concentration of the acid. The reaction solution was cooled down to room temperature and subjected to liquid separation. The resultant aqueous phase was extracted three times with 50 ml of isopropyl ether and combined with the organic phase, followed by washing with 100 ml of water. The solvent was distilled off by means of an evaporator and the residue was crystallized from n-hexane to obtain 4.3 g of n-hexyl resorcinol as colorless needle crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](Cl)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:17]([C:5]1([CH2:4][CH2:3][CH2:2][Cl:1])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:18]
Reactant: CNC
Reactant: O=C(Cl)C1(CCCCl)CC=CCC1c1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)C1(CCCCl)CC=CCC1c1ccccc1
Yield: 90.4 %

Procedure:
1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carbonyl chloride (5.22 g, 17.5 mmol) was treated with excess dimethylamine (10 g) in methylene chloride (100 ml) to afford 4.84 g (90% yield) of N,N-dimethyl-1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxamide as a viscous oil. The infrared spectrum had a carbonyl stretching frequency at 1660 cm-1 indicative of an amide which replaced the carbonyl stretch at 1790 cm-1 for the acid chloride. The tertiary amide isolated above (4.80 g, 15.1 mmol) was dissolved in DMF (25 ml) to which 10 ml of piperidine (excess) was added and the contents stirred at 50° C. under N2 for two days. The solution was concentrated in vacuo at 3 mm pressure. The resulting oil was dissolved in ethyl ether and washed with 2.5N aqueous HCl. The organic fraction was discarded. The aqueous phase was washed with 2.5N aqueous NaOH and extracted with ethyl ether. The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo to afford 5.38 g of a dark yellow viscous oil. Flash chromatography, employing 10% MeOH/CHCl3, as eluent, afforded 1.95 g of N,N-dimethyl-1-[3-(1-piperidinyl)propyl]-6-phenyl-3-cyclohexene-1-carboxamide as a tan solid, mp 105°-106° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[C:28]1([CH2:34][O:35][CH2:36][C:37]([O:39][CH:40](Cl)[CH3:41])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([O:17][CH2:41][CH2:40][O:39][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(Cl)OC(=O)COCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)COCc1ccccc1
Yield: 8.4 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (17) (0.8 g, 2.0 mmol) dissolved in 12 mL of anhydrous toluene was reacted with 1.4 g (6.0 mmol) of 1-chloroethyl 2-(phenylmethoxy)acetate (25) in the presence of 1.1 g (4.0 mmol) of silver carbonate (Ag2CO3). After work-up and further purification by mass-guided preparative HPLC, 0.1 g (8.4% yield) of the title compound (45a) was obtained as a colorless, viscous oil. MS (ESI) m/z 594.15 (M+H)+, 616.20 (M+Na)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CCC[C@@H](C)CC(=O)O
Solvent: c1ccccc1
Product: CC(C)CCC[C@@H](C)CC(=O)Cl
Yield: 95.4 %

Procedure:
A solution of 11.37 g (66.1 mmoles) of (R)-(+)-3,7-dimethyloctanoic acid in 50 ml of benzene was stirred while 10 ml (114.6 mmoles) of oxalyl chloride was added. The solution was stirred and refluxed overnight then concentrated in vacuo giving 12.03 g (95.6%) of (R)-(+)-3,7-dimethyloctanoyl chloride as an oil. An 8.2 g (43.0 mmoles) sample of this material in 10 ml of dichloromethane was added to a stirred solution of 6.2 (43.0 mmoles) of Meldrum's Acid and 8.68 ml of pyridine in 40 ml of dichloromethane, at 0° C. The resulting solution was stirred overnight then treated with cold 3N aqueous HCl. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The dichloromethane extracts were combined, dried (Na2SO4), and concentrated in vacuo giving 12.1 g of crude product. This material was dissolved in 100 ml of methanol and the solution was refluxed for 4 hr then cooled and concentrated in vacuo. The residue was chromatographed on silica gel giving (R)-5,9-dimethyl-3-oxodecanoic acid methyl ester as an oil, eluted with pet. ether-ether mixtures.