Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[C:25]([Cl:31])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:10]2[CH2:11][CH2:12][N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3][CH2:4]3)[C:9]2=[O:13])=[C:25]([Cl:31])[CH:24]=1
Reactant: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (Preparation 24) (20 mg, 0.11 mmol) in 3 mL dry THF, add 0.165 mL of 2M LDA (1.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of 4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, brine, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 10.5 mg of the title compound: mass spectrum (m/z): 389 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O.[Cu](I)I.O>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[CH2:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:3][CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(Br)cc2)C1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(-n3cncn3)cc2)C1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.60 g of 2-(4-bromophenyl)-4-(3,5-dichlorophenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrole, 0.53 g of 1,2,4-triazole, 1.01 g of potassium carbonate and 1.25 g of potassium iodide in 20 mL of N-methylpyrrolidone, 0.21 g of copper iodide was added and the resultant reaction mixture was stirred at 190° C. for 1 hour. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and was poured carefully into 50 mL of water, followed by extracting the reaction mixture with ethyl acetate (30 mL×2). The organic phase was dehydrated and dried over a saturated brine and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (3:2) to obtain 0.27 g of the objective substance as a white crystal.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([NH:19][CH3:20])[N:3]=1.[NH3:21]>>[NH2:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([NH:19][CH3:20])[N:3]=1
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1F
Reactant: N
Product: CNc1nc(N)nc2c1ncn2Cc1ccccc1F

Procedure:
In a manner analogous to that described in Example 2 it is also possible, by reacting 2-chloro-9-(2-fluorobenzyl)-6-(N-methylamino)-9H-purine (Example 6) with ammonia, to obtain the 2-amino-9-(2-fluorobenzyl)-6-(N-methylamino)-9H-purine, which has a melting range of from 207° to 208°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1ccc(N)c(C#N)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Yield: 72.7 %

Procedure:
A solution of 3.5 grams (0.022 mole) of 2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(l) iodide in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture was filtered to remove a solid. The aqueous layer and the organic layer were separated, and the aqueous layer was washed with ethyl acetate. The ethyl acetate wash was combined with the organic layer, and the combination was washed with an aqueous solution of 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with methylene chloride and filtered. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile, mp 136°-138° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([C:15]([O:17]C)=[O:16])[NH:13][C:12](=[O:19])[C:11]3[S:20][C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:22][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([C:15]([OH:17])=[O:16])[NH:13][C:12](=[O:19])[C:11]3[S:20][C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:22][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)[C@@H]1NC(=O)c2sc(N3CCOCC3)cc2[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl rel-(4R,5R)-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (274.0 mg, 0.6208 mmol) in tetrahydrofuran (10.0 mL) and sodium hydroxide (4.50 mmol, 4.50 mmol) in water (4.50 g) was stirred at rt. After 4 h, the mixture was acidified by 1N HCl and the precipitate was collected as pure product (0.250 g, 94%). LCMS: (AA), ES+: 425, 427.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][NH:21][CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][N:21]([C:26](=[O:28])[CH3:27])[CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CNCC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(C)CC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
Pyridine (0.055 mL, 0.68 mmol) is added to a solution of [3-(1,1-dimethyl-2-methylamino-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (150.0 mg, 0.59 mmol) in THF (2.0 mL) followed by the addition of acetyl chloride (0.048 mL, 0.68 mmol). The reaction mixture is stirred at room temperature for 3 h. After this time, more pyridine (0.028 mL, 0.34 mmol) and more acetyl chloride (0.024 mL, 0.34 mmol) are added to the reaction mixture and stirred for another 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides 87.0 mg of the title compound. Yield: 47%. m/z 312 [M+H].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12]Br>CC(O)=O>[CH3:1][C:2]1[NH:3][C:4]2[C:10]([Br:12])=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 0.9 g (6.1 mmol) of 2-methyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.16 ml of Br2 (3.1 mmol) dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (20% Isopropanol/EtOAC) to yield 0.56 g (2.5 mmol, 41%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:13].[C:14](N)(=S)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>C(O)CO>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:3]=2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: COc1cc(C(=O)O)cc(S)c1N
Reactant: NC(=S)c1ccccc1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: COc1cc(C(=O)O)cc2sc(-c3ccccc3)nc12
Temperature: 60 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
4-Amino-3-mercapto-5-methoxybenzoic acid (600 mg) and thiobenzamide (450 mg) were suspended in ethylene glycol (10 ml). Conc. hydrochloric acid (1.0 ml) was added thereto, and the mixture was stirred for 7 hours at 60° C. The reaction mixture was cooled to room temperature, then cold water was added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (280 mg, Y.:32%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].O>CC(C)=O>[C:29]([O:32][CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)C[C@@](O)(C(=O)CBr)CC3
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
The entire amount of 9(R)-bromoacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione was dissolved in acetone (110 ml). Potassium acetate (270 mg) was added to the above solution and the mixture was allowed to react at room temperature for 2 hours, followed by addition of water (100 ml). The precipitated crystals were collected by filtration to give reddish orange crystals of 9(R)-acetoxyacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P. 215°-217° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:45]=[CH:44][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:46][CH3:47])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[Cl-].[Ca+2].[Cl-]>[Fe].C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:45]=[CH:44][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:46][CH3:47])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc([N+](=O)[O-])c4)oc3C)c(OC)c2)cs1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(N)c4)oc3C)c(OC)c2)cs1
Yield: 38 %

Procedure:
A mixture of {4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (650 mg), iron (reduced) (284 mg), calcium chloride (11 mg) and 80% ethanol (8 mL) was heated under reflux for 2 hrs. Insoluble materials were removed by celite filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to give {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}amine as yellow amorphous form (150 mg, yield 38%).
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(C)(C)C)=O.[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:19](N)=[C:18]([Cl:24])[CH:17]=1>C(#N)C.ClCCl>[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:19]([CH2:4][C:5](=[O:6])[CH3:7])=[C:18]([Cl:24])[CH:17]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
In a 50 ml three-neck flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetonitrile (10 ml), were added cuprous oxide (1.5 g, 0.018 mol), isopropenyl acetate (13.6 ml, 0.125 mol) and tert-butyl nitrite (1.7 ml, 0.0125 mol). The resulting red suspension is stirred for 15 min at ambient temperature. A solution of 4-bromo-2,6-dichloroaniline (2.0 g, 0.0083 mol), dissolved in acetonitrile (15 ml) was added dropwise over a period of 20 minutes. During the addition, bubbling was observed. The mixture was stirred at 40° C. for 20 hours. The red crude mixture was passed through celite to remove solid particles and concentrated under reduce pressure to give a brown solid. The residue was dissolved in dichloromethane (120 ml) and washed with water (2×50 ml) and brine (40 ml). Organics were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one (2.3 g) as a dark brown oil.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C@H:42]4[CH2:47][C@@H:46]([O:48]C(=O)C)[CH2:45][CH2:44][O:43]4)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:52]>C(OCC)(=O)C>[ClH:52].[ClH:52].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:37]=[CH:38][C:39]([C@H:42]4[CH2:47][C@@H:46]([OH:48])[CH2:45][CH2:44][O:43]4)=[CH:40][CH:41]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc([C@H]4C[C@@H](OC(C)=O)CCO4)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc([C@H]4C[C@@H](O)CCO4)cc3)cc3ccsc23)CC1
Reaction time: 1 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.21 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-(cis-4-acetoxytetrahydropyran-2-yl)phenyl]thieno[2,3-c]pyridine. To the resulting reaction solution were added ethyl acetate and 2N hydrochloric acid, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic phase was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate twice. The pH of the solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and then the solution was extracted with ethyl acetate twice. After washing with brine and drying over magnesium sulfate, the solvent was evaporated. Methanol (10 ml) was added to the resulting residue and dissolved, followed by the addition of a 5N aqueous solution of sodium hydroxide (1 ml). The resulting solution was left as it was at room temperature for 1 hr, and then the solvent was evaporated. Water was added to the resulting residue, and then the mixture was extracted with ethyl acetate thrice. The extract was washed with brine, dried over magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.20 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCOc1ccc2cc(O)ccc2c1
Yield: 53.3 %

Procedure:
A solution of decylmonobromide (1.5 g), 2,6-dihydroxynaphthalene (1 g) and anhydrous potassium carbonate (0.8 g) in dimethylformamide (50 ml) was stirred at 130° C. for four hours. The solution was poured in water and was made neutral with dilute aqueous hydrochloric acid solution. To the solution was added diethyl ether in order to effect extraction and the extract was distilled to remove the solvent. The residue was washed with hexane and recrystallized from water/ethanol (1/9) to obtain the titled compound (about 1 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[N:33]([C@@:39]1([CH3:47])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]2=[O:48].CC#N>CN(C=O)C>[CH3:47][C@:39]1([N:33]2[C:32](=[O:48])[C:31]3[C:35](=[CH:36][CH:37]=[C:29]([CH2:28][NH:27][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=4)[CH:30]=3)[C:34]2=[O:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46]
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(S(C)(=O)=O)cc4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of 4-(methylsulfonyl)benzoic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and stirring proceeded at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and evaporated. The residue was chromatographed on silica gel using 99:1 methylene chloride-methanol as the mobile phase, providing 0.30 g, in 32% yield. The product was obtained as a white solid; mp 165.5-167.5° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.08 (96.23%); 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 2.22-2.28 (m, 1H), 2.73-2.95 (m, 3H), 3.47 (s, 3H), 4.86 (d, J=5.7 Hz, 2H), 7.98-8.04 (m, 3H), 8.25 (d, J=8.7 Hz, 2H), 8.32 (d, J=8.7 Hz, 2H), 9.58 (t, J=5.7 Hz, 1H), 11.21 (s, 1H); 13C NMR (DMSO-d6) δ 23.0, 30.6, 31.1, 44.8, 45.6, 60.8, 123.7, 125.2, 129.2, 130.3, 131.7, 133.4, 135.5, 140.4, 145.2, 149.0, 167.2, 169.7, 169.9, 174.1, 174.2; Anal. Calcd for C23H21N3O7S+0.3H2O: C, 56.50; H, 4.45; N, 8.59. Found: C, 56.61; H, 4.42; N, 8.30.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:6][CH:5]=1.Br.[OH-].[NH4+]>O>[NH:17]1[CH:18]=[C:14]([CH2:13][CH:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([OH:3])[CH:12]=3)[CH2:8][CH2:9]2)[N:15]=[CH:16]1
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Oc1ccc2c(c1)C(Cc1c[nH]cn1)CC2

Procedure:
A stirred mixture of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazole hydrochloride (140 mg) and 48% hydrobromic acid (7 ml) is heated under reflux for 45 minutes. The cooled reaction mixture is poured into water and is made basic with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is coverted to its hydrochloride salt in ethyl acetate. M.p. 206-208° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][NH:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)OCCCCC1CCCCC1
Reactant: CNCC1CCc2ccc(NC(C)=O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)Nc1ccc2c(c1)C(CN(C)CCCCC1CCCCC1)CC2

Procedure:
A mixture of 6-Acetylamino-1-(N-methylaminomethyl)indan (1.5 g), 4-cyclohexylbutan-1-ol mesylate (2.5 g), potassium carbonate (1.4 g), and a crystal of potassium iodide in MIBK (80 ml) were refluxed for 5 h. After cooling inorganic salts were filtered off and the solvent evaporated in vacuo. The remaining oil was subjected to column chromatography on SiO2 (eluted with ethyl acetate: heptane: triethylamine 80:20:4). The free base of the title compound was isolated as an oil. The sesquioxalate of 13a crystallized from acetone. Yield 1.6 g Mp: 145-155° C.
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.CC(C)([O-])C.[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([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:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 83.2 %

Procedure:
225 g of 1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 1100 ml of dimethyl-formamide, and 198 g of potassium tert.-butoxide were added in portions, with stirring. After one hour, 223 g of benzyl chloride were added dropwise over 30 minutes, and stirred overnight. The batch was added to 1500 ml of water/ice mixture and extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was subjected to fractional distillation under a high vacuum. At 150° C. and a pressure of about 0.1 mbar, 294 g of 8-benzyloxy-1,4-dioxaspiro[4.5]decane were obtained.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH+:6]1[CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7]1.[C:14]([Mg]Br)#[CH:15].[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O.O>[C:14]([C:13]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)#[CH:15]
Reactant: C#C[Mg]Br
Reactant: [CH+]1CCN2CCCC12
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC12CCCN1CCC2
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
1,2,3,5,6,7-Hexahydropyrrolizinylium perchlorate (1.0 g, 4.8 mmol) was added to a solution of 0.5M ethynylmagnesium bromide (29 mL, 14.3 mmol) in THF at room temperature. The reaction mixture was allowed to stir for 45 minutes, and 15% NaOH solution was added. The slurry was diluted with brine:water (1:1) and extracted with CH2Cl2 (3×). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 90:10) to afford an amber oil (463 mg, 71%): 1H NMR (CDCl3, 300 MHz) δ1.75-2.06 (m, 6H), 2.14-2.23 (m, 2H), 2.33 (s, 1H), 2.53-2.62 (m, 2H), 3.22-3.28 (m, 2H); MS (Cl/NH3) m/z: 136 (M+H)+.