Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][C@H:12]2[C:16](=[O:17])[O:15][CH2:14][N:13]2[C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([N:13]([CH3:14])[C@@H:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:16]([OH:17])=[O:15])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cccc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 4-(naphthalen-1-ylmethyl)-5-oxooxazolidine-3-carboxylate (0.750 g, 1.669 mmol) in DCM (8.0 ml) was added trifluoroacetic acid (8.0 mL, 104 mmol) followed by triethylsilane (0.799 ml, 5.01 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. Reaction mixture was dried on rotovap. The crude oil was dissolved in 15.0 mL of DCM and evaporated on rotovap twice. The crude product was obtained as an off-white gum and was purified by silica gel chromatography using dichloromethane and methanol as eluant. The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(naphthalen-1-yl)propanoic acid, was obtained as a colorless gum (0.692 g, 46%).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C([NH:39][C:40]1C=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[N:39]1[CH:40]=[CH:41][CH:42]=[C:43]([C:46]([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH2:9][CH2:10]2)=[O:51])[CH:44]=1
Reactant: O=C(NCCCCC1CCNCC1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CCN(C(=O)c2cccnc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting nicotinoyl chloride hydrochloride for acetyl chloride and N-[4-(piperidin-4-yl)butyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58-8.71 (m, 2H) 7.87 (d, J=7.5 Hz, 1H) 7.52 (dd, J=7.5, 4.8 Hz, 1H) 7.22-7.36 (m, 4H) 6.28 (br m, 1H) 4.56 (s, 4H) 4.44 (br m, 1H) 3.38-3.57 (br m, 1H) 2.95-3.15 (br m, 2H) 2.68-2.84 (br m, 1H) 0.95-1.84 (br series of m, 12H); MS (ESI(+)) m/e 407 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)c1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)C)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-isopropylpyridine (Preparation is described in Example 61).
Reaction SMILES: O1CCCC1.[CH:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH3:14][N:15]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[CH:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16](=[O:17])[N:15]([CH3:14])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=CN1CCNCC1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)C(=O)N1CCN(C=O)CC1
Yield: 49.7 %

Procedure:
Into 600 ml of tetrahydrofuran, were dissolved 41 g of 1-formylpiperazine and 54.5 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 56 g of 2,4,4-trimethylallophanyl chloride. The mixture was allowed to react at room temperature for 6 hours and the precipitate was removed by filtration. The filtrate was concentrated and the residue was recrystallized from tetrahydrofuran to obtain 41 g of 1-formyl-4-(2,4,4-trimethylallophanoyl)piperazine. This compound was mixed with 800 ml of 6N hydrochloric acid and the mixture was heated with stirring at 60° C. for one hour. The reaction mixture was concentrated and the residue was recrystallized from ethanol to obtain 35.2 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 215° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[C:29]([O:40][CH3:41])(=[O:39])[C:30]1[CH:38]=[CH:37][C:35]([OH:36])=[C:32]([O:33][CH3:34])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:34][O:33][C:32]1[CH:31]=[C:30]([CH:38]=[CH:37][C:35]=1[O:36][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1)[C:29]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2nc(C(F)(F)F)nc(-c3ccc(S(C)(=O)=O)cc3)c2-c2ccc(F)cc2)c(OC)c1
Reaction time: 4 h

Procedure:
4-Chloro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoro methyl)pyrimidine (0.5 g, 1.63 mmol), methyl vanillate (0.423 g, 2.33 mmol), potassium carbonate (0.24 g, 1.74 mmol) and acetonitrile (7 ml) were stirred at room temperature for 2 hours and subsequently the reaction mixture was refluxed for 6 hours. Further, potassium carbonate (0.08 g, 0.58 mmol) and vanillic ester (0.12 g, 0.66 mmol) were added to the reaction mixture and the refluxing was continued for another 4 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with ethyl acetate (25 mL) and washed with brine solution. Evaporation of the organic layer yielded the required product. 1H-NMR (DMSO-d6) δ: 3.24 (s, 3H), 3.81 (s, 3H), 3.88 (s, 3H), 7.26-7.30 (m, 2H), 7.44 (d, 1H), 7.49-7.53 (m, 2H), 7.61-7.69 (m, 4H), 7.91 (d, 2H); MS m/z: 576.8 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[CH2:8][CH2:7]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH:18][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: COc1cccc(N=C=O)c1
Reactant: NC1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Product: COc1cccc(NC(=O)NC2CCCCC2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)c1
Reaction time: 17 h
Yield: 44.9 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)piperazine (100 mg, 0.29 mmol) and 3-methoxyphenyl isocyanate (38 μl, 0.29 mmol) in methylene chloride (5 ml) was stirred at room temperature. After 17 h, the product was extracted into ethyl acetate, washed with a bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with methylene chloride/methanol (97:3) as the eluant gave 1-{2-[4-(3,4-dichlorobenzyl)piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea(64 mg) as an oil consisting of the trans diastereomer.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]([CH3:22])([CH3:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CO.[OH-].[Na+]>O1CCCC1>[CH3:21][C:4]([CH3:22])([CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1)C(=O)O
Temperature: 25 °C
Yield: 95.2 %

Procedure:
2,2-Dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg, 0.62 mmol) from above was dissolved in tetrahydrofuran (2 mL). Then methanol (4 mL) and sodium hydroxide solution (1N, 2 mL) were added. The mixture was stirred and refluxed for 8 hrs. Solvents were evaporated and the residue was dissolved in hot methanol. The solution was cooled to room temperature and hydrochloric acid (1N, 2 mL) was added. The resulting mixture was cooled in an ice bath and the solid was filtered and washed with water. The solid was dried in air to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid (181.5 mg). The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C15H21N3O4 (m/e) 307.34, obsd 308.1 (M+H).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:49][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH3:39])([CH3:10])([CH3:9])[CH3:11]
Reactant: NC1CCCCC1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NC2CCCCC2)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
7.6 mg of 2-hydroxypyridine (0.08 mmol) was added to a solution of 190 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (101b) (0.4 mmol) in cyclohexylamine (1.5 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 195 mg of the title compound (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.00 g (32.7 mmol) 6-methoxy-pyridine-2-carboxylic acid in 100 mL DCM was added 40.8 mL (81.6 mmol) 2 M oxalyl chloride solution in DCM and stirred at 40° C. for 2 h. The solvent was removed by distillation.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10][CH3:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][N:13]([CH3:17])[C:14]([N:7]1[C:8]([S:10][CH3:11])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:15]
Reactant: CSc1nnc(C(C)(C)C)[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CSc1nc(C(C)(C)C)nn1C(=O)N(C)C

Procedure:
A solution of 57.6 g (0.338 mol) of 3-tert.butyl-5-methylthio-4H-1,2,4-triazole and 38g (0.355 mol) of dimethylcarbamyl chloride in 300 ml of pyridine was maintained at reflux temperature for 16 hrs. After the pyridine was removed at reduced pressure on the rotary evaporator, water was added followed by chloroform. The organic layer was washed with successive portions of dilute hydrochloric acid, water and brine then dried over Na2SO4. The solvent was removed in vacuo to give 75 g, nD26 1.5165 of an oil. Spectral properties agree with the structure
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([O:11][CH2:12][CH3:13])[CH:4]=2)[C:17](=[O:16])[CH:18]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CCOc1cc(CNN)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
45.5 g of 4-chloro-3-ethoxybenzylhydrazine were added, under nitrogen, to a solution of 35 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 200 ml of ethanol. After stirring overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 143°, 15.2 g (26%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.C(OCC)(=O)C>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Under ice cooling, the solution of 5-bromosalicylic acid (21.7 g) in ether (200 ml) was slowly added dropwise to the suspension of LiAlH4 (5.7 g) in ether (200 ml). After stirring at room temperature for 30 minutes, the reaction solution was slowly poured into 3N HCl with floating ice for extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The oily residue generated after the evaporation of the solvent under reduced pressure was crystallized from ether-hexane, and the crystal was filtered, to give the title compound (15.5 g; 76.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14]/[C:15](=[CH:20]\[CH2:21][CH2:22]/[C:23](/[CH3:33])=[CH:24]/[CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)/[CH2:16][CH2:17][CH:18]=[O:19]>C1COCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]([OH:19])[CH2:17][CH2:16]/[C:15](/[CH3:14])=[CH:20]/[CH2:21][CH2:22]/[C:23](/[CH3:33])=[CH:24]/[CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of 10.7 g of 1,4-dibromobenzene in 80 ml of absolute THF is cooled to −78° C. and treated within 30 min. with 25.6 ml of 1.6M butyllithium in hexane. After 30 min. 6.08 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca4,8-dienal in 20 ml of THF are added dropwise. After 1 hr. at −78° C. the bath is removed until the suspension has dissolved and subsequently 7.2 ml of acetic acid in 10 ml of ether are added dropwise at −78° C. The solution is poured into saturated ammonium chloride solution/ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and evaporated. After silica gel chromatography with hexane/ethyl acetate 95:5 there are obtained 4.3 g of (4E,8E)-1-(4-bromo-phenyl)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dien-1-ol.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]([F:17])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:16])=[CH:8]2>[OH-].[Na+]>[Br:16][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[C:6]([F:17])[C:5]([CH2:4][C:3]([OH:18])=[O:2])=[C:14]([F:15])[CH:13]=2
Reactant: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A suspension of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (10.0 g, 31.6 mmol) in 48 mL of aqueous NaOH (2N) was heated to reflux for 2 hrs then cooled to r.t. The mixture was washed with dichloromethane (50 mL×2) and the aqueous phase acidified with 5N hydrochloric acid to pH 4. The white precipitate was collected via filtration, washed with water and dried. 9.6 g of the title compound was obtained as white powder in 100% yield. 1H NMR (DMSO-d6): δ 12.87 (s, 1H), 9.05 (s, 1H), 8.76 (s, 1H), 7.75˜7.79 (d, 1H), 3.87 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[C:5]([C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:6]#[N:7])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Cl:34])[C:25]=1[NH:35][NH2:36].Cl>C(O)C>[NH2:7][C:6]1[N:35]([C:25]2[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:31])([F:33])[F:32])=[CH:27][C:26]=2[Cl:34])[N:36]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(OCC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
An aliquot of the above solution of step A containing approximately two millimoles of 3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitrile was reacted with 0.49 g (2.0 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol under reflux overnight. The cooled mixture was poured into dilute hydrogen chloride (HCl) and the product was extracted into ethyl acetate (EtOAc), washed with water and brine, and dried over magnesium sulfate (MgSO4). Chromatography on silica gel with 4:1 hexane/EtOAc gave the title product, 320 mg (31%), m.p. 77-78° C. from pentane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N+:6]([O-:8])=[O:7])[CH3:2].C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:26][C@H:25]2[CH3:39])=[O:23])=[C:18]([CH2:42]Cl)[CH:17]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([N+:6]([O-:8])=[O:7])[CH2:42][C:18]1[CH:17]=[C:16]([Cl:15])[CH:41]=[CH:40][C:19]=1[O:20][CH2:21][C:22]([N:24]1[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:26][C@H:25]1[CH3:39])=[O:23])[CH3:2]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C)[N+](=O)[O-]
Temperature: 60 °C
Yield: 47 %

Procedure:
To nitro-acetic acid ethyl ester (0.32 g, 2.39 mmol), sodium bicarbonate (0.10 g, 1.19 mmol) and tetrabutyl ammonium iodide (0.088 g, 0.24 mmol) in dimethyl formamide (5 ml) was added 2-(4-chloro-2-chloromethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.52 g, 1.19 mmol). After 1 hour of heating at 60° C. the reaction was concentrated and then diluted with methylene chloride. After washing with aqueous saturated sodium bicarbonate and saturated sodium chloride the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.30 g).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[C:27]3[C:28]([CH3:35])=[C:29]([NH2:34])[C:30]([CH3:33])=[C:31]([CH3:32])[C:26]=3[O:25][CH2:24]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(N(CC)CC)C>C1COCC1.CN(C=O)C.O>[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[C:27]3[C:28]([CH3:35])=[C:29]([NH:34][C:3](=[O:4])[C:2](=[O:1])[CH2:6][CH3:7])[C:30]([CH3:33])=[C:31]([CH3:32])[C:26]=3[O:25][CH2:24]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCC(=O)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 2-oxobutanoic acid (259 mg, 2.54 mmol) in THF (5 mL) was added dropwise with ice-cooling oxalyl chloride (0.33 mL, 3.80 mmol) and added DMF (three drops), and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred at the same temperature for 1 hour, and then the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and the product was added dropwise with ice-cooling to a solution of 3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (500 mg, 1.69 mmol) obtained in Reference Example 30 and triethylamine (0.24 mL, 1.69 mmol) in THF (5 mL), and the resulting mixture was stirred for 30 minutes. After the reaction solution was warmed to room temperature, water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 363 mg (yield: 57%) of the title compound. Yield: 57%. Melting point: 97-98° C. (ethyl acetate-hexane).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=1[Cl:13].[OH-].[Na+].[ClH:16]>>[Cl:13][C:7]1[C:8]([CH3:12])=[N:9][CH:10]=[CH:11][C:6]=1[Cl:16]
Reactant: Cl
Reactant: Cc1nccc(N)c1Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
Sodium nitrite (36 g) was added in portions to a stirred solution of 4 -amino-3 -chloro-2 -picoline (24.85 g) in conc. hydrochloric acid (750 ml) cooled to 0°-5°. After 1 hour at 0°-5 ° and a further 2 hours at room temperature the mixture was basified (NaOH), allowing the temperature to rise to ca. 50°, and extracted with ether. After drying (K2CO3 ), the extract was evaporated to dryness to give 3,4 -dichloro-2 -picoline (26.5 g) as a low melting solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1.C(#N)C.Cl>ClCCl>[O:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1
Reactant: COC(CCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)OC
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: O=CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 500 mL round-bottomed flask with a magnetic stirrer was added biphenyl-2-ylcarbamic acid 1-(9,9-dimethoxynonyl)piperidin-4-yl ester (7.7 g, 15.9 mmol) and then acetonitrile (70 mL) and aqueous 1M hydrochloric acid (70 mL). The resulting mixture was stirred at room temperature for 1 h and then dichloromethane (200 mL) was added. This mixture was stirred for 15 min. and then the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (6.8 g), which was used in the next step without further purification.