Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12].S(=O)(=O)(O)[OH:26].C(O)(=O)C.OO>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCc1ccc2c(Cl)cccc2c1O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCC1=CC(=O)c2c(Cl)cccc2C1=O
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 5.4 parts of 5-chloro-2-dodecyl-1-naphthalenol, 18 parts of 96% sulfuric acid, 71.5 parts of glacial acetic acid, and 29 parts of water was stirred at 70° C. and 8.85 parts of cold 30% hydrogen peroxide was added dropwise over 8 hours. Stirring at 70° C. was continued for another 17 hours. The mixture was cooled and an orange solid taken up in methylene chloride, and the extract washed with water, dried and stripped. The resulting tan solid was purified by column chromatography from 1-chlorotutane on silica gel to give 2 parts of 5-chloro-2-dodecyl-1,4-naphthoquinone, m.p. 57.5°-58.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[N+:17](=[CH2:19])=[N-:18].CC(O)=O>C1COCC1>[N+:17](=[CH:19][C:14]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:15])=[N-:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [N-]=[N+]=CC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 3-nitro-napthalene-1-carbonyl chloride (8.4 g, 35.7 mmol) in anhydrous THF (70 mL) was added an ethereal solution of diazomethane (250 mL) dropwise at 0° C. The reaction mixture was stirred for 5 h, and then warmed to RT overnight. Excess diazomethane was decomposed by the dropwise addition of AcOH (50 mL). The mixture was extracted with Et2O (3×150 ml), washed with brine and saturated NaHCO3 aqueous solution, dried and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography to yield 2-diazo-1-(3-nitronaphthalen-1-yl)ethanone (7.0 g, 81% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.35 (s, 1H), 7.84 (t, J=7.2 Hz, 2H), 7.76 (t, J=7.8 Hz, 2H), 6.84 (s, 1H); MS (ESI) m/z: 242 (M+H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].[OH-:19].[Na+].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18]
Reactant: [OH-]
Reactant: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1ccc2ncc(O)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.50 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mL of tetrahydrofuran, 3 mL of a 20% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux while stirring for 1 hour. Thereto was added 3 mL of water, and the mixture was heated under reflux while stirring for 3 hours 30 minutes. Thereto was added 3 mL of a 20% aqueous sodium hydroxide solution, and the mixture was heated under reflux while stirring for 4 hours. Tetrahydrofuran was distilled off under reduced pressure, and the mixture was then heated under reflux while stirring for 1 hour 30 minutes. After cooling to room temperature, the reaction mixture was added with 2 mol/L hydrochloric acid and adjusted to pH 5. Thereto was added ethyl acetate, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.32 g of 1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=O)[CH:8]=O.[CH2:15]([NH2:18])[CH2:16][NH2:17].[BH4-].[Na+].O>C(O)C.O1CCOCC1>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH:7]1[CH2:8][NH:18][CH2:15][CH2:16][NH:17]1
Reactant: Cc1c(C(=O)C=O)sc2ccccc12
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(C2CNCCN2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5 g portion of the above aldehyde was dissolved in a mixture of 100 ml of ethanol and 10 ml of dioxane. To this mixture, in an ice bath was added a solution of 1.61 g of ethylenediamine in ethanol. The mixture was stirred for one hour at room temperature, recooled to 0°-5° C. and 2.04 g of sodium borohydride added. The mixture was stored at room temperature overnight, water was added and all the solvents were removed. The residue was extracted with dichloromethane, water washed, dried, filtered and evaporated. This residue was purified by flash column chromatography, eluting with chloroform:-methanol (9:1), giving 2.39 g of 2-(3-methylbenzo[b]-thien-2-yl)piperazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][CH2:3]1.CN1CCOCC1.[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26](Cl)=[O:27]>CCOCC>[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:27]
Reactant: CC1(C)CCc2c(N)cccc21
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2cccc3c2CCC3(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 15 ml of an ether solution of 1.5 g (8.57 mmols) of 1,1-dimethylindane-4-amine, 2 ml of N-methyl morpholine and 1.4 g (8.83 mmols) of 2,5-dimethyl-3-furan carboxylic acid chloride were added under cooling. The mixture was stirred at room temperature for 1 hour and then washed sequentially with water and brine. The solution was dried with magnesium sulfate. The resultant concentrate was purified with silica gel column chromatography (solvent for elution; ethyl acetate/n-hexane=1/4), thereby obtaining 2.1 g of light yellow crystals (Compound No. 20 shown in Table 6). The yield was 85.8%.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][O:12][CH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCN(CCO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CCOCc1ccc(C(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
2-(N-Ethylanilino)ethanol (3.03 g, 18.4 mmol, 1.2 eq) in THF (20 cm3) was treated with NaH (60% dispersion in oil, 524 mg, 13,1 mmol, 1.4 eq) and stirred at 20° C. for 1 hour. 4-Bromomethylbenzophenone (4.21 g, 15.3 mmol) was then added and stirring continued for 72 hours. Excess solvent was removed in vacuo and the residue diluted with DCM, washed with water and NaHCO3 solution (sat.), dried (MgSO4) and solvent removed under vacuum. The resulting oil was purified by flash chromatography, eluting with petroleum (bp 40-60° C.):EtOAc (9:1), to give the desired product as a yellow oil (4.36 g, 80%), Rf=0.54 (4:1, petrol:EtOAc) (Found: C, 78.34; H, 6.86; N, 5.29. C24H25NO2 requires C, 80.19; H, 7.01; N, 3.90%); νmax (film/cm−1 1658 (s), 1598 (s), 1506 (s); δH (200 MHz; CDCl3) 1.22 (3H, t, J 7, CH3), 3.49 (2H, q, J 7, CH2CH3), 3.58-3.79 (4H, m, OCH2CH2N), 4.66 (2H, s, ArCH2O), 6.69-6.79 (3H, m, ArH o- and p- to NR2), 7.28 (2H, dd, J 7, 7, ArH m- to NR2), 7.46-7.68 (5H, m, ArH), 7.80-7.88 (4H, m, ArH o- to C═O), δC (50.3 MHz; CDCl3) 12.2 (CH3), 45.5 (NCH2CH3), 50.1 (NCH2CH2O), 68.5 (NCH2CH2O), 72.2 (ArCH2O), 111.8 (ArCH o- to NR2), 115.8 (ArCH p- to NR2), 127.0, 128.3, 129.3, 130.0 and 130.3 (ArCH o- and m- to C═O and ArCH m- to NR2), 132.4 (ArCH p- to C═O), 136.8 and 137.7 (4° ArCC═O), 143.2 (4° ArCCH2O), 147.7 (4° ArCNR2), 196.4 (C═O); m/z (APCI+) 360 ([M+H]+, 30%); HRMS C24H26O2N requires 360.1963; found 360.1963.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CI
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CNc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A mixture of 2,4-dichloroaniline (20.2 g, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 90: 10-80:20) afforded 13.6 g (50%) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21](O)=[O:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.O[NH:44][C:45](=[NH:47])[CH3:46]>CC#N.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[C:20]([C:21]5[O:22][N:47]=[C:45]([CH3:46])[N:44]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: O=C1CC(c2cccc(C(=O)O)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid (Example 163) (262 mg, 0.7 mmol) and 1-hydroxybenzotriazole (130 mg, 0.84 mmol) in CH3CN/DMF (7 mL/10 mL), cooled to 0° C., was added EDC (161 mg, 0.84 mmol) and the mixture was stirred at 0° C. for 1 h. N-hydroxy-acetamidine (62 mg, 0.84 mmol) was added and stirring was continued for 4 h at 23° C. The reaction mixture was partitioned between ethyl acetate and H2O and the organic layer was dried over Na2SO4 and evaporated in vacuum. The residue was heated in toluene (30 mL) for 20 h at reflux. The mixture was cooled, evaporated in vacuum and the residue was chromatographed on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was triturated with ethyl acetate to give the title compound as light yellow solid (49 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH:35]([CH3:37])[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](\[C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)/[CH:35]([CH3:37])[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(C)C(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 2.27 mmol) was dissolved in DMF (10 mL). Copper (I) iodide (86 mg, 0.452 mmol), L-proline (0.075 g, 0.652 mmol) and potassium phosphate (0.963 g, 4.54 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromo-3-methylbut-1-en-2-yl)pyridine (0.65 g, 2.87 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 100° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.50 (d, 2H), 7.60 (d, 2H), 7.40 (s, 1H), 7.10 (d, 2H), 7.05 (s, 1H), 4.70 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.10 (m, 6H), 1.30 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([O-:5])=O.[Na+].[CH3:18][N:19]1[CH:23]=[C:22]([C:24]2[N:29]=[N:28][C:27]([NH:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=2)[CH:21]=[N:20]1.N1C=CN=C1.S(Cl)(Cl)=O>C(#N)C>[F:16][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([N:28]1[N:29]=[C:24]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:25]=[CH:26]/[C:27]/1=[N:30]\[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:5]
Reactant: O=C([O-])C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)cn1
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1cc(-c2cc/c(=N\NC(=O)OC(C)(C)C)n(C(=O)C(F)(F)c3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
900 mg (3.67 mmol) of sodium difluoro(quinolin-6-yl)acetate was dissolved in acetonitrile (27 mL). 1.17 g (4.04 mmol) of tert-butyl 2-[6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl]hydrazinecarboxylate was added and 300 mg (4.41 mmol) of 1H-imidazole was added at once. 0.561 mL (7.71 mmol) of thionyl chloride was added over 5 minutes at room temperature. The mixture was stirred for 2 hours at room temperature, giving tert-butyl (2E)-2-{2-[difluoro(quinolin-6-yl)acetyl]-6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-ylidene}hydrazinecarboxylate. Then, 0.722 mL (11.0 mmol) of methanesulphonic acid was added at room temperature and stirred for 16 h. The resulting solids were filtered off under argon atmosphere, yielding 6-{1,1-difluoro-2-[(6E)-6-hydrazono-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-1(6H)-yl]-2-oxoethyl}quinoline and used as such in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1c(C(=O)O)cc(O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Yield: 80 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-3-nitrobenzoic acid (3.50 g, 17.8 mmol) in methanol (40 mL) was added thionyl chloride (3.9 mL, 53 mmol) at 0° C. The reaction mixture was heated at reflux for 3 h. On completion, the solvent was removed under reduced pressure. Aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (3.0 g, 80%).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[CH2:26]([CH2:28][NH2:29])[OH:27].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH2:28][NH:29][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Reaction time: 68 h
Yield: 84.6 %

Procedure:
To a stirred solution of 6-(5-hydroxymethyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (0.11 g, 0.32 mmol) in toluene (0.5 mL) was added ethanolamine (0.03 g, 0.39 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.03 g, 0.17 mmol). The reaction mixture was stirred for 68 h, adsorbed on silica gel and purification by chromatography (silica, dichloromethane:methanol=100:0 to 90:10) afforded the title compound as a white solid (0.10 g, 85%). MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:13])[CH2:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=O.C([O-])(O)=O.[Na+].C(OCC)C>CO.O>[CH2:16]([O:15][CH2:14][C:10]1([CH3:13])[CH2:11][N:12]2[C:8](=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:24]2)[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(COCc2ccccc2)CN=C(Cc2ccccc2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC1(COCc2ccccc2)Cc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1
Reaction time: 48 h

Procedure:
5-Benzyl-3-(benzyloxymethyl)-3-methyl-3,4-dihydro-2H-pyrrole (108 g, 0.368 mol), 2-bromo-1-(4-chlorophenyl)-1-ethanone (100 g, 0.428 mol) and NaHCO3 (34.6 g, 0.42 mol) are dissolved in methanol abs. (950 ml) in a 2 l flask and, adjusted to a temperature of 40° C., stirred for a total of 2 d with exclusion of light. The supernatant methanol phase is poured off from the viscous, green-brown substance at the bottom of the solution formed during the reaction, and the material is taken up with diethyl ether (1 l) and water (800 ml) and partitioned. The water phase is extracted 2 times with ether (600 ml). The collected ether solution is dried over Na2SO4 sicc. and concentrated. Solvent residues are removed in a high vacuum. 124 g of a viscous, swelling residue remain, which consists of the compound sought and which can be employed for. further reactions without further purification. For characterization, the substance is purified by means of column chromatography (Al2O3/hexane-diethyl ether 4:1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH2:36])[CH2:32][N:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH:36][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:32][N:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Reactant: CN(C)C[C@@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=377.5 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 10-phenyldecanoic acid was coupled in step 3 with (S)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (S)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dilinoleyl methanol (4.0 g, 7.2 mmol) and anhydrous potassium carbonate (0.4 g) in 100 mL of CH2Cl2 was added pyridinium chlorochromate (PCC, 4.0 g, 19 mmol). The resulting suspension was stirred at room temperature for 2 hours. Ether (300 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of silica gel (150 mL). The silica gel pad was further washed with ether (3×75 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 5.1 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 200 mL) eluted with 0-4% ethyl acetate in hexanes. This afforded 3.0 g (79%) of dilinoleyl ketone (V).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:35]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and cyclohexanecarbonyl chloride in the same manner as in Example 32.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=CCNC2)cc1
Yield: 18 %

Procedure:
To a suspension of 0.43 mmol rac-3-(4-Trifluoromethyl-phenyl)-pyrrolidin-3-ol in 0.4 ml dichloromethane under argon, was added 0.4 ml TFA. The reaction mixture was stirred at reflux for 5 days and concentrated. The residue was dissolved in ethyl acetate and NaOH 2N was added until pH 9-10. The organic phases were dried over Na2SO4 and evaporated to yield the title compound (18%) as an oil MS (m/e): 214.2 ([M+1], 100%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=C.[O:17]=[O+][O-].CSC>CO>[CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=[O:17]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)ncn1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C=O)ncn1
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 6-vinylpyrimidin-4-ylcarbamate (4.4 g, 0.020 mol) in MeOH (200 mL) at −78° C. was bubbled O3 for 1 hour. N2 was bubbled through the mixture for 10 minutes and then dimethylsulfide (1.24 g, 0.020 mol) was added dropwise. After addition, the solvent was removed under reduced pressure to give the crude desired product (4.6 g, over 100% yield) which was used in the next step without purification. LCMS (ESI) m/z: 224.1 [M+H+].