Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:37]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CC(C)CCNCCC(C)C
Product: CCOC(=O)c1c(CN(CCC(C)C)CCC(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diisopentylamine to give ethyl 4-(3,4-dimethoxyphenyl)-2-(N,N-diisopentylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 114°-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: Cc1nc2c(O)cc([N+](=O)[O-])cc2o1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(O)cc(N)cc2o1

Procedure:
To a solution of 6-nitro-4-hydroxy-2-methylbenzoxazole (5.1 g, 0.026 mole) in THF (100 ml) and methanol (50 ml) were added about 0.5 g of 10 percent palladium on carbon. The mixture was placed on the Parr-shaker apparatus and hydrogenated two hours. At this time hydrogen uptake was complete (6.3 psi, 0.079 mole). The catalyst was removed and the solvents were removed under reduced pressure. The resulting off-white solid (4.1 g, 97.0 percent) was collected and dried. TLC showed the product to be pure. A ninhydrin test for amines was positive. A silver test for hydroxylamine was negative.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:4]=1[C:24]([O:26][CH3:27])=[O:25].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)(C)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:4]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:31][CH2:30]1
Reactant: COC(=O)c1c(CBr)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: COC(=O)c1c(CN2CCN(C)CC2)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To a suspension of methyl 6-bromomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (1.5 g) in isopropyl alcohol (15 ml) was added N-methylpiperazine (0.88 g) at 70° C. The reaction mixture was stirred for 10 minutes at the same temperature. After evaporating the solvent, the residue was dissolved in a mixture of chloroform (50 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on alumina (100 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residual crystal was recrystallized from a mixture of diethyl ether and ethanol to give methyl 6-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.37 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:14]=[C:13]([CH3:15])[C:9]([C:10](O)=[O:11])=[C:8]([F:16])[CH:7]=1)([CH3:5])[CH3:4])#[N:2].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]([C:3]([CH3:5])([CH3:4])[C:6]1[CH:14]=[C:13]([CH3:15])[C:9]([C:10]([NH2:19])=[O:11])=[C:8]([F:16])[CH:7]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(C)(C)C#N)cc(F)c1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C#N)cc(F)c1C(N)=O
Reaction time: 2.5 h

Procedure:
4-(2-cyanopropan-2-yl)-2-fluoro-6-methylbenzoic acid (14 g, 35 mmol, 75% pure) was taken up in dry tetrahydrofuran (100 ml). To this was added 1,1′-carbonyldiimidazole (11.2 g, 69.1 mmol) in four equal portions over 15 minutes. The mixture was stirred for 2.5 hours and then a 28% aqueous solution of ammonium hydroxide (20.4 ml) was added via drop-wise addition. The material was stirred for 4 hours and then concentrated under reduced pressure to remove 90% of the volatiles. The residue was taken up in water (80 ml) and dichloromethane (80 ml) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with dichloromethane (3×60 ml). The combined organic phase was dried (magnesium sulfate), filtered and concentrated in vacuo and the resultant semisolid was purified via trituration from hot dichloromethane/hexanes to provide the desired product as a slightly-impure off-white solid (10.71 g, 80% purity). (M+H)+=221 m/e.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:11][C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]3[C:9]([NH:11][C:12]4[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=4)([N:10]=2)[N:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: CC1CCNCC1
Reactant: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC23N=CN=C2C=NC(N2CCC(C)CC2)=N3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2) and rinsed with Et2O (×2) to afford IV-33 as a white solid (225 mg, 90%): mp >300° C.;
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:24])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:25]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[C:1]12([O:11][CH2:12][C:13]3[NH:17][N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(Br)c(COC23CC4CC(CC(C4)C2)C3)[nH]n1C1CCCCC1
Yield: 48.1 %

Procedure:
A CCl4 solution (10 mL) of 5-(adamantan-1-yloxymethyl)-2-cyclohexyl-2H-pyrazol-3-ol (0.11 g, 0.33 mmol), azobisisobutyronitrile (2 mg) and N-bromosuccinimide (70 mg, 0.4 mmol) was irradiated by a 100 W light source for 0.3 h at rt. After filtration to the filtrate was concentrated in vacuo to afford a crude product as a purple solid, which was purified by chromatography with EtOAc-DCM (1:4) as eluant. The product was obtained as a white glassy solid (65 mg, 48%).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:17]2[C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cccc(-c5ccccc5)c4c3CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Yield: 121.7 %

Procedure:
A mixture of 3-benzyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g, 0.62 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.11 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.198 g (90%) of a brown foam. Crystallization from ethyl acetate gave 0.030 g of the title compound as a beige solid: mp >250° C.; 1H NMR (300 MHz, CDCl3) δ 7.97, 7.48-7.36, 7.16, 6.94, 3.12-3.08, 3.02-2.98, 2.87-2.83, 2.47-2.43; IR (drift) 3053, 3025, 2927, 2895, 2833, 1458, 1428, 1415, 1335, 1292, 1262, 790, 760, 751, 703 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found 263.1550.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Cl)=[N:5][C:6]([Cl:12])=[N:7]2.C(N(CC)CC)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:24][CH2:23][CH2:21][OH:22])=[N:5][C:6]([Cl:12])=[N:7]2
Reactant: NCCO
Reactant: Clc1nc(Cl)c2c(Br)cccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCNc1nc(Cl)nc2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5-bromo-2,4-dichloroquinazoline (2.3 g, 8.2 mmol) and triethylamine (1.5 ml, 11 mmol) in dichloromethane (100 ml) was added ethanolamine (0.64 ml, 11 mmol), and the mixture was stirred for 30 min. The solvent was evaporated and the residue treated with a mixture of water (30 ml) and ether (20 ml) giving the title compound as a crystalline precipitate which was collected by filtration and dried, m.p. 165°-67° C.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:21]3[CH2:23][CH2:22]3)=[C:15](Br)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:21]3[CH2:23][CH2:22]3)=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)N1CCn2c(c(C(N)=O)c(Br)c2C2CC2)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C(N)=O)c3n(c2C2CC2)CCN(C(=O)NC(C)(C)C)C3)cc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To a mixture under nitrogen of 0.750 g (1.96 mmol) of N2-tert-butyl-7-bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 0.446 g (2.94 mmol) of 4-methoxyphenylboronic acid (CAS 5720-07-0) and 5.8 ml (12 mmol) of aqueous 2M caesium carbonate solution in a mixture of 15 ml of toluene and 15 ml of ethanol under argon is added 0.64 g (0.78 mmol) of tetrakis(triphenyl-phosphine)palladium (CAS 14221-01-3), and the mixture is heated at 100° C. for 17 hours. After cooling, the mixture is filtered through Celite and the filtrate concentrated under reduced pressure. The residue is then taken up in dichloromethane, the organic phase is washed with water, dried over sodium sulfate and filtered, and the solution is concentrated under reduced pressure. The residue is chromatographed on a column of 15 g of silica gel, eluting with a mixture of 10 to 100% ethyl acetate in dichloromethane, to give 0.19 g of N2-tert-butyl-6-cyclo-propyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white solid after crystallizing from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying, and is identical to the compound obtained according to the procedure of Example 12.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:5]=1[CH2:6][CH2:7][NH2:8])[CH3:2].Cl.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>O>[N+:17]([C:11]1[C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(OCC)c(CCN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c(OCC)cc1CCN
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
5.23 g (25 mmol) 2,5-diethoxyphenethylamine N5 was mixed with 10 ml water and cooled to 0° C. while 3 ml conc. HCl was added slowly. The resultant milky emulsion was to cooled 0 to 5° C. and 13.5 ml conc. HNO3 was added slowly and carefully within about 2 hours. The temperature was kept below 10° C. The mixture solidified when about half of the HNO3 had been added. 50 ml icy water was added to render the mixture stirrable. Then the rest of the HNO3 was added. The mixture was warmed up to room temperature and stirred at room temperature for 3 hours, basified to pH>12 with 40% NaOH and then extracted with 2×100 ml CHCl3. The CHCl3 extraction was back washed with 3×100 ml 0.5 M NaOH and dried over 10 g K2CO3. The solvent was evaporated to afford 3.22 g orange oil (yield: 52%), which crystallized when cool.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CN1.[N+:11]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[C:21](=[O:23])[N:20]([C@@H:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=1)[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:19]2)([O-:13])=[O:12].[H][H].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].C(OC1C=C([C@H](N)CS(C)(=O)=O)C=CC=1OC)C.C(OC1C=C([C@@H](N)CS(C)(=O)=O)C=CC=1OC)C>>[N+:11]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[C:21](=[O:23])[N:20]([CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=1)[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:19]2)([O-:13])=[O:12]
Reactant: [H][H]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: CCOc1cc([C@@H](N)CS(C)(=O)=O)ccc1OC
Agent: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: O=C([O-])O
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC

Procedure:
In a particular embodiment, the isoindolin-1-one compound of Formula (I) is Compound (1), i.e., (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one, where X1 is nitro; each of X2 X3 and X4 is hydrogen; R3 is methyl; R1 is methoxy; and R2 is ethoxy. Referring to Scheme A below, Compound (1) can be prepared from reaction between Compound (2) (i.e., (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine) and Compound (3) (i.e., methyl 2-bromomethyl-6-nitrobenzoate) in the presence of an inorganic catalyst such as potassium carbonate and sodium hydrogen carbonate. In another embodiment, the (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine) is replaced with (1R)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine) to form (1N)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:27]([C:34]1([OH:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([C:34]1([OH:40])[CH2:39][CH2:38][N:37]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])=[CH:8][CH:9]=2)=[O:17])[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 76.4 %

Procedure:
N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide (1.14 g, 3.8 mmol) was dissolved in dimethylformamide (DMF) (12 ml) and stirred for 19 hours at room temperature in the presence of triethylamine (0.79 ml, 5.7 mmol) and 4-benzyl-4-hydroxypiperidin (0.87 g, 4.56 mmol). The reaction mixture was concentrated, dissolved in CH2Cl2 and washed with H2O (2×30 ml). The organic phase was dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate 1:1 then ethyl acetate) to provide 2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acetamide (1.32 g, 78%) as a yellow solid, m.p. 105°-108° C. and MS: m/e=455.5 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Na].Cl>O1CCCC1.C(O)(=O)C>[CH:9]1([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1CCCCC1
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 21 h
Yield: 59.9 %

Procedure:
To a solution of 900 mg of (3S)-3-piperidylmethanol in 60 ml of tetrahydrofuran, 1.05 g of cyclohexanecarbaldehyde, 0.54 ml of acetic acid and 2.5 g of sodium triacetoxyborohydrate were successively added at room temperature by the order stated, followed by 21 hours' stirring at the same temperature. The reaction liquid was rendered acidic with 1N hydrochloric acid and washed with chloroform. The aqueous layer was rendered basic with 4N aqueous sodium hydroxide solution, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 990 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1.[CH3:13]O>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2
Product: COC(=O)C1CCc2cc(C)sc21
Yield: 74 %

Procedure:
A solution of 9.4 g (0.051 mole) of 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid and 0.4 g of paratoluenesulfonic acid monohydrate in 400 cc of methanol was stirred at ambient temperature for 20 hours then concentrated dry under reduced pressure. The residue was picked up with ethyl acetate. The resulting solution was washed with an aqueous solution of sodium bicarbonate then water. It was dried on sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was distilled. 7.5 g (yield=74%) of methyl 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylate was obtained. Bp0.6=107° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19])=[O:8].[CH2:20](Cl)[CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([N:9]([CH:7]=[O:8])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19])[CH:21]=[CH2:20]
Reactant: C=CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(C=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
155 g of potassium carbonate were introduced into 500 ml of dimethylformamide. 50 g (0.28 mol) of N-formyl-2-methyl-4-nitroaniline were added to this mixture to give an orange solution, which became blood-red after 128.6 g (136.8 ml, 1.68 mol) of allyl chloride were added. The resultant reaction mixture was stirred overnight and subsequently poured into 1.5 1 of ice water. The crude product which deposited was extracted twice from the aqueous phase with 400 ml of dichloromethane in each case. The two combined dichloromethane phases were washed three times with 500 ml of water in each case, subsequently dried over sodium sulfate and then evaporated, to give 58.3 g of N-allyl-N-formyl-2-methyl-4-nitroaniline (yield: 95%) as an orange oil which crystallized in the refrigerator. The product had a melting point of 56° C. and the following physical/chemical properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[Br:16][CH2:14][C:7]1[C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1oc2ccc(F)cc2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1oc2ccc(F)cc2c1CBr
Temperature: 50 °C
Reaction time: 60 h
Yield: 71.1 %

Procedure:
To a solution (150 mL) of methyl 5-fluoro-3-methyl-1-benzofuran-2-carboxylate (15.4 g) synthesized above in acetonitrile were added N-bromosuccinimide (19.8 g) and 2,2′-azobis(isobutyronitrile) (1.21 g), and the mixture was stirred under argon atmosphere at 50° C. for 2.5 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20-30% ethyl acetate/hexane) to give a white solid. The obtained solid was washed with hexane to give the title object compound (15.1 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2].O1CCCC1.O.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19]/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2C/C=C/C(=O)O)nc1
Reaction time: 16.5 h

Procedure:
A stirred solution of ethyl 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline-1-crotonate, (E)- (1.16 g, 3.25 mmol) in 1:1 tetrahydrofuran/water is treated with sodium hydroxide (0.45 g, 11.3 mmol) at once. The resulting mixture is stirred at reflux for 1.5 hours, then at room temperature for 16.5 hours. After this period, the reaction mixture is diluted with water, and washed with ether. The aqueous layer is acidified with 1N hydrochloric acid (15 mL), and extracted with ether. The organic extract is dried over sodium sulfate, decolorized with charcoal and vacuum filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give the title product as a yellow solid, mp 53°-58° C.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:11]=[N:12][C:13]([O:16]C)=[CH:14][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][N:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(-c3ccccc3)cc2)nn1
Agent: Cl
Product: O=c1ccc(S(=O)(=O)c2ccc(-c3ccccc3)cc2)n[nH]1

Procedure:
The product of step 1 was treated with concentrated hydrochloric acid accordin to step 3 of Example 1 to obtain the title compound. Mp. 219-220° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[CH3:20].CCOC(C)=O.CCCCCCC>CC(C)=O.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]([O:12][CH2:19][CH3:20])[C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[CH:8]=1
Reactant: CCBr
Reactant: Oc1cc(Br)cn2ccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOc1cc(Br)cn2ccnc12
Reaction time: 48 h
Yield: 50 %

Procedure:
6-Bromoimidazo[1,2-a]pyridin-8-ol hydrochloride (40 mg, 0.16 mmol) and Cs2CO3 (104 mg, 0.32 mmol) in acetone (0.64 mL) and DMF (0.2 mL) was added ethyl bromide (12 μL). The reaction was stirred for 48 h then the volatile solvents were removed and the residue then added water (0.8 mL). The resulting solids were stirred, filtered, and rinsed with water. The water filtrate was extracted with EtOAc and then combined with the solid crude products. The residue was purified via column chromatography (25% then 50% EtOAc/heptane) to afford the product (19 mg, 50% yield).