Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl. acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1)[CH3:15]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
(4-Cyano-3-fluoro-phenyl)-acetic acid methyl ester (3.06 g, 15.84 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled in a dry ice-acetone bath. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.42 mL) was added under a nitrogen atmosphere. The solution was stirred for 1 h, at which point methyliodide (4.91 mL) was added dropwise. The reaction was allowed to warm to ambient temperature while stirring. Upon reaction completion satd. aq. ammonium chloride (100 mL) was added and the bulk of the tetrahydrofuran evaporated under a nitrogen stream. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography with ethyl acetate:hexanes (3:17) to give the title compound (1.73 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nc(C2CCN(C(=O)Nc3ccccc3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-amino-4-(4-piperidinyl)quinazoline (100 mg, 0.44 mmol) obtained in Example 11(1) and triethylamine (133 mg, 1.3 mmol) in dichloromethane (50 ml) was added phenyl isocyanate (50 mg, 0.42 mmol) under a nitrogen atmosphere. The mixture was stirred for about 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silicagel column chromatography (chloroform:methanol=99:1) to give the titled compound (127 mg).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:5]2[CH2:4][NH:3]1.O>C1COCC1>[CH2:4]1[NH:3][CH2:2][CH2:8][CH2:7][N:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:5]12
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2CN1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccccc1N1CCCNCC21
Temperature: 0 °C

Procedure:
A solution of 7.5 g 2,3,4,5,11,15b-hexahydro-3-oxo-1H-dibenz[3,4:6,7]azepino[1,2-a](1,4)diazepine in 200 ml THF is added to a vigorously stirred suspension of 5 g LiALH4 in 400 ml dry THF. The mixture is boiled under reflux for 3 hours, after which it is cooled to about 0° C. 20 ml water is then added slowly to the mixture and the inorganic precipitate which forms is removed by filtration. The filtrate is evaporated to dryness, leaving a crystalline residue. Yield 5.3 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[CH:30]O)[C:23](=[O:29])[NH:24]2>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[CH:30][NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:17][CH:16]=1)[C:23](=[O:29])[NH:24]2
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: Nc1ccc(OCCCCN2CCCCC2)cc1
Product: Cc1cccc2c1C(=CNc1ccc(OCCCCN3CCCCC3)cc1)C(=O)N2
Yield: 53.2 %

Procedure:
In a manner similar to that described in Example 231, 4-(4-Piperidin-1-yl-butoxy)-phenylamine (1.19 g, 1.1 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.79 g, 4.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (0.97 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:7]([CH3:19])=[CH:6][C:5]=1[O:20][CH3:21].FC(F)(F)S(O[C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:34]([C:44](=[O:47])[NH:45][CH3:46])[C:33]=2[CH:48]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([C:8]4[C:7]([CH3:19])=[CH:6][C:5]([O:20][CH3:21])=[C:4]([CH:9]=4)[C:3]([O:2][CH3:1])=[O:22])=[CH:48][C:33]=3[C:34]=2[C:44](=[O:47])[NH:45][CH3:46])=[CH:42][CH:41]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Methyl-2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.2 g, 3.92 mmol, 1 eq), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.6 g, 3.92 mmol, 1 eq), Cesium carbonate (3.8 g, 11.7 mmol, 3 eq) and Tetrakis triphenylphosphinepalladium (0.13 g, 0.11 mmol, 0.03 eq) were dissolved in 1,4-dioxane/water and the above solution was stirred at 90° C. for 10 h. Then the reaction mixture was diluted with water and product was extracted with ethyl acetate and purified by combiflash chromatography using 40% ethyl acetate/hexane as eluent. Yield: 0.95 g (55%). 1H NMR (400 MHz, DMSO-d6): δ 2.3 (s, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 7.15 (s, 1H), 7.51 (s, 1H), 7.64 (m, 2H), 7.65 (m, 2H), 7.74 (d, 1H, J=8.48 Hz), 8.00-8.01 (m, 2H), 8.48 (d, 1H). LCMS: (ES+) m/z=448 (M+H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Cl:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1CNCCc2cc(OC)c(Cl)cc21
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.421 g, 1.25 mmol) in methanol (30 mL) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.241 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H), 2.91 (s, 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 0.93 (dd, J=8, 8 Hz, 3H). MS calculated for C13H18cINO+H: 240, observed: 240.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br/[CH:19]=[CH:20]/[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])(/[CH:19]=[CH:20]/[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C/C=C/Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C/C=C/C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (636 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from trans-1-bromo-1-propene (1.35 mL), a small iodine flake, and magnesium powder (382 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:11]1CCC[CH2:12]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:4]([C:3]1([CH3:8])[CH2:9][O:10][C:12](=[O:11])[O:1][CH2:2]1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(CO)CO
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a 500 mL three neck RB flask were added methyl 2,2-bis(hydroxymethyl)propionate (12.45 g) and tetrahydrofuran (THF) (100 mL). The resulting mixture was stirred under nitrogen via a mechanical stirrer until a homogeneous solution results. Triphosgene (8.78 g) was added and the solution cooled to -78° C. Triethylamine (18.3 g) was slowly added to the cooled solution. The resulting mixture was stirred at this temperature for one hour and then allowed to warm to room temperature. The triethylamine/HCl salt was filtered off and the resulting filtrate pass through a shallow bed of silica gel. The filtrate was concentrated at reduced pressure and then dried under vacuum affording 13.4 g of product which had a small amount of contamination. This contamination was removed via washing with warm diethyl ether. 1H NMR (CDCl3) ppm: 4.67 (ab doublet, 2H), 4.20 (ab doublet, 2H), 3.77 (S, 3H), 1.30 (S, 3H).
Reaction SMILES: [C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9](Cl)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.[Pd](Cl)Cl>[C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCc2c(Cl)nc3ccnn3c21
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)N1CCc2cnc3ccnn3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In a mixed solvent of 300 ml of tetrahydrofuran and 150 ml of methanol were dissolved 11.30 g of 8-tert-butyl-5-chloro-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo-[1,5-a]pyrimidine, and the reaction system was cooled to 0° C. To the solution were gradually added 3.75 g of palladium chloride and 7.83 g of sodium borohydride, and the mixture was stirred for 30 minutes at 0° C. Furthermore, 7.50 g of palladium chloride and 5.66 g of sodium borohydride were gradually added, and the resultant mixture was stirred for 30 minutes at 0° C. and for 2 hours at room temperature. The reaction solvent was distilled off under reduced pressure, and the resultant crude product was subjected to column chromatography on silica gel (ethyl acetate→ethyl acetate:methanol=10:1) to obtain 3.94 g (yield: 40.4%) of the intended product. White crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][O:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH:31]([OH:32])[CH2:33][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(COCC2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COCc3ccccc3)CC1)O2

Procedure:
Compound 171 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(benzyloxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 466 [M+H]; Rt=1.01 min.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CC(C)=O>>[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C

Procedure:
Chloroacetone (0.89 ml, 1.04 g, 11.2 mmol) is added to a mixture of 4-(3-methyl-2-butenoxy)phenol (2.0 g, 11.2 mmol), potassium carbonate (25 g) and potassium iodide (2.6 g) in 125 mol of anhydrous acetone. The mixture is heated under reflux for 4.5 hours and then is allowed to cool to RT to give 4-(3-methyl-2-butenoxy)phenoxyacetone.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:18][CH2:19][O:20][CH3:21])[S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[CH3:21][O:20][CH2:19][CH2:18][C:8]1[S:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(CCOC)sc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Temperature: 55 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
A solution of 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.17 g, 0.56 mmol) in methanol (1.00 ml) was treated with a 2.55 N solution of KOH in water (0.66 ml). The mixture was stirred at 55° C. for 40 min, then the volatiles were evaporated. The residue was redissolved in water (1.30 ml) and acidified to pH 3 with 1N HCl. Filtration and drying under vacuum afforded 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.08 g, 50%), MS (ISP): m/e=278.1 (M−H)
Reaction SMILES: [CH2:1]([S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C1CCNCC1
Reactant: CC(C)CCS(=O)CCCCCCl
Product: CC(C)CCS(=O)CCCCCN1CCCCC1

Procedure:
Heat 5-chloropentyl isopentyl sulfoxide (760 mg, 3.38 mmoL) and piperidine (2 mL) at 125° C. for 1 hour. Partition between 5N sodium hydroxide and ethyl ether. Separate the organic phase and extract the aqueous phase with ethyl ether (2×25 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 1.01 g yellow oil. Purify by silica gel chromatography (CHCl3 :MeOH:NH4OH/100:10:1) to yield 740 mg (80%) yellow oil which crystallizes. Purify further by silica gel chromatography (50% methanol/methylene chloride) to yield 79 mg of the title compound as a white solid; mp 44°-45° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=3[Cl:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(Cl)cc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)cc2Cl)CC1
Yield: 32.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.23 g) as starting compound, potassium carbonate (0.34 g) and 6-bromo-1-(2,4-dichlorophenyl)-1-hexanone (0.20 g) were reacted and treated in the same manner as in Example 172 to give 0.11 g of 4-amino-5-chloro-N-((1-(6-(2,4-dichlorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C:7](=[O:15])[C:6]1=[O:16].[N+:21]([CH3:24])([O-:23])=[O:22]>O>[Br:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1])[C:6](=[O:16])[C:7]2([OH:15])[CH2:24][N+:21]([O-:23])=[O:22]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Br)cc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2Cl)c2ccc(Br)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
1-(2-chlorobenzyl)-5-bromoindoline-2,3-dione (0.175 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:22](C(O)=O)=[CH:21][N:20]=1.N>O>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(C(=O)O)c(-c2cccnc2)n1
Agent: N
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 180 °C

Procedure:
To 25 mL N-methylpyrrolidone, 5.0 g 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylic acid and 0.2 g cupric oxide is added. The mixture is heated to 180° C. for 2 hours, then cooled to 60° C., and 30% aqueous ammonia 1 mL and 50 mL water is added. It is cooled to 25° C., and the precipitate is filtrated, yielding, upon drying, 4.3 g of product with HPLC purity of 97% (A %), which is identified through GC-MS.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a suspension of 1 g (2.96 mmol) of trans-N-(4-hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 12 mL of toluene were added 0.9 ml (6.04 mmol, 2 eq) of bromo-acetic acid tert-butyl ester, 100 mg (0.3mmol, 0.1 eq) of tetra-N-butylammonium hydrogensulfate and 12 mL of 50% aqueous NaOH. The mixture was stirred at 500 for 1 h. The organic phase was dissolved in EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 1.3 g (97%) of trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester as an off-white solid, MS: 469 (M+NH4+).
Reaction SMILES: O1CCCC1.[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1.[C:17](=S)=[S:18]>>[N:6]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)=[C:17]=[S:18]
Reactant: S=C=S
Reactant: CCOC(=O)N1CCC(N)C1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(N=C=S)C1
Temperature: -10 °C
Yield: 99.8 %

Procedure:
(a-3) To a stirred and cooled (10° C.) mixture of 37 parts of N,N-methane-tetraylbis[cyclohexanamine] and 594 parts of tetrahydrofuran were added 91.2 parts of carbon disulfide. After cooling to -10° C., 27.5 parts of ethyl 3-aminopyrrolidinecarboxylate were added during a period of 5 minutes (exothermic reaction). The reaction mixture was allowed to reach room temperature and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 32 parts (99.8%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate as a residue (interm. 6).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:20]1[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][CH:21]=1)([O-])=O>CN(C)C=O>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:20]2[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OC(c2ccccc2)c2ccccc2)cc1

Procedure:
Diphenylmethanol (18.4 g, 0.1 m) was added portionwise to a suspension of sodium hydride (2.4 g, 0.1 m) in dimethylformamide (300 ml) under nitrogen. After the reaction had ceased, the suspension was treated dropwise with a solution of 4-nitropyridine-1-oxide (14 g, 0.1 m) in dimethylformamide (500 ml). This caused the colour of the mixture to change from orange to dark blue. After a further twelve hours at room temperature, the mixture was filtered and evaporated under reduced pressure, leaving a residue that crystallised from toluene giving 19.8 g of 4-[diphenylmethoxy]pyridine-1-oxide as light yellow crystals, m.pt. 155°-157° C.