Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:7][C:6]=1[NH2:18])=[O:4].[OH-].[Na+].O>CO>[NH2:18][C:6]1[S:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(C(=O)O)c(N)s2)cc1
Yield: 90.5 %

Procedure:
To a stirred solution of 2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester (6.6 g, 26.6 mmol) in MeOH (200 mL) was added 6N NaOH (100 mL) and water (50 mL). The reaction was heated to reflux for 2 h or until starting material was gone by TLC or LCMS. The solution was concentrated under vacuum to about half of the original volume. The pH of the resultant cloudy mixture was adjusted to 3-5 by the careful addition of 6N HCl (˜150 mL) while stirring. The gummy red precipitate was filtered and dried. Purification was achieved by triturating in boiling hexanes. The product (6.0 g, 91%) was isolated in pure form by filtration after cooling to room temperature and drying in a vacuum oven overnight. 1H NMR (d6-DMSO δ 7.37, d, 2H, δ 7.11, s, 1H; δ 7.10, br s, 2H; δ 6.94, d, 2H), LC/MS (APCI, ES, M+H=250).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1F

Procedure:
2-Fluorophenol and 2,5-dibromo-1-nitrobenzene were reacted together under Ullmann conditions to give 1-bromo-4-(2-fluorophenoxy)-3-nitrobenzene which was reduced and deaminated to give the desired product b.p. 112°-116°C./0.8mm.
Reaction SMILES: N1C=CN=N1.[N-]=[N+]=[N-].ClC1N=[C:17]2[C:13](NC=N2)=[C:12](Cl)N=1.C(N)C1C=CC=CC=1.[Cl:28][C:29]1[N:37]=[C:36]2[C:32]([NH:33][CH:34]=[N:35]2)=[C:31]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:30]=1.C(Br)C#C>CS(C)=O>[Cl:28][C:29]1[N:37]=[C:36]2[C:32]([N:33]=[CH:34][N:35]2[CH2:17][C:13]#[CH:12])=[C:31]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:30]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Agent: C#CCBr
Agent: [N-]=[N+]=[N-]
Agent: c1c[nH]nn1
Solvent: CS(C)=O
Solvent: NCc1ccccc1
Product: C#CCn1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reaction time: 0.25 h

Procedure:
In one example of the application, a triazole and its fluorinated derivatives can be prepared by a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of the corresponding alkyne and azide substrates. As shown below in Scheme 1, synthesis can begin with the reaction of 2,6-dichloropurine (Compound 3) with benzylamine (a) as described, for example, by Oumata, N. et al., Org. Process Res. Dev. 13:641-644 (2009). Using the conditions set forth in the Example below, the reaction can be completed in about 15 minutes at about 60° C. 2-chloro-6-benzylaminopurine (Compound 4) can be propargylated using propargyl bromide in DMSO under mild conditions to yield 2-chloro-6-benzylamino-9-(2-propynyl) purine (Compound 5). The Cu(I)-catalyzed azide-alyne click reaction (as described, for example, by Amblard, F. et al., Chem. Rev. 109:4207-4220, 2009) of 2-chloro-6-benzylamino-9-(2-propynyl) purine (Compound 5) with fluorinated benzyl azides (which can be prepared in situ from their corresponding benzyl bromides) can then yield 1,4-disubstituted triazoles or, more specifically, 2-chloro-6-benzylamino-9-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 7), 2-chloro-6-benzylamino-9-[1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 8), and 2-chloro-6-benzylamino-9-[1-(pentafluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 9).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccc1I

Procedure:
4-[5-(4-Iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide and 1-Boc-piperazine following a procedure similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C22H27N4O3I [M+H]+: 523.1201. Found: 523.1202.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[I:12][C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[I:12][C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cc(I)nc2C)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (7.9 g), 4-iodo-2-methylimidazole (9.0 g) and sodium carbonate (4.5 g) was heated with stirring in dimethylformamide (50 cm3) at 120° for 16 hours under nitrogen. The mixture was poured into water (50 cm3) and extracted with chloroform (3×100 cm3). The combined and dried (MgSO4) organic extracts were concentrated in vacuo to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:toluene, 1:5 by volume. Combination and evaporation of appropriate fractions afforded a solid which was recrystallised from dichloromethane-hexane to give the title compound, m.p. 146°-8°, (4.0 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12](O)[CH3:13])=[N:10][CH:11]=2)=[CH:2]1.P(Br)(Br)[Br:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-]>[Br:16][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:11][N:10]=1)[CH3:13]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(-c2ccoc2)cn1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Br)c1ccc(-c2ccoc2)cn1
Temperature: 2.5 °C
Yield: 73.8 %

Procedure:
To a solution of 1-(5-(furan-3-yl)pyridin-2-yl)ethanol (0.075 g, 0.403 mmol) in chloroform (5 ml) was added PBr3 (0.321 g, 1.209 mmol), at 0-5° C., the reaction maintained at the same temperature for 15 min, the reaction was slowly warmed to rt and was maintained at rt for another 2 h. The contents were diluted with ethyl acetate (100 mL), bicarbonate solution (10 mL) was added, the organic layer was separated, the organic layer dried over sodium sulphate and distilled to provide 2-(1-bromoethyl)-5-(furan-3-yl)pyridine (0.075 g, 75% yield). LC-MS m/z calcd for [M+H]+ 253.99. found 254.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:26].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[C:3]([CH:22]=[O:26])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1Cl
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-chloro-5-(4-methoxybenzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (3.60 mL)-acetonitrile (3.60 mL)-water (3.60 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.31 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:22])[CH:27]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)no1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 99.1%, 455.2 (M+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[N:11]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:12]([CH3:36])=[C:13]([C:31]([O:33]CC)=[O:32])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16]([O:18]CC)=[O:17]>CC(C)=O.C1(C)C=CC=CC=1>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:36][C:12]1[N:11]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[C:10]([CH3:9])=[C:15]([C:16]([OH:18])=[O:17])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[C:13]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1=C(C)N(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)C(C(=O)O)=C(C)N1CCN1CCOCC1
Yield: 106.9 %

Procedure:
A solution of 1.2 g (0.010 mol) of maleic acid in 6 ml of acetone was poured into a solution of 5.1 g (0.010 mole) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate in 30 ml of toluene. The precipitated solid was collected, washed with toluene, and dried to yield 6.1 g (97%) of 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate maleate. This material was partitioned between 30 ml of toluene and 25 ml of 10% aqueous NaOH and the separated toluene phase was diluted with 60 ml of heptane. Chilling overnight yielded 3.4 g (67%) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl[4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate. Recrystallization from 10 ml of 2-propanol yielded 2.9 g of the title compound which contained, as determined by HPLC, 0.19% of ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C@@H:11](O)[CH3:12])=[C:5]([CH3:14])[CH:4]=1.[C:15](OCC)([O:20]CC)([O:17][CH2:18][CH3:19])[CH3:16]>C(O)(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9](/[CH:10]=[CH:11]/[CH3:12])[CH2:16][C:15]([O:17][CH2:18][CH3:19])=[O:20])=[C:5]([CH3:14])[CH:4]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(/C=C/[C@H](C)O)c(C)c1
Solvent: CCC(=O)O
Product: C/C=C/[C@H](CC(=O)OCC)c1ccc(OC)cc1C
Temperature: 155 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a stirred solution of (S,E)-4-(4-methoxy-2-methylphenyl)but-3-en-2-ol 28.5 (2.00 g, 10 mmol) (99% ee) in triethyl orthoacetate (20 mL, 109 mmol) at 23° C. was added propanoic acid (0.01 mL, 0.1 mmol). The reaction mixture was heated to 155° C., and stirred for 24 hours. The reaction was cooled to room temperature and concentrated in vacuo. The resulting product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound (S,E)-ethyl 3-(4-methoxy-2-methylphenyl)hex-4-enoate 28.6 (1.22 g, 45% yield) as a clear oil. MS ESI (pos.) m/e: 280.1 (M+H2O), 263.1 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][C:12]=1[CH:27]=O>C1COCC1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][C:11]3[O:3][C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:27][C:12]=3[CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CO
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(o1)CCN(S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
To a solution of ethyl glycolate (1 eq) in THF was added sodium hydride (2.5 eq) at 0° C. and the reaction mixture was stirred for 1 h 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde (1 eq) obtained in step II of example 200 in THF was added at 0° C. and was refluxed for 2 h. Reaction was quenched with water and extracted with ethyl acetate, organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the ethyl 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: C[C@H](O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 80.9 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.107 g, 0.40 mmol) was reacted with (S)-1-(4-aminophenyl)propan-2-ol (0.066 g, 0.44 mmol) to afford the title compound (0.123 g, 80%) as a light yellow solid. MW=379.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.29-8.16 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 4.54 (d, J=5.0 Hz, 1H), 3.87-3.80 (m, 1H), 2.93-2.84 (m, 4H), 2.72-2.66 (m, 1H), 2.58-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H), 1.06 (d, J=6.0 Hz, 3H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](Cl)=[O:13])[CH2:4][CH2:3]1.[Mg].[CH2:17](Br)[CH3:18]>CCOCC.[Cu]I>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:13])[CH2:17][CH3:18])[CH2:4][CH2:3]1
Reactant: CCBr
Reactant: CC1(C)CCC(C(=O)Cl)c2ccccc21
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Reaction time: 5 h
Yield: 64 %

Procedure:
223 g (1 mol) of 1,1-dimethyl-tetralin-4-carboxylic acid chloride and 11 g of copper (I) iodide are placed in a 1-liter flask provided with a thermometer, stirrer, dropping funnel and reflux condenser and there is allowed to drop in from the dropping funnel at -10° C. to -5° C. a Grignard solution freshly prepared from 27 g (1.1 mol) of magnesium shavings and 122 (1.12 mol) of ethyl bromide in 500 ml of absolute ether. In so doing, the mixture must be diluted with a small amount of ether. The mixture is stirred for a further 5 hours while cooling and then the cooling source is removed. After the mixture has reached room temperature, it is poured into cold, saturated ammonium chloride solution, extracted with ether, washed neutral with water, dried over sodium sulphate and evaporated. Fractional distillation gives 138 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 64%. Ventilation can further improve the olfactory quality. Odour: see (3).
Reaction SMILES: N1C=CC=CC=1.F.[C:8]([O:13][C:14]1[CH2:28][C@@H:27]([O:29][Si](C(C)(C)C)(C)C)[C@H:26](/[CH:37]=[CH:38]/[CH:39]([OH:48])[C:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]>>[C:8]([O:13][C:14]1[CH2:28][C@@H:27]([OH:29])[C@H:26](/[CH:37]=[CH:38]/[CH:39]([OH:48])[C:40]([CH3:46])([CH3:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(C)(C)C(O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCCC(C)(C)C(O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)CCC)C[C@H]1O

Procedure:
Using as the materials a hydrogen fluoride-pyridine solution (0.25 ml) and methyl(11R,12S,13E)-9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16,16,20-trimethyl-7-thiaprosta-8,13-dienoate (100 mg), the same procedure as in Example 2 was performed to separately obtain two stereoisomers of methyl(11R,12S,13E)-9-butyryloxy-11,15-dihydroxy-16,16,20-trimethyl-7-thiaprosta-8,13-dienoate different at the 15-position. (Low polarity compound: 26 mg, 33%; high polarity compound: 28 mg, 35%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with 1-bromodecane gave 3,4-bis(decyloxy)nitrobenzene (mp 60°-61°, Anal. Calcd for C26H45NO4 : C, 71.68; H, 10.41; N, 3.22. Found: C, 71.63; H, 10.55; N, 3.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].N12CCN(CC1)CC2>CC#N>[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[S:11])=[CH:3][C:2]=1[F:1])(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (60 mg, 0.19 mmol, Compound A of Example 3), 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (50 mg, 0.19 mmol, Compound D of Example 1) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 21.3 mg, 0.19 mmol) was added MeCN (5 mL). The reaction was stirred at RT for 1 h and concentrated in vacuo. The residue was purified by flash chromatography (eluted with 1–15% MeOH/CH2Cl2) to give the title compound (91 mg, 86%) as a white solid. 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.54 (s, 1H), 7.87 (m, 3H), 7.29 (m, 4H), 7.12 (m, 2H), 3.71 (s, 2H), 2.43 (s, 3H), 1.39 (s, 9H); MS(ESI+) m/z 554 (M+H) +.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([NH2:14])[N:11]2[N:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:10]2[N:9]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:5]2[CH2:6][CH:1]3[CH2:7][CH:4]2[CH2:3][N:2]3[C:8]2[N:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:10]3[N:9]=2)=[CH:26][CH:25]=1
Reactant: Nc1nc(N2CC3CC2CN3)nc2nc(-c3ccco3)nn12
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(N2CC3CC2CN3Cc2ccc(F)cc2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.25 mmol; see Example 13(a) above) was dissolved in 4 mL of CH2Cl2 along with 1.2 eq of 4-fluorobenzaldehyde and 2 eq of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 8.20 (brs, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 7.2-7.4 (m, 4H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 6.30 (s, 1H), 4.80 (brs, 2H), 4.20-4.30 (m, 8H). MS m/z: 407 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([NH2:17])=O)[CH2:6][C:5]2=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][NH2:17])[CH2:6][C:5]2=1
Reactant: NC(=O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 0 °C
Yield: 52 %

Procedure:
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide (0.6 g, 2.42 mmole) was dissolved in THF (20 ml). The reaction was cooled to 0° C. Lithium aluminum hydride (4.8 ml, 1M, 4.8 mmole) was portion wise carefully added. The reaction was refluxed for 2 hours. After cooling the mixture to room temperature water was carefully drop wise added to deactivate the Li—Al-complex. The formed solids were filtered and the filtrate diluted with ethyl acetate, washed with water (2×), brine and the separated organic layer dried over magnesium sulfate, filtered and evaporated in vacuo. The product was crystallized from ethyl acetate/hexane, 80:20. A white solid was obtained, 0.293 g, 52% yield. mp. 142-144° C. MS: ES [M−H]− 233.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:10][C:9]=2[F:19])[O:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:4]=2)=[C:9]([F:19])[CH:10]=1
Reactant: Fc1cc(OCCCCl)ccc1-c1nc(CCl)co1
Reactant: C1CCNCC1
Solvent: CC#N
Product: Fc1cc(OCCCCl)ccc1-c1nc(CN2CCCCC2)co1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 4-(chloromethyl)-2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazole i84 (0.23 g, 0.75 mmol, 1 eq) in acetonitrile (10 ml) is treated with piperidine (0.14 ml, 1.5 mmol, 2 eq). The mixture is stirred at room temperature for 24 h and concentrated under vacuum. The residue is taken up in dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of 1-({2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazol-4-yl}methyl)piperidine i86.