Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26]O)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26][N:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CO
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CN1CC(C(=O)OC)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {3-ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.19 g, 0.50 mmol) that was obtained in Example 22 (22f), carbon tetrabromide (0.33 g, 0.99 mmol), triphenylphosphine (0.26 g, 0.99 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.75 mmol), N,N-diisopropylethylamine (0.22 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 4:6) as the eluent to afford the title compound (0.17 g) in a yield of 72% as a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(C)(=O)=O)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 82 mg, 0.26 mmol) and methanesulfonyl chloride (59.6 mg, 0.52 mmol) in THF (6.0 mL) was added N,N-diisopropylethylamine (227 μL, 1.3 mmol) at 0° C. under a nitrogen atmosphere. The resulting suspension was allowed to warm to room temperature during a period of 2 hours and then stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and brine solution, and the organic compound was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with brine solution and dried over anhydrous MgSO4, filtered, and concentrated to give a crude brown oil which was purified by flash chromatography (40 g ISCO column, eluting with 0-100% ethyl acetate/hexanes) to give [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (56 mg, 55%) as an off-white solid. MS cald. for C20H25FNO4S [(M+H)+] 394, obsd. 393.9.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:41][C:5]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCCc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Yield: 105.5 %

Procedure:
A solution of 2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.062 g, 0.106 mmol) in ethanol (8 mL) is treated with aqueous 5 N NaOH (1 mL) and heated to reflux 1 h. The reaction mixture is cooled, the solvent removed in vacuo. The resultant residue is acidified with aqueous 1 N HCl (20 mL) and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to afford 0.062 g (100%) 2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C31H34N2O4F3 (M+1) 555.2471. Found m/z 555.2459.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[N:38]=[N:39][N:40](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:41]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:41][N:40]=[N:39][N:38]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)[C@H](Cc2cccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)CCC1
Agent: Cl
Solvent: CO
Product: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)[C@H](Cc2cccc(-c3ccccc3-c3nnn[nH]3)c2)CCC1
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of (S)-2-(4,5-diphenyloxazol-2-yl)-1-{3-{2-[2-(triphenylmethyl)tetrazol-5-yl]phenyl}benzyl}-2-cyclohexene (0.8 g) in methanol (20 ml) was added conc. HCl solution (2 ml). After being stirred for 4 hours, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (S)-2-(4,5-diphenyloxazol-2-yl)-1-{3-[2-(tetrazol-5-yl)phenyl]benzyl}-2-cyclohexene (50 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=1)[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:15][CH:16]=2)=[O:31])(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(2-pyridinyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 510 [M+H]+, 508 [M−H]−, 1H-NMR (CDCl3) □1.17 (3H, t, J=7.3 Hz), 2.65 (2H, q, J=7.7 Hz), 2.80-2.88 (2H, m), 3.42-3.55 (2H, m), 6.78 (1H, br), 7.15-7.28 (4H, m),7.42 (2H, d, J=8.4 Hz), 7.58 (1H, s), 7.71 (1H, t, J=6.0 Hz), 7.80-7.89 (3H, m), 8.51 (1H, d, J=6.0 Hz).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=1)=[O:39].N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=2)=[O:39])=[O:21])=[CH:17][CH:16]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{2-{[(tert-butyl)amino}sulfonyl}phenyl}benzoic acid (167 mg, 0.5 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.09 ml, 1 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). The compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.17 g, 0.6 mmol) and pyridine (0.122 ml, 1.5 mmol) were added to the solution. The mixture was stirred at r.t. overnight. The solvent was evaporated to give (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide. MS found for C29H26Cl2N4O4S M+=597, (M+2)+=599.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1F
Yield: 86.2 %

Procedure:
N-(3-fluoro-4-nitrophenyl)morpholine (6.01 g, 26.59 mmol) and a catalytic amount of palladium on carbon (10%) were suspended in 100 mL methanol in a Parr flask. The reaction mixture was placed on the Parr Hydrogenator at 60 psi for 2 H. The reaction mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure to give 4.50 g of N-(3-fluoro-4-aminophenyl)morpholine an off-colored solid. 1HNMR (DMSO-d6) δ: 6.73 (t, 1H, J=9.34), 6.28 (m, 2H), 3.64 (bt, 4H, J=4.58 Hz), 2.76 (bt, 4H, J=4.58 Hz). ESI mass spectrum analysis m/z (relative intensity) 197 (M+H, 100). 19FNMR (DMSO-d6) δ: −124.455.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.C(Cl)Cl>[OH:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)C(C)C)ccc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.0 g of 4'-hydroxy-3'-methoxy-2-methylpropiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2N) in 40 ml of glacial-acetic acid are added dropwise thereto while stirring within 15 minutes. After 15 minutes the reaction mixture is poured into ice-water and the separated crystals are filtered under suction, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up in methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 85°-87°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C@H:19]([CH2:20][CH3:21])[C@@H:18]([CH3:22])[O:17][CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][O:17][C@H:18]([CH3:22])[C@H:19]1[CH2:20][CH3:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@@H]1[C@@H](C)OCC(=O)N1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@@H](C)OCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
LiAlH4 (217 mg, 37.95 mmol) was added to a solution of (5R,6R)-4-benzyl-5-ethyl-6-methylmorpholin-3-one (200 mg, 0.85 mmol) in THF (10 mL). The reaction mixture was heated at 70° C. for 3 hours and then cooled to 0° C. At 0° C. was added aqueous sodium sulfate (15 mL). The mixture was stirred at room temperature for 10 minutes, and the white solid was removed by filtration. The filtrate was extracted with EtOAc (3×15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 30% EtOAc/hexanes) afforded (2R,3R)-4-benzyl-3-ethyl-2-methylmorpholine. MS APCl calc'd for C14H21NO [M+H]+ 220. found 220.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Br-].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14](/[CH:15]=[CH:32]/[C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][N:24]=3)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4-methanesulfonylpiperazin-1-yl)-2-nitrobenzaldehyde (0.36 g, 1.1 mmol) obtained in Step 1 in methanol (5.0 mL), (1H-indazol-3-ylmethyl) triphenylphosphonium bromide (0.54 g, 1.1 mmol) and potassium carbonate (0.31 g, 2.3 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain (E)-3-{2-[4-(4-methanesulfonylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.48 g, 26%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH2:5].[F-].[Cs+].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])=[O:31])[CH:24]=[CH:25][C:26]=1[F:27]>CS(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:28]([CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)=[O:5])[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])=[O:31])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: C=C(O[Si](C)(C)C)c1ccc2ccccc2c1
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(naphthalen-2-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [Na].[C:2]([C:5]1[C:6]([CH3:29])=[C:7]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:15]([OH:28])[CH2:14]2)[C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])(=[O:4])[CH3:3].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CC(C)=O>[C:2]([C:5]1[C:6]([CH3:29])=[C:7]([CH:13]2[CH2:14][C:15](=[O:28])[C:16]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:17]([O:19][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:18]2)[C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])(=[O:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c(C(C)=O)c2C)CC1=O
Agent: [Na]
Solvent: CC(C)=O
Product: CCCC(=NOCC)C1=C(OS(=O)(=O)c2ccc(C)cc2)CC(c2c(C)cc(C)c(C(C)=O)c2C)CC1=O
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
The sodium salt of 5-(3-acetyl-2,4,6-trimethylphenyl)-2-[1-(ethoxyimino)butyl]-3-hydroxy-cyclohex-2-en-1-one (0.10 g; 0.26 mmole) was dissolved in acetone and then 4-toluenesulfonyl chloride (0.05 g; 0.26 mmole) was added. The mixture was stirred for 15 minutes and then the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product was purified by column chromatography over silica gel (eluant dichloromethane) to give 5-(3-acetyl-2,4,6-trimethylphenyl)-2-[1-(ethoxyimino)butyl]-3-(4-toluenesulfonyl)oxy-cyclohex-2-en-1-one (0.13 g; 95.6%) as a yellow oil.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:38][CH:37]=1>>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[CH:38][CH:37]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)COCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)COCCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 62.7 %

Procedure:
The compound (222 mg, 0.475 mmol) obtained in Example 26c and tert-butyl 4-aminobenzoate (92 mg, 0.475 mmol) were used according to the method described in Example 18b to give the title compound (192 mg; yield, 63%) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][NH:8][CH:9]=[O:10]>C(Cl)(Cl)Cl>[CH3:7][N:8]([CH:9]=[O:10])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1]
Reactant: CNC=O
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C=O)C(=O)C(Cl)Cl
Yield: 86 %

Procedure:
25 g of dichloroacetyl chloride (1.25 eq.) was added to a solution of 50 g N-methylformamide (NMF) in chloroform at ambient temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried with magnesium sulfate and the solvent was evaporated off in vacuum to give N-methyl-N-formyl-α,α-dichloroacetamide (86% yield) in high purity as a yellow oil. The chemical structure was confirmed by APCl-MS, FT-IR, 1H and 13C magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Cl

Procedure:
8.5 g 7-chloro-3-nitro-quinolin-4-ol (Example 15a) are heated for 7 h in 80 ml POCl3 under reflux. After standing over night, light yellow needles have formed, which are filtered off and washed with water. The POCl3-filtrate is poured into 1 l of ice-water; additional compound precipitates and is filtered off. The solid materials are dissolved in 300 ml CH2Cl2 and washed first with aqueous sodium hydroxide (300 ml water and 30 ml 2N NaOH), then again with pure water. The organic phase is dried over MgSO4 and evaporated. Colorless needles are formed which are filtered off, washed with hexane, and dried for 16 h at 60° C. (high vacuum). mp: 165-167° C.; MS: 244 (M++1); HPLC: tret=12.88 min (Grad 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=1)[CH:22]=O)([CH3:17])[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]2[CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=[C:19]([O:18][CH:15]([CH3:17])[CH3:16])[CH:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc(OC(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.0 equiv), 3,5-diisopropoxy-benzaldehyde (5.33 g, 24.0 mmol, 1.2 equiv; intermediate D7, vide infra) and acetic acid (4.6 mL, 4.80 g, 80.0 mmol, 4.0 equiv) in ethanol (16 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (2.51 g, 40.0 mmol, 2.0 equiv), dissolved in ethanol (8 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified on a Isolute flash NH2 chromatography column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.23 g (40%) of the title compound. MS (ISP): 407.4 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
As in Synthetic Example 1, to 84.7 g of L-arginine were added 706 g of isopropyl alcohol and 302 g of water. Thereto were concurrently added dropwise 147 g of palmitoyl chloride (manufactured by Aldrich) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being at 10.5 to 11.5 and the reaction temperature, at 27 to 30° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to below pH 1.8 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 1,200 g of water and 320 g of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 190 g of mono-Nα-palmitoyl-L-arginine as flake-shaped crystals (yield 94.7%).