Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(NC[C@H]1CC[C@H]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=O)CC1)=O)(C)(C)C.[ClH:30].O1CCOC[CH2:32]1>O1CCOCC1>[ClH:30].[CH3:32][N:18]([CH3:16])[C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:21]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Agent: Cl
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the compounds (I) (19.15 g) was added dry 1,4-dioxane (50 ml) and 4N hydrogen chloride/1,4-dioxane solution (250 ml), and the mixture was stirred under room temperature for 2 hours. The solvent was removed under a reduced pressure and toluene was added and reevaporated to give L-phenylalanine 4-carbamoylanilide hydrochloride (II) quantitatively as a white powder. On the other hand, trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (13.36 g) was dissolved in dry tetrahydrofuran (500 ml), and triethylamine (7.80 ml) was added under ice-cooling, followed by stirring at the same temperature for 10 minutes. Subsequently, a solution of ethyl chlorocarbonate (5.64 g) in dry tetrahydrofuran (50 ml) was added dropwise under ice-cooling for 3 minutes, and the mixture was again stirred at the same temperature for 20 minutes. The above mixture was added to the suspension of the hydrochloride (II) previously obtained and triethylamine (8.53 ml) in N,N-dimethylformamide (150 ml) under ice-cooling, followed by stirring at the same temperature for 2 hours, and under room temperature for 6 hours. Ice-water (1.4 liter) was added and the insolubles were collected by filtration, thoroughly washed with water, and further washed with 10% aqueous citric acid, water 5% aqueous sodium hydrogen carbonate, followed by washing with water at 40° to 50° C., and drying, to give N-[4-trans-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine 4-carbamoylanilide (III) (24.63 g). The structure was confirmed by NMR.
Reaction SMILES: C([N:4]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][C:6]([O:8]CC)=[O:7])(=O)C.O[Li].O>CO.O>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NCC(=O)O)cc1
Reaction time: 120 h
Yield: 69.1 %

Procedure:
To a stirred solution of N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (Step 1) (0.24 g, 0.54 mmol) in methanol was added LiOH.H2O (0.06 g, 1.36 mmol) in water. After 5 days the reaction was complete and the solvents were removed in vacuo. The resulting semi-solid was partitioned between ethyl acetate and 1N KHSO4 solution. The ethyl acetate phase was dried over MgSO4, filtered and concentrated in vacuo yielding N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine (0.139 g, 69%) as a white powder: mp 242-248° C. 1H NMR (CDCl3/300 MHz with DMSO-d6) 7.76 (d, 2H, J=8.5 Hz), 7.33-7.22 (m, 5H), 7.19 (d, 2H, J=8.5 Hz), 6.35 (t, 1H, J=5.4 Hz), 3.63 (d, 2H, J=5.4 Hz), 2.39 (s, 3H). FABLRMS m/z 373 (M+H). FABHRMS m/z 372.0786 (M+, Calc'd 372.0780). Anal. Calc'd for C18H16N2O5S: C, 58.06; H, 4.33; N, 7.52. Found C, 58.09; H, 4.44; N, 7.45.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:9]/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OC/C=C/C1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrC/C=C/C1CCCCC1
Yield: 61 %

Procedure:
To a stirred solution of (E)-3-cyclohexyl-2-propen-1-ol (A. G. M. Barrett et al, Tetrahedron, 1996, 52, 15325), (1.47 g, 10.5 mmol) in diethyl ether (20 ml) and pyridine (1 ml) was added phosphorus tribromide (1.40 ml, 15 mmol) dropwise at room temperature under an atmosphere of nitrogen. Afler 16 h, the reaction mixture was carefully poured onto ice water (100 ml) and extracted with diethyl ether (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (20 g) column chromatography cluting with hexane:ethyl acetate (4:1) to give the title compound as a colourless oil (1.3 g, 61%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: Cc1ccc(CCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(C)cc2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g 0.367 mmol), 2-p-tolylethylamine (0.0546 g, 0.404 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol) in ethyl acetate to give 6-{2-methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamide (0.143 g, 97.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.168 g, ˜100%): TOF MS ES+ 392.1 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1966, time 0.39 min; HPLC [Waters XTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 15 min], tR=8.4 min, 100% purity.
Reaction SMILES: [S:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)([CH3:4])(=[O:3])=[O:2].[ClH:26].CCCCCC>C(OCC)(=O)C>[ClH:26].[CH3:4][S:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCOS(C)(=O)=O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.06 g of tert-butyl N-(12-mesyloxydodecyl)carbamate in 60 ml of ethyl acetate was added 10 ml of hydrochloric acid under ice-cooling and the mixture was stirred at room temperature for one hour. The reaction solution was cooled with ice, hexane was added, the crystal thus precipitated out was recovered by filtration and dried under reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23]O)=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[OH-].[Na+].[BrH:32]>C(O)(=O)C.O>[Br:32][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:29])([F:28])[F:1])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: Br
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Oc1cccc(Oc2nn(-c3ccc(C(F)(F)F)cc3)nc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-[3-(Trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.17 g, 0.4 mmol) was suspended in 33% hydrobromic acid in acetic acid (2 mL) and 48% hydrobromic acid in water (2 mL). The mixture was heated to reflux with stirring for 4 h. The reaction mixture was cooled to 0° C. and basified with 50% aqueous sodium hydroxide solution. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3×15 mL), and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain the title compound (0.19 g) as a pale yellow solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](CC(O)=O)=[O:3].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:28]3[C:29]4[C:34]([O:35][C:36](=[O:37])[C:27]=3[N:26]3[C:17]=2[C:18]2[C:23]([CH2:24][CH2:25]3)=[C:22]([O:41][CH3:42])[C:21]([O:43][CH3:44])=[C:20]([O:45][CH3:46])[CH:19]=2)=[CH:33][C:32]([OH:38])=[C:31]([O:39][CH3:40])[CH:30]=4)=[CH:12][C:11]=1[OH:47].[C:48](OC(=O)C)(=[O:50])[CH3:49]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][C:2]([O:47][C:11]1[CH:12]=[C:13]([C:16]2[C:28]3[C:29]4[C:34]([O:35][C:36](=[O:37])[C:27]=3[N:26]3[C:17]=2[C:18]2[C:23]([CH2:24][CH2:25]3)=[C:22]([O:41][CH3:42])[C:21]([O:43][CH3:44])=[C:20]([O:45][CH3:46])[CH:19]=2)=[CH:33][C:32]([O:38][C:48]([CH3:49])=[O:50])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH:14]=[CH:15][C:10]=1[O:9][CH3:8])=[O:3]
Reactant: COc1ccc(-c2c3n(c4c(=O)oc5cc(O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2c3n(c4c(=O)oc5cc(OC(C)=O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1OC(C)=O
Temperature: 18 °C
Reaction time: 26 h
Yield: 83 %

Procedure:
Lamellain T diacetate: Lamellarin T (48 mg, 0.088 mmol) was dissolved in a solution of acetic anhydride (1.0 mL) and pyridine (1.0 mL) containing DMAP (several crystals) and the solution stirred at 18° C. for 26 h. The solution was then diluted with ethyl acetate (15 mL) and washed with NaHCO3 (a saturated solution in H2O, 20 mL) and citric acid (10% in H2O, 20 mL) dried over (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (sequential elution with 2:1, 1:1 hexane/ethyl acetate) the relevant fractions (Rf 0.42 1:1 hexane/ethyl acetate) were concentrated giving the title compound (47 mg, 83%) as a white solid mp 251–2° C. IR (KBr disc, cm−1) 2937, 2840, 1769, 1718, 1603, 1545, 1507, 1475, 1456, 1414, 1295, 1266, 1201, 1141, 1117, 1036. 1H NMR (300 MHz, CDCl3) δ 7.31 (dd, J=2.1, 8.4 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 4.90 (m, 1H), 4.60 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H), 3.13 (m, 2H), 2.30 (s, 6H). 13C NMR+APT (75.5 MHz CDCl3) δ 168.7 (C), 168.4 (C), 155.0 (C), 151.9 (C), 147.5 (C), 144.8 (C), 142.2 (C), 140.6 (C), 138.7 (C), 135.6 (C), 129.5 (CH), 127.6 (C), 127.2 (C), 125.4 (CH), 122.6 (C), 119.8 (C), 116.1 (C), 114.8 (C), 114.4(C), 112.9 (CH), 111.7 (CH), 105.4 (CH), 105.0 (CH), 60.9 (CH3), 60.8 (CH3), 56.2 (CH3), 55.5 (CH3), 55.2 (CH3), 42.1 (CH2), 21.7 (CH2), 20.4 (CH3). MS (70 eV) m/z (%): 629 (53, M+•), 587 (100, M+•-CH2CO); HRMS calcd for C34H31NO11 629.1897. Found 629.1907.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>ClCCl>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CN(C)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OC(=S)N(C)C)ccc(C(C)=O)c1O
Yield: 41.4 %

Procedure:
Stir a mixture of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3 mmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 mL) at room temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol) and stir at room temperature overnight. Wash the mixture with 1M hydrochloric acid (25 mL), dry over magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamic acid O-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.2 g, 41%) as a light yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250° C. for an hour and purify by silica chromatography eluting with hexanes to 6:4 hexanes:ethyl acetate to give the title compound (1.08 g, 90%) as a white solid. LCMS (m/z) 280 M−1.
Reaction SMILES: C(N(CC)CC)C.C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.[CH3:24][CH:25]1[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1>ClCCl>[N+:21](=[C:28]1[C:29](=[O:31])[CH2:30][CH:25]([CH3:24])[CH2:26][C:27]1=[O:32])=[N-:22]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(=O)C(=[N+]=[N-])C(=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
12.25 ml (87.2 mmol; 2.2 eq.) of triethylamine and 8.57 g (35.67 mmol; 0.9 eq.) of 4-acetamidobenzenesulphonylazide are added to a solution of 5 g (39.6 mmol) of 5-methylcyclohexane-1,3-dione in 100 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature, then cooled down to 0° C. and filtered on a silica bed. After concentration under reduced pressure, the solution is washed with 3 times 50 ml of water. The organic phases are combined, dried over sodium sulphate and concentrated. The resulting solid is taken up in ethyl ether followed by filtering and drying under reduced pressure. It is used in the following stage without other purification.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)[N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:29]1([C:23]2[CH:22]=[C:21]([C:18]3[N:17]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([CH2:34][CH3:35])[CH:11]=4)[O:20][N:19]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
Pd/C (150 mg, 10% Pd) is added to a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2-cyclopentyl-6-methoxy-pyridine (1040 mg, 2.22 mmol) in THF (20 mL) and methanol (20 mL). The mixture is stirred under 1 bar of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated and dried to give 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (672 mg) as an off-white solid; LC-MS**: tR=0.97 min, [M+H]+=380.27.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:15][CH2:14][C:13](=[N:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]1[CH3:25])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:18]([O:17][N:16]=[CH:13][CH:12]1[CH2:25][CH2:14][CH2:15][N:11]1[C:9](=[O:10])[C@@H:8]([NH2:7])[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1C(=NOCc2ccccc2)CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CCCC1C=NOCc1ccccc1)C1CCCCC1

Procedure:
The solution of {(S)-2-[benzyloxylimino-methyl-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (1.76 g, 3.97 mmole) and TFA (10 ml) in dichloromethane (20 ml) is stirred for a hour. Solvent is removed under vacuum. The residue is carried to next step without further purification. M+H+=344.2
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH:10]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[CH2:26][CH2:25]2)=[O:23])[CH2:9]1)=O)(C)(C)C.[ClH:38]>C(O)C>[ClH:38].[CH3:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])=[O:23])[CH2:25][CH2:26]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(C(=O)OC(C)(C)C)CCN3c3ccc(F)cc3C)CC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CNCCN3c3ccc(F)cc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (133 mg) in ethanol (5 mL) was added a saturated solution of hydrogen chloride in ethanol (1 mL). The mixture was stirred at room temperature for 2 h, and was concentrated to give [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(4-fluoro-2-methyl-phenyl)-piperazin-2-yl]-methanone hydrochloride as crude white solid, MS: 411.5 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([Cl:9])[C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([Cl:9])[C:5]([CH3:8])=[N+:6]([O-:16])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncc(Br)c(C)c1Cl
Solvent: ClCCl
Product: Cc1c(Br)c[n+]([O-])c(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a solution of 5-bromo-3-chloro-2,4-dimethylpyridine (441 mg; 2.0001 mmol) in dichloromethane (10 mL; 156.0 mmol) was added 3-chloroperoxybenzoic acid (70%, 0.5547 g; 2.250 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with additional dichloromethane (100 mL), washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 374.1 mg (79%) of the title compound. LCMS (ESI): M+H=236.2; 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 2.47 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:20][OH:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH:20]=[O:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1cccs1)n1cc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution (20 mL) of [5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanol (480 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (80 mg), N-methylmorpholine N-oxide (407 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as colorless crystals (yield 272 mg, 57%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)[CH3:16])=[O:23])=[CH:20][CH:19]=1
Reactant: CN[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CO)cc2)CC1

Procedure:
from trans-4-(4-hydroxymethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 211°-213° C.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:8](=[O:10])[CH3:9])\[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(O)(=O)C.ClCCl>[Br:11][CH2:9][C:8](=[O:10])/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([OH:7])=[O:6]
Reactant: CO/N=C(/C(C)=O)C(=O)O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CO/N=C(\C(=O)O)C(=O)CBr

Procedure:
145 g of (Z)-2-methoxyimino-3-oxo-butyric acid are dissolved in 1000 ml of alcohol-free anhydrous dichloromethane. 10 ml of 30% hydrobromic acid in glacial acetic acid are added to this solution. Then, a solution of 37.5 ml of bromine in 112.5 ml of dichloromethane are added dropwise during about 2 hours, the temperature of the mixture being held at 20°-25° C. by means of slight cooling. Now, in order to remove hydrogen bromide from the mixture, nitrogen is vigorously blown through. Subsequently, 250 g of ice, 250 ml of water and 2 l of ether are successively added. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried with sodium sulphate and evaporated in vacuo. There remains a brown oil which is crystallized from carbon tetrachloride. There is obtained almost colourless (Z)-4-bromo-2-methoxyimino-3-oxo-butyric acid.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH3:10])[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[P:11](Cl)(Cl)(=[O:23])[O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][P:11](=[N:2][C@@H:3]([CH3:10])[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])=[O:23]
Reactant: O=P(Cl)(Cl)Oc1ccc2ccccc2c1
Reactant: Cl
Reactant: CC(C)OC(=O)[C@H](C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
(S)-isopropyl 2-aminopropanoate hydrochloride (Oakwood, 500 mg, 2.98 mmol) and naphthalen-2-yl phosphorodichloridate (724 mg, 2.98 mmol) was suspended in anhydrous DCM (25 mL). The reaction was cooled to −78° C. Triethylamine (604 mg, 830 μl, 5.97 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, then allowed to warmed up to room temperature and stirred for 5 h. The solvent was removed, and the residue was washed with dry ethyl ether and filtered. The filtrate was concentrated to give crude (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate as a light yellow oil (0.8 g, 75%) and used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:19][C:7]1[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][C:8]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:32])([F:31])[F:20])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2C(F)(F)F)cc1

Procedure:
Compound (102) was prepared from compound (20) and (2-trifluoromethyl-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.93 mins, m/z (ES−)=375 (M−H for C20H15F3O4).