Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:20])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
32 g (0.1 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 300 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 12.7 ml (0.1 mol) of N-ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were added and the solution was stirred for 20 minutes while maintaining the temperature at -10° C. 9.3 ml of aniline were then added and the mixture was stirred at 0° C. for 1 hour. The mixture was found to be slightly acidic and a further 1 g of N-ethylmorpholine was added. The solution was then left to stand at room temperature for 16 hours. The solution was evaporated, there being obtained a white crystalline solid which was treated with 500 ml of ether, filtered, washed and dried to give 31.8 g of N-benzyloxycarbonyl-L-alanyl-L-proline anilide of melting point 139.5°-140.5° C.; [α]D20 =-125.5° (c=1.195% in methanol). A second crop (1.4 g; melting point 138°-139° C.) was obtained by evaporating the mother liquor to a small volume, when crystallisation took place. The total yield was 81%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.P([O-])(O)(O)=O.[K+].[Cl:21][O-].[Na+].C(O)(=O)C>C(Cl)Cl.O>[Cl:21][CH:3]1[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[CH:7]([CH2:8][CH2:9][C:10](=[O:11])[CH3:12])[C:2]1=[CH2:1]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: [O-]Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: C=C1C(Cl)CCC(C)(C)C1CCC(C)=O
Temperature: 25 °C

Procedure:
388 g (2 mol) of dihydro-α-ionone was placed in 2.2 l of methylene chloride in a 10 l four-necked flask fitted with a stirrer, thermometer, condenser and dropping funnel. Then, 660 g (4.6 mol) of potassium dihydrogen phosphate dissolved in 3 l of water was added and the resulting emulsion was cooled in an ice bath. 1.6 (2.3 mol) of sodium hypochlorite solution (~12%) was added at about 10° within 1.5 hours and, after about 3 hours at 15°, a further 350 ml (0.5 mol) was added. The pH value of the mixture was adjusted to ~5.5 with acetic acid and it was stirred at room temperature. After a total reaction time of 27 hours the phases were separated and the aqueous phase was extracted 4 times with methylene chloride. The combined organic phases were washed neutral once with water, twice with saturated NaHCO3 solution and a further 3 times with water, dried over MgSO4, filtered and evaporated (bath temperature=room temperature). 407.45 g 4-(3-chloro-2-methylidene-6,6-dimethyl-cyclohex-1-yl)-butan-2-one was obtained as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]1[O:31][CH2:30]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]([OH:31])[CH2:30][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: COc1ccc(S)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(SCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h

Procedure:
4-Methoxythiophenol (1.0 ml) and triethylamine (1.0 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (1.57 g) as obtained in Example 1-A) in methanol (50 ml), and the mixture was stirred for 1.5 hours under reflux. The reaction mixture was concentrated and the residue was poured into ice-water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from a mixted solution of hexane-ethyl acetate to give 2.16 g of the title compound as colorless needles.
Reaction SMILES: [N+](=CC([C:6]1([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=[CH:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=O)=[N-].[C:20]([O:23]CC)(=[O:22])[CH3:21]>O1CCOCC1.O.CCCCCC>[N:11]1([C:6]2([CH2:21][C:20]([OH:23])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1
Reactant: [N-]=[N+]=CC(=O)C1(n2ccc3cccnc32)CCCC1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 2 h
Yield: 54 %

Procedure:
To a stirred solution of 2-diazo-1-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-ethanone (396) (0.95 g, 3.82 mmol) in dioxane:water (10:1) (27.5 mL) was added silveracetate (319 mg, 1.91 mmol) and stirring was continued for 2 h at room temperature (TLC, 30% ethyl acetate in hexane, Rf=0.2). The mixture was filtered over a celite bed, washed with ethyl acetate (3×20 mL) and concentrated. The crude product was purified by Combi-Flash column (eluted at 30% ethyl acetate in hexane) to get (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetic acid (397) (0.5 g, 54%) as a brown solid.
Reaction SMILES: [N+:1]([CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[N+:1]([CH:4]([CH3:15])[CH:5]([O:14][C:21](=[O:23])[CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(O)CCc1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(CCc1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Crude 4-Nitro-1-phenyl-pentan-3-ol (179) from above was dissolved in CH2Cl2 (60 mL) and cooled in an ice bath under nitrogen. Concentrated sulfuric acid (0.76 mL, 14.2 mmol) then acetic anhydride (13.83 mL, 146.2 mmol) were added slowly, and the reaction was allowed to warm to room temperature, and was stirred until judged complete by HPLC (3 h, 40 min). (Note: The reaction turned black soon after the addition of the acetic anhydride.) The reaction was quenched by pouring slowly into water, then the organic layer was removed, washed with aq. NaHCO3, dried, filtered, and concentrated. The crude product was purified by purified by silica gel chromatography (Combiflash column, 95:5 Hexanes: EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC: 10.45 min.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH:6]1([C:12]2[C:13]3[CH:14]=[CH:15][C:16]4[C:17](=[O:60])[NH:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][NH:25][C:26](=[O:59])[CH2:27][N:28]([C:57]=3[CH:58]=4)[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[C:42]([N+:44]([O-])=O)[CH:41]=[CH:40][C:39]=3[N:47]3[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]3)=[CH:32][CH:31]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1.C(O)C>[CH:6]1([C:12]2[C:13]3[CH:14]=[CH:15][C:16]4[C:17](=[O:60])[NH:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][NH:25][C:26](=[O:59])[CH2:27][N:28]([C:57]=3[CH:58]=4)[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:39]=3[N:47]3[CH2:48][CH2:49][N:50]([S:53]([CH3:56])(=[O:54])=[O:55])[CH2:51][CH2:52]3)=[CH:32][CH:31]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(c2ccc(N)cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Temperature: 25 °C

Procedure:
Tin(II) chloride dihydrate (400 mg, 1.77 mmol) was added to a solution of 3 (55 mg, 0.0715 mmol) in THF (1 mL) and ethanol (1.5 mL). The reaction mixture was heated at reflux for 3 days, then allowed to cool down to room temperature. Then, volatiles were evaporated under vacuum and the residue was successively partitioned between a diluted solution of NaHCO3 and ethyl acetate, dried (Na2SO4) and evaporated. Purification by column chromatography (CH2Cl2/methanol, 97.5:2.5) afforded the title compound 4 as a yellowish powder: m/z=740 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][Br:24])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Yield: 100.9 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (126 mg, 0.72 mmol, 2.1 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). Then, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 138.6 mg of crude N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II), which contained 93% of N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:1])=[CH2:29])[CH:23]=1)[CH3:20]
Reactant: CC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Methyl triphenylphosphonium bromide (2.33 g; 6.52 mmol) was suspended in tetrahydrofuran (15 ml). While the suspension was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.68 M: 4.6 ml; 7.82 mmol) was added dropwise. After the reaction mixture turned deep red, the mixture was cooled in an ice bath, and Compound 1 (1.54 g; 5.43 mmol) in tetrahydrofuran (15 ml) was added dropwise thereto. After completion of the addition, the mixture was removed from the ice bath, and stirred for 30 minutes at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.69 g of the target compound (yield: 45.2%).
Reaction SMILES: [OH:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:29][O:28][C:26]([O:1][CH:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:27]
Reactant: COC(=O)Cl
Reactant: O=C1CCCCCCCCCCC(O)CCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OC1CCCCCCCCCCC(=O)OCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
480 g (1.89 mol) of 12-hydroxy-15-pentadecanolide (VII) are dissolved in 900 ml of methylene chloride with 205.5 g of pyridine. 213 g (2.2 mol) of methyl chloroformate in 900 ml of methylene chloride are added dropwise to this mixture at 0° to 5° C. in the course of 1 hour. The reaction mixture is stirred at room temperature for a further 5 hours. The organic phase is washed neutral and dried over Na sulphate. The organic phase is freed from methylene chloride and subjected to fractional distillation. 540 g of 12-methoxycarbonyloxy-15-pentadecanolide are obtained; yield: 91% of theory.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17](F)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17]([N:30]([CH3:31])[CH3:29])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)C(CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a suspension of γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (2.0 g) in benzene (160 ml) were added 80 g of 40 % aqueous solution of dimethylamine, and the resulting mixture was stirred at room temperature for 27 hours. The benzene layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sufficiently triturated and washed with n-hexane to afford γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-dimethylamino-4-fluorobutyrophenone. M.P. 83° - 85°C.
Reaction SMILES: [NH2:1]/[C:2](=[N:19]\[OH:20])/[CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH3:21][O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH3:30])=[O:28])=[O:24]>CO>[NH2:1]/[C:2](=[N:19]\[O:20]/[C:25](=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])/[C:23]([O:22][CH3:21])=[O:24])/[CH:3]([N:10]([C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:17])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: CC(O)CCCC(/C(N)=N/O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/O/N=C(\N)C(CCCC(C)O)N(C)C(=O)OC(C)(C)C)C(=O)OC
Temperature: -10 °C
Reaction time: 48 h

Procedure:
The tert-butyl {1-[(Z)-amino(hydroxyimino)methyl]-5-hydroxyhexyl}methylcarbamate (161 g, overweight) was dissolved in methanol (250 mL) and cooled to −10° C. DMAD (65 mL) was added dropwise without allowing the reaction temperature to rise above −5° C. then the reaction mixture was stored in a freezer at −10° C. for 2 days. The reaction mixture was then concentrated to dryness. It was azeotropically dried twice with toluene and dried in vacuo at 30° C. to constant weight to afford the title product: ES MS M+1=431.9.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[C:33]([OH:36])(=[O:35])[CH3:34].CCOCC>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:36][C:33](=[O:35])[CH3:34])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Yield: 43 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin 5(R)-ylmethyl}-carbamic acid 1(R,S)-chloro-ethyl ester (11) (0.49 g, 1 mmol), mercury(II) acetate (0.37 g, 1.175 mmol), and acetic acid (6.3 mL, 109 mmol) are stirred at RT overnight. Ether and water are added and the layers are separated. The organic layer is washed several times with water, brine, dried over Na2SO4 and conc in vacuo. After purification by silica gel chromatography, the product is re-dissolved in CH2Cl2 and washed with several portions of sat NaHCO3, water, dried over Na2SO4 and conc in vacuo to give the title compound in 43% yield (0.51 g) as a mixture of two diastereomers in a 1:1 ratio. 1H NMR (400 MHz, CDCl3): δ 7.46 (dt, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 6.88 (q, 1H), 4.82 (m, 0.5H), 4.75 (m, 0.5H), 4.13 (m, 1H), 4.04 (m, 2H), 3.73 (dd, 0.5H), 3.67 (dd, 0.5H), 3.12 (m, 5H), 2.55 (s, 1.5H), 2.53 (s, 1.5H), 2.38 (m, 2H), 2.17 (m, 2H), 2.13 (s, 1.5H), 2.06 (s, 1.5H), 1.57 (d, 1.5H), 1.54 (d, 1.5H). MS-APCI (m/z+): 341, 385, 427, 515.
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=O)[CH2:6]2)[CH2:4][CH2:3]1.Cl.[NH2:14][OH:15]>CO>[CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([O:9][CH2:8][C:7](=[N:14][OH:15])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)CC(=O)CO2
Reactant: NO
Agent: Cl
Solvent: CO
Product: CN1CCC2(CC1)CC(=NO)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 3 (0.6 g, 3.5 mmol) was dissolved in methanol (50 ml) and placed under nitrogen. Hydroxylamine hydrochloride was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Li]CCCC.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([CH2:27]Br)[CH:21]=1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:27][C@H:7]1[C:6]([O:9][CH3:10])=[N:5][C@H:4]([CH:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8]1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2 mL, 11.03 mmol) in THF (90 mL) at −78° C. was added n-BuLi (1.6 M in hexanes solution, 7.5 mL, 12 mmol). After stirring for 30 min, 1-bromo-3-(bromomethyl)-5-fluorobenzene (2.68 g, 10 mmol) in THF (10 mL) was added dropwise over 30 min. The temperature was maintained at −78° C. for 30 min then allowed to warm to ambient temperature. After stirring for 16 h, saturated aqueous NH4Cl (30 mL) was added followed by dilution with EtOAc and H2O. The THF was removed in vacuo and the remaining organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.17 g, 77%). MS (m/z) 371 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.ClC1C=CC(C(=O)C)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]Br)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)[CH2:5][CH2:4]1
Reactant: Cc1ccc(OCCBr)cc1
Reactant: NCC1CCNCC1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCN2CCC(CN)CC2)cc1

Procedure:
A mixture of 4-aminomethylpiperidine (3.58 g) and 4'-chloroacetophenone (4.85 g) in toluene (100 ml) was boiled under reflux with a catalytic amount of p-toluenesulphonic acid for 5 hours, removing the water formed by means of a Dean and Stark apparatus, to give a solution. The solution was cooled and 2-bromoethyl 4-methylphenyl ether (6.68 g) was added, followed by triethylamine (4.4 ml). This mixture was boiled under reflux for 6 hours then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added to the residue and the mixture heated on a steam bath for 16 hours. The mixture was evaporated to near dryness, water (50 ml) was added and the mixture was washed with ether. The aqueous layer was basified with 2M sodium hydroxide solution and extracted with dichloromethane to give 4-aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine as an oil. The oil was cooled in ice and 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution) were added. The mixture was heated on a steam bath for 4 hours then evaporated to near dryness and the residue treated with 2M hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane, basified with 2M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 150° C. at 0.13 mbar. This distillate was dissolved in ether and the solution acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether and recrystallised from absolute ethanol to give 4-dimethylaminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride, m.p. 278°-280° C.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:15]([O:17]C(Cl)=O)[CH3:16]>ClCCl>[CH2:15]([O:17][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])[OH:7])[CH3:16]
Reactant: CCCC[PH](=O)O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butylphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butyl-phosphonic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[CH:30])[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[C:30][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(OCc3ccccc3)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(OCc4ccccc4)c3n2)n1
Yield: 6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (82 mg, 0.43 mmol) and 8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (119 mg, 0.43 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 10 mg of 8-(benzyloxy)-2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 6%) beige solid (Mp=92-94° C.)