Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([N:45]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH2:60]([N:45]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:46]([NH:48][C@H:49]([C:57](=[O:58])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:13])[CH3:14])[CH:10]=[CH2:11])[CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at room temperature with 100 mg of N-(dibenzylcarbamoyl)-3-phenyl-L-alanine and 113 mg of BOP and subsequently stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent yielded 130 mg of 1,1-dibenzyl-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]urea in the form of an amorphous solid. MS: 761 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH3:23])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([C:25]([F:26])([F:27])[F:28])([OH:24])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH3:23])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Yield: 66.7 %

Procedure:
Analogously to Example 35, 153 mg (0.34 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol in 17 ml of CH2Cl2 is reacted with 6.8 ml of 1M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane-ethyl acetate (0-55%), 99 mg of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH:14]=C)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C[OH:19]>>[CH:14]([C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:19]
Reactant: CO
Reactant: C=Cc1cc(C(=O)OCC)cc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(C=O)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
25.39 g (103.96 mmol) of ethyl 3-(trifluoromethyl)-5-vinylbenzoate 33 is dissolved in dry MeOH (200 mL) and reaction vessel Is cooled down to −78° C. Then O3 is bubbled through for 1.5 hours until the reaction mixture turned dark blue. Then ozone is turned off and nitrogen is bubbled through the reaction mixture to remove extra ozone from the solution. 9.6 g of dimethyl sufide (155.95 mmol, 1.5 eq) is added and the reaction mixture is stirred at −78° C. for 2 hours followed by at room temperature for another hour. All the solvents are removed and ethyl 3-formyl-5-(trifluoromethyl)benzoate 34 is isolated via flash column chromatography (5-10% EtOAc/Hex). MS: m/z [M+H+]) 247.18, 1H NMR 10.16 (s, 1H), 8.73 (s, 1H), 8.56, (s, 1H), 8.35 (s, 1H), 4.46-4.51 (q, 2H, J=7.21 Hz), 1.45-1.49 (t, 3H, J=7.21 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.N1C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(Cl)Cl.CCOC(C)=O>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:4]([O:3][CH3:2])=[O:10])(=[O:28])=[O:27])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-proline methyl ester hydrochloride salt (2.5 g, 15.2 mmol) in DCM (20 mL) was added pyridine (2.6 mL, 33 mmol) and 4-nitrobenzenesulfonyl chloride (3.06 g, 13.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 18 h and then diluted with EtOAc (100 mL). The organic phase was washed with 1 N HCl (20 mL), brine (20 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo to give a crude yellow solid that was used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]([C:5]1C=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([OH:14])(=O)[CH3:12].[CH:15]([NH2:17])=[NH:16].[Na]>COC(OC)N(C)C.C(O)C>[N:16]1[CH:2]=[CH:3][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:12][C:11]=2[OH:14])=[N:17][CH:15]=1
Reactant: CC(=O)O
Reactant: N=CN
Reactant: O=C(CO)c1ccccc1
Agent: COC(OC)N(C)C
Agent: [Na]
Solvent: CCO
Product: Oc1ccccc1-c1ccncn1
Yield: 3427.5 %

Procedure:
2-Hydroxyacetophenone (220 mmol, 30 g) is stirred in a mixture of dimethylformamide-dimethyl acetal for 5 hours at 70° C., cooled and recrystallised from diethylether. The intermediate is dissolved in dry ethanol (200 ml) and formamidine acetate (0.61 mmol, 63.5 g) is added. A solution of sodium (0.61 mol, 14 g) in ethanol (450 ml) is added in several portions and the mixture is refluxed for 18 hours and evaporated. Recrystallisation from diisopropylether yielded 3.6 g (10%) of 2-(pyrimidin-4-yl)phenol as a solid. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10]CC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([NH:30][CH3:31])[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:32](N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([N:30]([CH3:31])[C:12](=[O:14])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]([CH3:10])[CH3:32])[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: CN[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)C(C(=O)N(C)[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-methyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aR,4S,6aS)-2-benzyl-N-methyloctahydrocyclopenta[c]pyrrol-4-amine for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 2: 1H NMR (300 MHz, CDCl3) δ ppm 7.59-7.41 (m, 5H), 7.39-7.16 (m, 5H), 3.64 (d, J=13.2, 1H), 3.50 (d, J=9.5, 1H), 2.69-2.52 (m, 2H), 2.50-2.33 (m, 3H), 2.25-2.15 (m, 1H), 2.05 (dd, J=6.3, 9.2, 1H), 1.88-1.67 (m, 2H), 1.34 (dd, J=13.4, 19.6, 3H), 1.08 (d, J=6.4, 3H), 1.03-0.95 (m, 1H), 0.79-0.66 (m, 6H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 15 h
Yield: 37.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (1.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (1.6 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling isopropanol (2 cc), 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.5 g) is obtained, m.p. 88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C[S:17]N=C=O.[CH3:21][N:22]([CH3:25])C=O>>[CH3:21][NH:22][C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[S:17]
Reactant: CN(C)C=O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSN=C=O
Product: CNC(=S)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 40 ml of dry dimethylformamide (DMF) was dissolved 8.13 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone. To this solution was added 3.5 g of methyl thioisocyanate, and the mixture was stirred for 4 hours at room temperature. The mixture was stirred for an additional 30 minutes at 50° C. and the solvent was distilled off under reduced pressure. To the residue was added 50 ml of dichloromethane/ether (1:1) to precipitate crystals which were then collected by filtration and washed with dichloromethane, whereby 10.1 g of the above-identified compound was obtained. M.P. 213° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH3:30]>>[CH3:30][N:25]1[CH:24]=[N:23][C:22]2[C:26]1=[N:27][CH:28]=[N:29][C:21]=2[NH:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:11])[CH2:17][CH2:16]1
Reactant: Cn1cnc2c(Cl)ncnc21
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Cn1cnc2c(NCC3CCN(S(=O)(=O)CCc4ccccc4)CC3)ncnc21

Procedure:
EXAMPLE 84 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-9-methyl-9H-purine (6-chloro-9-methyl-9H-purine prepared according to G. B. Eilon, J. Org. Chem., 27:2478–2491(1962): MS (m+1)=415.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: CCC#CCOc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC#CCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 54.9 %

Procedure:
Piperidine (0.24 mL, 2.5 mmol) was added to a suspension of 4-methoxy-3-(pent-2-ynyl)oxybenzaldehyde (0.54 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.53 g, 2.4 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(4-Methoxy-3-(pent-2-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.50 g, 60%) was obtained as a yellow crystalline solid; mp 124-125° C.; δH (400 MHz, DMSO-d6) 1.06 (t, J=7.4 Hz, 2H, CH2CH3), 2.23 (q, J=7.4 Hz, 3H, CH2CH3), 3.80 (s, 3H, OCH3), 4.81 (s, 2H, OCH2), 6.73 (d, J=15.6 Hz, 1H, CH═CHCO), 7.01 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.28 (dd, J5′,6′=8.4, J2′,6′=1.6 Hz, 1H, H6′), 7.42 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.57 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 13.6, 55.6, 56.6, 74.9, 89.3, 111.9, 112.5, 116.5, 119.9, 120.3, 122.7, 123.3, 127.0, 131.1, 134.0, 141.1, 141.6, 146.8, 151.0, 164.1, 169.5; HRMS (ESI) calculated for C22H21NO6 [M+Na]+ 402.1312. found 402.1317; vmax 753, 1015, 1257, 1506, 1584, 1659, 2920, 3246, 3520 cm−1.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:29][CH2:28]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Reaction time: 24 h
Yield: 33.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (599 mg, 1.7 mmole) was added to a solution of 3-piperidine-4-yl-1H-indole (340.5 mg, 1.7 mmole) in dioxane (12 ml). The reaction mixture was a clear solution above 40° C., and this solution was boiled for 24 hours under reflux. No precipitate was formed even at RT. The solvent was distilled off in vacuo. The residue contained, besides phenol, the two diastereoisomers of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol/EE (1:1; 800 ml) and methanol (500 ml) were used as eluent. The non-polar diastereoisomer (281 mg, m.p. 89°-93° C., 36%) and the polar diastereoisomer of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (262 mg, m.p. 104°-107° C., 34%) were thereby obtained in pure form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][OH:20])[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COS(C)(=O)=O)n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.7 mmol) in methylene chloride (5 mL) was added methanesulfonyl chloride (0.1 g, 0.9 mmol) and triethyl amine (0.14 g, 1.4 mmol) at 0° C. After stirred at 0° C. for 1 hour, the mixture was diluted with EtOAc and washed with H2O, brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:50])[C@H:25]([CH2:48][OH:49])[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>N1C=CC=CC=1.O>[C:27]([NH:26][C@H:25]([C:24]([OH:23])=[O:50])[CH2:48][O:49][P:6]([OH:8])([OH:7])=[O:5])(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CO)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous pyridine (3 ml) was added to dry N-arachidonoyl-L-serine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 20 h, the mixture was cooled to 0° C., water (0.5 ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-arachidonoyl-L-serine methyl ester was eluted from column with chloroform-methanol (30-40:70-60, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (70-60:30-40, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired product was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TLC plates with molybdate spray were combined and evaporated to dryness to give 82 mg (35%) of (6): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1,3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 14 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-nitro-3-trifluoromethylaniline (618 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture between 13-15° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 430 mg (62%) of allyl-4-nitro-3-trifluoromethylbenzene as a light yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.86, (d, 1H, J=8.3 Hz), 7.65, (d, 1H, J=1.2 Hz), 7.55, (dd, 1H, J=8.3, 1.4 Hz), 6.00-5.89, (m, 1H), 5.26-5.14, (m, 2H), 3.54, (d, 2H, J=6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 146.5, 135.0, 133.3, 128.5, (q, J=5.0 Hz), 125.8, 124.4, 124.1, 123.8, 121.1, 118.8, 40.0; Anal HRMS Calcd. for C10H8F3NO2 (M): 231.0507. Found: 208.0499.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>CCOC(C)=O>[CH2:12]([O:15][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2)[C:13]#[CH:14]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: C#CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOC12CC3CC(CC(C3)C1)C2
Yield: 100.9 %

Procedure:
A mixture of 1-bromoadamantane (10.8 g, 50.2 mmol), propargyl alcohol (30 ml, 515 mmol) and triethylamine (7.0 ml, 50.3 mmol) were heated at reflux for 4 hours. The reaction mixture was diluted with EtOAc (70 ml) and was washed sequentially with water (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulfate and the filtrate was evaporated to give the title compound (9.64 g, 100%). 1H NMR (CDCl3) 4.14 (2H, d, J=2.4 Hz), 2.36 (1H, t, J=2.4), 2.16 (3H, s), 1.80-1.79 (6H, m), 1.67-1.57 (6H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.[F:24][CH2:25][CH2:26][OH:27]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:27][CH2:26][CH2:25][F:24])[C:16]=2[N:17]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: OCCF
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Nc1nc(OCCF)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
Potassium tert-butoxide (2.8 mL; 1M in THF) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (0.7 g) and 2-fluoroethanol (0.83 mL) in DCM (100 mL). After stirring at room temperature for 10 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(2-fluoro-ethoxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.3 g, yield: 44%) was characterized by its mass spectrum as follows: MS (m/z) 243.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[C:10]=12)=[O:5])[CH3:2].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[NH:21][NH2:22].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([NH:22][NH:21][C:20]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)NNc1nc2ccccc2n2cnc(C(=O)OCC)c12
Yield: 58.4 %

Procedure:
To a solution of 4-chloroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (5.5 g) in acetonitrile (120 ml) was added ethyl carbazate (9 g) and triethylamine (20 ml) with stirring. The mixture was refluxed for 18 hours, then evaporated under water aspirator vacuum to dryness. The residue was taken up in chloroform, washed with water, dried by magnesium sulfate, concentrated to a small volume, then put through a silica gel dry column (2% methanol in chloroform as eluant). From column the product was isolated as an off-white solid (4 g, 58% yield). Recrystallized from a mixture of chloroform and hexane, m.p. 126°-128° C.