Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH:8]=[CH:9]Cl)=[CH:4][CH:3]=1.[CH2:11]([OH:14])[C:12]#[CH:13].N1C=CC=CC=1.[O:21]1CCCC1>>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([O:14][CH2:11][C:12]#[CH:13])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC=CCl)o1
Reactant: C#CCO
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: C#CCOC(=O)C=Cc1ccc(C)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 11.5 g of 3-(5-methylfuran-2-yl)-propenyl chloride in 30 ml of absolute tetrahydrofuran was cooled to 0° to 5° C., and 4.2 g of propargyl alcohol and 20 ml of pyridine were added. The mixture was stirred for 12 hours at room temperature, the precipitated hydrochloride was filtered off and concentrated under reduced pressure, and the concentrate taken up in 200 ml of ethyl acetate and 50 ml of water. After washing three times with water, drying over Na2SO4 and removal of the solvent under reduced pressure, the residue was purified chromatographically (toluene/ethyl acetate=1/2). There was obtained 10.9 g of propargyl 3-(5-methylfuran-2-yl)-propenoate; refractive index nD26 =1.578.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH3:14])[CH:9]=[N:8]1.[ClH:16].Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH2:32]=O>C(O)C>[ClH:16].[CH3:12][C:11]1[N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[N:8]=[CH:9][C:10]=1[C:13](=[O:15])[CH2:14][CH2:32][N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(N2CCN(CCC(=O)c3cnn(-c4ncccn4)c3C)CC2)cc1
Yield: 50.7 %

Procedure:
1.0 g of 1-(2-pyrimidinyl)-4-acetyl-5-methyl-pyrazole was dissolved in 50 ml of ethanol. After adding 1.3 g of 1-(4-methoxyphenyl)piperazine dihydrochloride and 0.8 g of paraformaldehyde, the mixture was heated under reflux for 24 hours. Further, 0.8 g of paraformaldehyde was added and the resulting mixture was heated under reflux for additional 48 hours. Then the reaction mixture was concentrated and neutralized by adding a saturated aqueous solution of sodium hydrogencarbonate. After extracting with chloroform, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=50:1), converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and then recrystallized from ethanol. Thus 1.1 g of the title compound was obtained in the form of a pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[NH:21][C:22]2[C:31]3[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:9][CH:8]=1)C.CCO>[OH-].[Na+]>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][CH:9]=2)=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Sc2ccc(OCC(=O)O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
The product from Example 64 (0.246 g 0.535 mmol) was dissolved in 10 mL of 5% NaOH and 10 mL of EtOH and heated to 100° C. for 2 hrs and then stirred at room temperature for 110 hrs. At this time all the solvent was removed under vacuum and the brown oil was redissolved in water, to which 2 mL of HCl was added and a yellow precipitate formed. Precipitate collected by filtration and solid dried in under vacuum overnight (150 mg, 64%) 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3H), 2.75 (s, 3H), 5.42 (s, 2H), 6.46 (d, J=7.35 Hz, 1H), 6.52 (s, 1H), 6.75 (d, J=8.46 Hz, 2H), 6.99 (d, J=8.46 Hz, 1H), 7.15-7.40 (m, J=8.46 Hz, 4H), 7.85 (s, 1H), 8.62 (s, 1H), 9.08 (d, J=8.09 Hz, 1H), 9.90 (s, 1H); MS (ESI) m/z 432 (M+H)+, (ESI−) m/z 430 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[C:9]2[CH3:24])=[CH:4][CH:3]=1.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([C:21]([NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[C:9]2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCN
Reactant: COc1ccc(-c2cc(C(=O)O)c(C)n2CCc2ccc(Br)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)n(CCc2ccc(Br)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (2.00 g, 4.83 mmol) in DMF (10 ml) were added n-decylamine (838 mg, 5.33 mmol), diethyl cyanophosphate (946 mg, 5.80 mmol) and triethylamine (0.673 ml, 4.83 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction solution were added n-decylamine (838 mg, 5.33 mmol), diethyl cyanophosphate (946 mg, 5.80 mmol) and triethylamine (0.673 ml, 4.83 mmol) and the mixture was stirred room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate anhydride, and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the object compound as a solid. 2.16 g (80.9%)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5](Br)=[CH:4][C:3]=1[F:10].C([Sn](CCCC)(CCCC)C([O:18][CH2:19][CH3:20])=C)CCC.C1C[O:32][CH2:31][CH2:30]1>>[C:31]([C:5]1[C:6]([F:8])=[CH:7][C:2]([C:19](=[O:18])[CH3:20])=[C:3]([F:10])[CH:4]=1)(=[O:32])[CH3:30]
Reactant: C1CCOC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc(Br)c(F)cc1Br
Product: CC(=O)c1cc(F)c(C(C)=O)cc1F
Yield: 100 %

Procedure:
1,4-dibromo-2,5-Difluorobenzene (2.5 g, 9.2 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.645 g, 0.92 mmol), tributyl-(1-ethoxyvinyl)tin (10 g, 27.7 mmol), and THF (50 mL) were combined in a manner analogous to the procedure described in example 14 to provide the intermediate title compound, 1-(4-acetyl-2,5-difluorophenyl)ethan-1-one, (1.8 g, 100%) as a white crystal. Electron spray M.S. 197.9 (M*−H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (3.83 g, 18.1 mmol) in 1,2-dimethoxyethane (30 ml) was added sodium hydride (60% in oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (9.30 g, purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene-toluene:ethyl acetate=5:1) to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (6.67 g, 88%) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][C:33]3=[O:37])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CN1CCNC(=O)C1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCN(C)CC5=O)ccc43)cc2OC)cn1

Procedure:
1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (Step 5, Example 6) and 4-methylpiperazin-2-one using the procedure outlined for Example 3-14: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.70-7.68 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.90-6.89 (m, 1H), 6.78-6.74 (m, 3H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J=5.5 Hz, 2H), 3.35 (s, 2H), 2.86 (t, J=5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1)=488.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:15]2[CH2:18][C:17](=O)[CH2:16]2)=[CH:10][CH:9]=1.[CH3:27][S:28]([CH2:31][C:32]1[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1)(=[O:30])=[O:29].CS(Cl)(=O)=O>O1CCCC1.C(OCC)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[N:15]2[CH2:18][C:17](=[C:31]([S:28]([CH3:27])(=[O:29])=[O:30])[C:32]3[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=3)[CH2:16]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)s1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
2.47 g of potassium tert-butoxide are added to a suspension of 6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.15 g of methyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate in 200 cm3 of tetrahydrofuran, under an argon atomosphere, cooled to −70° C. The mixture is stirred for 1 hour 30 min at a temperature close to −70° C., and then 1.7 cm3 of methanesulfonyl chloride in solution in 8 cm3 of ethyl ether is added. After stirring for 1 hour at a temperature close to −70° C., the mixture is allowed to return to room temperature and then 80 cm3 of distilled water are added. The mixture is concentrated in a rotary evaporator to one third of its initial volume, and is then extracted with 500 cm3 of dichloromethane. The organic phase is washed with three times 80 cm3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.02-0.04 mm, diameter 7.5 cm, height 35 cm), eluting at a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 40 cm3 fractions. Fractions 19 to 29 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine are obtained in the form of a cream-colored foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 2.91 (s, 3H), 3.88 (s, 3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53 (s, 1H), from 7.25 to 7.45 (mt, 9H), 7.71 (d, J=3.5 Hz, 1H)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:40]1([CH2:46][NH2:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:46][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC2CCCCC2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and cyclohexanemethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15](=O)[NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:32]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:32][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.4 mmol) and ammonia acetate (3.7 g, 20 eq.) in Xylene (2 mL) was heated in microwave at 110° C. for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, containing 15% starting material, yield 35%). LCMS-ESI−: calc'd for C19H21BrN4O2: 417.30. Found: 418.9 (M+H+).
Reaction SMILES: Cl[C:2]([O-:4])=[O:3].[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[CH2:6].[CH:14](N(C(C)C)CC)([CH3:16])[CH3:15].[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O)=[CH2:24].Cl[C:33]([O-])=O.C1CCCCC1.ClCCl>C1COCC1>[C:2](=[O:3])([O:4][C:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH2:24])=[CH:26][CH:27]=1)[O:13][C:8]1[C:9]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=[CH:12][C:7]=1[CH:5]([CH3:33])[CH3:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C([O-])Cl
Reactant: C=Cc1ccccc1O
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(=O)Oc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
The reaction is based on that described by Whitcombe et al (J Am Chem Soc 117, 7105–7111 (1995)); the molar ratios were choroformate:vinylphenol: diisopropylethylamine 1:1.2. The vinylphenol was dissolved in dry THF and the base added; the flask was kept in an ice bath an the chlorformate added dropwise; the flask was allowed to get to room temperature and the reaction was monitored (TLC 60–40 cyclohexane-dichloromethane)), the solvent was removed and the raw mixture was dissolved in CH2Cl2. After extraction with water the organic layer was taken down to dryness and the monomer was separated by purification on a silica column using a stepwise gradient of CH2Cl2-hexane (from 5% CH2Cl2 to 80%). The analysis showed purity >98%. The overall reaction scheme for preparation of them monomer is illustrated in Reaction Scheme I.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O.O>[CH2:40]([O:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=CCCCCC(CO)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Reaction time: 18 h

Procedure:
To a suspension of 7.4 g of 60% sodium hydride in 100 ml of dimethylformamide was added a solution of 8-hydroxy-7-methoxy-1-octene in 150 ml of dimethylformamide over 1.5 hours. A 63.4 g portion of the tosylate of 1-hexadecanol was added and the mixture was stirred for 18 hours, poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 41.5 g of the title compound as a oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[O:6].[C:16](OC)(OC)(OC)[CH3:17].C(OC(=O)C)(=O)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:5](=[O:6])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[C:16]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:17]
Reactant: COC(C)(OC)OC
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)c1ccc(C)c(C)c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C(=O)c1ccc(C)c(C)c1)=C(C)Nc1ccccc1

Procedure:
10.6 g (51.4 mmol) of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester was heated with 12.4 g (103 mmol) of trimethyl orthoacetate and 5.51 g (54.0 mmol) of acetic anhydride at 115° C. for 3 days. The mixture was evaporated and combined with 4.69 mL (51.4 mmol) of aniline. Yield: 8.60 g of a yellow solid (after flash chromatography contains inseparable 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester): LC-MSD, m/z for C20H21NO3 [M+H]+=324.2; HPLC retention time: 2.1 min.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]([OH:33])=O.Cl.CNOC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:10][N:9]([O:8][CH3:4])[C:31]([C:27]1[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=1)=[O:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1ccnc1C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 212.1 %

Procedure:
HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (1.75 g; 4.60 mmol) was added in on portion to a stirring solution of 1-methyl-1H-imidazole-2-carboxylic acid (509 mg; 4.04 mmol), N,O-dimethylhydroxylamine hydrochloride (391 mg; 4.01 mmol), and diisopropylethylamine (2.0 mL; 11.9 mmol) in anhydrous DMF (14 mL). The mixture was stirred at room temperature for 17 hours and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo, giving a colourless oil (1.45 g). This was purified by column chromatography, giving the title compound as a colourless oil (494 mg; 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:14])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Oc1ccc2cc(Br)ccc2c1F
Temperature: 60 °C
Yield: 83 %

Procedure:
To a solution of 6-bromonaphthalen-2-ol (2.23 g, 10.0 mmol) in CH3CN (50 mL) was added Selectfluor (4.20 g, 12.0 mmol). The reaction mixture was heated at 60° C. overnight and concentrated. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 6-bromo-1-fluoronaphthalen-2-ol using ethyl acetate and hexanes as solvents (2.0 g, 83% yield).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:30][CH2:29]2)[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)=[CH:6][CH:5]=1.[OH-].[K+]>CO>[OH2:2].[F:27][C:24]([F:25])([F:26])[C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1)[CH2:13][O:12][CH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=1)[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][CH2:33]1.[F:27][C:24]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1)[CH2:13][O:12][CH2:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=1)[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)([F:26])[F:25]
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C(=O)OC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O
Product: O=C(O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C(=O)O)cc2)CC1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
In a round-bottomed flask were introduced 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-methoxycarbonylmethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester (compound 316 prepared at example 2; 2 g, 3.56 mmoles), KOH (0.4 g, 7.12 mmoles) and MeOH. The reaction mixture was heated at 60° C. for 6 hours. MeOH was removed under reduce pressure and the residue was taken up by water. The pH was adjusted to 3-4 and the solution was extracted with AcOEt. The organic combined layers were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/H2O: 90/10/1 v/v/v) to give 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carboxymethyl-piperazin-1-yl)-ethyl]-benzoic acid hemihydrate (compound 319; 0.88 g, 45%).
Reaction SMILES: [BrH:1].N([O-])=O.[Na+].[CH3:6][O:7][C:8]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]([O:24][CH3:25])=[C:18]([CH3:26])[C:9]=1[O:10][C:11]1[CH:17]=[CH:16][C:14](N)=[CH:13][CH:12]=1.[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])[CH:28]=[CH2:29]>O.CC(C)=O>[Br:1][CH:28]([CH2:29][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]2[C:8]([O:7][CH3:6])=[C:21]([CH3:22])[C:20]([CH3:23])=[C:19]([O:24][CH3:25])[C:18]=2[CH3:26])=[CH:12][CH:13]=1)[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30]
Reactant: COc1c(C)c(C)c(OC)c(Oc2ccc(N)cc2)c1C
Reactant: Br
Reactant: C=CC(=O)OCCCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCOC(=O)C(Br)Cc1ccc(Oc2c(C)c(OC)c(C)c(C)c2OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.7 g of a 47% w/v aqueous solution of hydrobromic acid and a solution of 1.3 g of sodium nitrite in 3 ml of water were added dropwise, in that order, to a solution of 4.3 g of 4-(2,5-dimethoxy-3,4,6-trimethylphenoxy)aniline [prepared as described in step (c) above] in 10 ml of acetone, after which 21 ml of butyl acrylate were added to the mixture. After that, 0.3 g of cupric bromide was gradually added and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure from the extract, and the residue thus obtained was purified by column chromatography through silica gel, using a 3:7 by volume mixture of hexane and benzene as the eluent, to give 5.7 g of the title compound.