Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13].[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1.O>[CH3:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)=[CH:8][C:7]=1[B:20]([OH:25])[OH:21]
Reactant: Cc1nnc(-c2ccc(C)c(I)c2)o1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(B(O)O)c2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 10 mL, 20.0 mmol) was added dropwise over 20 minutes to a stirred solution of 2-(3-Iodo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole (preparation 55c, 4.0 g, 13.3 mmol) in tetrahydrofuran (40 mL) at −10° C. The mixture was stirred for 1 hour at −10° C. then triisopropyl borate (4.71 mL, 20.0 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour at −10° C. Then, the mixture was warmed to room temperature and stirred overnight. Water was then added, the mixture was cooled by means of an ice-water bath and the pH was adjusted to 3-4 with 2M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (1.92 g, 66%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[K+]>C(O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:22]=[CH:12][C:11]=1[CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1

Procedure:
A mixture of 11-4 (5.0 g, 24.8 mmol), 1-3, 2-amino-3-formylpyridine (3.6 g, 29.8 mmol) and 20% KOH (1 ml) in absolute ethanol (100 mL) was heated at reflux for 8 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 11-6 as a yellow oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)=[C:26]([CH2:48][CH2:49][CH3:50])[N:25]4[N:51]=[CH:52][CH:53]=[C:24]34)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)=[C:26]([CH2:48][CH2:49][CH3:50])[N:25]4[N:51]=[CH:52][CH:53]=[C:24]34)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c([N+](=O)[O-])c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c([N+](=O)[O-])c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogen carbonate (0.68 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-nitrobiphenyl-2-carbonitrile (0.30 g) was added, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.105 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.097 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].Cl[C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH:25]1[O:31][C:32](=[O:34])[CH3:33])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:9]=1[N:10]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH:25]1[O:31][C:32](=[O:34])[CH3:33])=[O:23])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: CC(=O)OC1CC(C)CCC1C(=O)Cl
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1OC(C)=O)C(C)C
Yield: 12.4 %

Procedure:
To a solution of 5-(3-Fluoro-phenyl)-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (200 mg, 0.683 mmol) in 1,2-dichloroethane (5 mL), acetic acid 2-chlorocarbonyl-5-methyl-cyclohexyl ester (148 mg, 0.679 mmol) and triphenylphosphine (197 mg, 0.751 mmol) were added under an atmosphere of N2. The reaction mixture was refluxed for 12 h and then diluted with chloroform and water. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC plate using 15% ethyl acetate in hexane to obtain 3[(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-(3-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester as a white solid (40 mg, 12%). 1H NMR (CDCl3, 400 MHz): δ7.45-7.25 (m, 4H), 7.13-6.95 (m, 1H), 5.13 (m, 1H), 4.87-4.75 (m, 1H), 3.80 (s, 3H), 2.37-0.62 (m, 20H).
Reaction SMILES: O.C(O)(=O)C.[Cl:6][C:7]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:8]=1[CH:9]([OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].CO.O.C>O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:6][C:7]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:8]=1[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[O:18]
Reactant: COc1ccccc1C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h

Procedure:
A solution of chromium(VI) oxide (91.0 g, 0.919 mol) in a water/acetic acid solution (1:4) is added portionwise to 2-chloro-2'-methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) while maintaining the reaction mixture temperature at 25° C. to 35° C. The reaction mixture is then stirred at 25° C. to 35° C. for one hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue. The residue is diluted with water, and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g), and filtered. The filtrate is concentrated in vacuo to obtain an oil. A solution of the oil in a methanol/water solution is decolorized with charcoal and concentrated in vacuo to yield a residue. Column chromatography of the residue using silica gel and methylene chloride/hexanes solutions gives the title product as a white solid.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([Cl:12])([Cl:11])[Cl:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:14]([S:16]Cl)=[O:15]>ClC1C=CC=CC=1>[O:15]=[C:14]1[NH:1][C:2]([C:9]([Cl:10])([Cl:11])[Cl:12])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:16]1
Reactant: CCOC(=O)/C=C(\N)C(Cl)(Cl)Cl
Reactant: O=C(Cl)SCl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1C(Cl)(Cl)Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
to 130.14 g (1.00 mole) of ethyl acetoacetate was added 1.5 g of sodium. The reaction temperature increased spontaneously to 50° C. The reaction mixture was cooled with an ice bath. To the cooled reaction mixture was added, with vigorous stirring at 30°-50° C., 144.3 g (1.00 mole) of trichloroacetonitrile in 30 minutes. After complete addition of the trichloroacetonitrile, the reaction mixture was cooled with a dry ice bath. No precipitate of the ethyl 2-acetyl-3-amino-4,4,4-trichlorocrotonate formed. Part of the above product was stirred with 100 ml. of concentrated 28-30% ammonium hydroxide for 2 hours. The reaction mixture was then extracted with ether. The ether solution was dried (CaSO4) and concentrated to give 180 g (82.5%) of crude ethyl 3-amino-4,4,4-trichlorocrotonate. Part of this crude material (20 g) was distilled at 0.5 mm Hg to give 11.7 g of pure product, m.p. 91°-95° C. To a cold (10° C.) solution of 21.8 g (0.0937 mole) of crude ethyl 3-amino-4,4,4-trichlorocrotonate in 15 ml. of chlorobenzene was added 13.5 g (0.103 mole) of chlorocarbonylsulfenyl chloride. The reaction temperature rose spontaneously to 35° C. after the ice water bath was removed. The reaction mixture was stirred at 65° C. for 1 hour, cooled and triturated with petroleum ether to give 10.3 g (38%) of ethyl 2,3-dihydro-2-oxo-4 -trichloromethyl-5-thiazolecarboxylate, m.p. 109°-110° C. A mixture of 14.5 g (0.05 mole) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, 10.4 g ) 0.05 mole) of phosphorus pentachloride, and 100 ml. of phosphorus oxychloride was held at reflux for 7 days. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with ice water and the aqueous mixture was extracted with ether. The ether solution was extracted with 10% sodium hyroxide, dried (CaSO4) and concentrated under reduced pressure to give 3.2 g of oil which was chromatographed on silica gel using 5% ethyl acetate-petroleum ether as eluant. The first 1.2 l. of eluant gave 2.27 g of solid which was recrystallized from petroleum ether at low temperature to give 2.13 g (13.8%) of ethyl 2-chloro-4-trichloromethyl-5-thiazolecarboxylate, m.p. 42.5°-43.5° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:22][OH:23])[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
General Procedure P. 1-(5,6-Diphenyl-pyridin-2-yl)-ethanone (Compound 75, 119 mg, 0.44 mmol), NH2OH—HCl (103 mg, 1.48 mmol) and pyridine (272 mg, 0.27 mmol) was dissolved in EtOH (2 ml), and the mixture was heated to 70° C. under nitrogen for 3 hours. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as an oil.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:26][CH2:27][CH:28]1O[CH2:29]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CC.Cl.[CH:32]([OH:35])(C)[CH3:33]>O>[ClH:1].[OH:35][CH:32]([CH:14]([O:26][CH2:27][CH2:28][CH2:29][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:33]
Reactant: CC(C)O
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCC(OCCCNCCCC[C@H](N)C(=O)O)C(C)O
Yield: 23.7 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 10.1 g of Nε-(2-hydroxy-3-dodecyloxy)propyl-L-lysine hydrochloride (yield 23.7%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:26]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: CCCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-butoxyphenyl)pyrimidin-6-one sulphate (1.5 g) with formamide (5 ml) afforded the title compound, 0.65 g, m.p. 247°-248° C., (recrystallised from ethanol).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]([O:8][CH:9]([Cl:11])[CH3:10])=[O:7].N1C=CC=CC=1>C(OCC)C>[C:6](=[O:7])([O:4][CH:1]([CH3:3])[CH3:2])[O:8][CH:9]([Cl:11])[CH3:10]
Reactant: CC(C)O
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
0.66 g of isopropanol was added to 1.43 g of 1-chloroethyl chloroformate, and the solution was cooled to 0° C. in an ice-water bath. The mixture of 0.84 g of pyridine and 10 ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10% hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461 g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7%. The crude was directly used in the next reaction without purification.
Reaction SMILES: COC1CCCC1.[C:8]1([CH3:20])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16](O)([CH3:18])[CH3:17]>C1COCC1>[CH3:18][C:16]([C:9]1[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH3:20])=[CH2:17]
Reactant: Cc1cc(C)c(C(C)(C)O)c(C)c1
Solvent: C1CCOC1
Solvent: COC1CCCC1
Product: C=C(C)c1c(C)cc(C)cc1C
Yield: 66.8 %

Procedure:
The same experiment as in Example 4 was carried out, except for using a mixed solvent of CPME and THF (1:1 by volume) instead of 50 ml of CPME. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 66.8% and 14.7%, respectively.
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[Cl:20][CH2:21][C:22](=[O:24])[CH3:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][CH:21]([CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:22](=[O:24])[CH3:23]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CCl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C(Cl)C(C)=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
A solution of BF3.Et2O (9.35 mL; 108 mmol; 2 eq.) in DCM (100 mL) was added dropwise at −30° C. over 50 minutes to diethoxymethoxy-ethane (18 mL; 108 mmol; 2 eq.). The reaction mixture was stirred at this temperature for a further 40 minutes then allowed to return to room temperature and was stirred at room temperature for 1 hour. After cooling down to −78° C., 1-chloro-propan-2-one (4.3 mL; 54 mmol; 1 eq.) was added dropwise followed by DIEA (28 mL; 162 mmol; 3 eq.) at such a rate to keep the temperature below −70° C. The resulting mixture was stirred at −70° C. for one hour then poured onto sat. aq. NaHCO3. The two layers were separated and the aqueous phase extracted with DCM. The combined organics were washed with cold diluted H2SO4 then water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (6 g, 48%) as a brown oil which was used without further purification. 1H NMR (DMSO-d6) δ 4.81 (d, J=6.0 Hz, 1H), 4.64 (d, J=6.0 Hz, 2H), 3.70-3.44 (m, 4H), 2.25 (s, 3H), 1.30-1.17 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:30][CH2:29][CH2:28][CH:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:30][CH2:29][CH2:28][CH:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCCNC1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (43 mL, 558 mmol) was added to benzyl 1-(tert-butoxycarbonyl)nipecotate (7.11 g, 22.3 mmol) in dichloromethane (20 mL). The mixture was stirred for 3 hours. Subsequently, the reaction mixture was concentrated and water was added to the residue, followed by addition of 1 mol/L aqueous sodium hydroxide solution to make the mixture basic. The mixture was then extracted with ethyl acetate. The organic layer washed with brine and was dried over sodium sulfate. The solvent was evaporated to give 5.97 g (quant.) of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:12]1[C:13]([NH:14][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ccc(Nc2ccc(Cl)cc2)cc1
Reaction time: 0.67 h
Yield: 35 %

Procedure:
p-Chloroiodobenzene (14 g), p-chloroaniline (11.23 g), potassium carbonate (12.15 g), and cuprous chloride (1.16 g) were suspended in dimethylsulfoxide (15 ml), and heated with stirring at 180°-190° C. for 3 hours and 40 minutes. After cooling the reaction mixture, ethyl acetate was added thereto, and washed with conc. aqueous ammonia 2 times, and with aqueous sodium chloride solution 3 times, and then, the mixture was concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/n-hexane [1:2 (v/v)] to give 4,4'-dichlorodiphenylamine (4.89 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:25])[CH3:24]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)s1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCCCS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-hydroxypropanesulfonyl)thiophene-2-sulfonamide (1.2 g, 4.2 mmol) in 75 ml of THF was added 0.5 ml of pyridine and 0.5 ml of acetyl chloride. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oily residue was dissolved in ethyl acetate and the ethyl acetate was washed with aqueous sodium bicarbonate solution and then brine. After drying over sodium sulfate the ethyl acetate was concentrated under vacuum, giving a solid residue. This solid was recrystallized from dichloroethane to give 1.0 g of product; m.p. 103°-104.5°. 1H-NMR,δ (DMSO, d6) 7.97 (2H, S); 7.75 (1H, d, J=3); 7.57 (lH, d, J=3); 4.00 (2H, t, J=6); 3.50 (2H, m); 1.90 (5H, m).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][C:29]2=[O:40])[CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
650 mg (1.17 mmol) of 1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one is dissolved in 30 mL of methanol, combined with palladium on charcoal (10%), and hydrogenated at ambient temperature and 3 bar hydrogen pressure. Yield: 240 mg (44%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].[CH:25]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([CH2:27][CH3:28])[CH3:26]>>[CH:25]([C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)(=[O:23])=[O:22])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:33][CH:34]=1)([CH2:27][CH3:28])[CH3:26]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCC(C)c1ccc(N2CCC3(CCN(S(=O)(=O)c4cccs4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 433.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), thiophene-2-sulphonyl chloride and 4-sec-butyl-phenylamine.
Reaction SMILES: [BH4-].[Na+].[H][H].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]([CH2:19][N+:20]([O-])=O)[CH2:14][C:15](OC)=[O:16])[CH:12]=1)#[N:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:6][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]2[CH2:19][NH:20][C:15](=[O:16])[CH2:14]2)[CH:12]=1
Reactant: [H][H]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1cc(C#N)ccc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(CN)cc1C1CNC(=O)C1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Adapting a literature known protocol (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2 6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of methyl 3-(5-cyano-2-methyl-phenyl)-4-nitro-butanoate (22b) (2.62 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are partially evaporated under reduced pressure using a rotary evaporator and the crude material is heated to 50-60° C. to complete the lactamization. Purification by silica gel column chromatography with mixtures of (MeOH) and dichloromethane (DCM) furnishes the title compound 4-[5-(aminomethyl)-2-methyl-phenyl]pyrrolidin-2-one (22c).