Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccon3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Reaction time: 4 h
Yield: 14.2 %

Procedure:
A mixture of (-) (2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino) -1,2,2a,3,4,5-hexahydrobenz[cd]indole (400 mg, 1.2 mmol) and 1 g of MnO2 in 100 ml of CH2Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 55 mg of title product as an oil. MS m/e 323 (FD)
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16](OC(OC2C=CC=CC=2)=S)[C@H:15]([N:28]2[C:32]3[N:33]=[C:34]([NH2:38])[NH:35][C:36](=[O:37])[C:31]=3[S:30][C:29]2=[O:39])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=N[C:42](C)([CH3:45])[C:43]#N.C([Sn](CCCC)(CCCC)CCCC)C=C>C1(C)C=CC=CC=1>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([CH2:45][CH:42]=[CH2:43])[C@H:15]([N:28]2[C:32]3[N:33]=[C:34]([NH2:38])[NH:35][C:36](=[O:37])[C:31]=3[S:30][C:29]2=[O:39])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(=S)Oc2ccccc2)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@H]1C[C@@H](C(CC)OC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 179.6 %

Procedure:
A mixture of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-phenoxycarbothioyloxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26e, 1.14 g, 2.0 mmol), 2,2′-azobisisobutyronitrile (168 mg, 1 mmol) and allyl(tributyl)stannane (3.08 mL, 10 mmol) in anhydrous toluene (15 mL) was degassed with argon and then heated with stirring at 80° C. for 4 hours. The resulting mixture was stirred with saturated aqueous NH4F at room temperature for 2 hours and extracted with DCM twice. The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 820 mg of 1-[(2S,4R,5R)-4-allyl-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl benzoate (compound 26f) as a brown solid. MS obsd. (ESI+) [(M+H)+]: 457.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][CH2:40][O:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:44])[CH2:42][O:41][CH2:40][CH2:39][O:38][CH3:37])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Reactant: COCCOCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCC(=O)N(CCOC)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a suspension of 113 (120 mg, 0.237 mmol) in THF (3 mL) was added 2-(2-methoxyethoxy)acetyl chloride (54.2 mg, 0.355 mmol) and TEA (71.9 mg, 0.711 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc then washed with saturated ammonium chloride solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to give title compound 115 (113 mg, 77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.50 (d, J=5.48, 1H), 8.05 (s, 1H, rotamer), 7.90 (m, 2H, rotamer), 7.75 (m, 1H), 7.20 (m, 3H), 7.19 (m, 1H), 6.59 (m, 2H), 4.61 (s, 1H, rotamer), 4.31 (s, 2H, rotamer), 3.61 (m, 2H), 3.49 (m, 6H), 3.23 (m, 7H), 2.55 (m, 1H), 0.64 (m, 2H), 0.43 (m, 2H). MS (m/z)=623.66 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>N1C=CC=CC=1.[Cu].O>[C:5]([C:4]1[CH:3]=[C:2]([O:21][C:17]2[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(I)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of methyl 3-iodobenzoate (2.54 g), 3-nitrophenol (1.48 g), and K2CO3 (3.97 g) in 60 mL of pyridine was warmed to 100° C. under nitrogen atmosphere. Copper powder (1.84 g) was added, and the reaction mixture was heated to reflux. After 22 h, The reaction was cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed twice with 10% aq. HCl solution, then with sat. aq. NaHCO3 solution, then with brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (CH2Cl2) provided the product as a yellow oil.
Reaction SMILES: [CH3:1][S:2](=[O:19])([CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[CH3:8])=[N:3][C:4]([NH2:6])=[S:5].Br[CH:21]([CH3:25])[C:22](=O)[CH3:23]>CCO>[CH3:25][C:21]1[N:6]=[C:4]([N:3]=[S:2]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=2)[CH3:8])([CH3:1])=[O:19])[S:5][C:22]=1[CH3:23]
Reactant: CC(=O)C(C)Br
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(N)=S
Solvent: CCO
Product: Cc1nc(N=S(C)(=O)C(C)c2ccc(C(F)(F)F)nc2)sc1C
Temperature: 85 °C

Procedure:
In a microwave crimp tube, N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (200 mg, 0.642 mmol) was suspended in EtOH (3 mL) and 3-bromobutan-2-one (151 mg, 69 μL, 0.642 mmol) was added via syringe, while stirring. The reaction was sealed and heated to 85° C. for 15 min in the microwave. The solvent was subsequently removed on the rotary evaporator and the remaining residue purified by preparative reverse phase chromatography (water/acetonitrile). 5-{1-[(4,5-dimethyl-1,3-thiazol-2-yl)(methyl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (67) was obtained in form of a slightly yellow oil as a 1:1 mixture of diastereomers (67 mg, 0.185 mmol, 29%). 1H-NMR (CDCl3, 400 MHz): δ=1.89 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 1); 1.93 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 2); 2.15 (s, 1.5H, thiazole-CH3, one diastereomer); 2.17 (s, 1.5H, thiazole-CH3, one diastereomer); 2.18 (s, 1.5H, thiazole-CH3, one diastereomer); 2.20 (s, 1.5H, thiazole-CH3, one diastereomer); 3.04 (s, 1.5H, S—CH3, diastereomer 1); 3.15 (s, 1.5H, S—CH3, diastereomer 2); 5.11 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 1); 5.22 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 2); 7.71 (d, J=8.1 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.73 (d, J=8.1 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.08 (dd, 3J=8.1 Hz, 4J=2.0 Hz, 0.5H, pyr-C4-H, diastereomer 1); 8.10 (dd, 3J=8.1 Hz, 4J=2.0 Hz, 0.5H, pyr-C4-H, diastereomer 2); 8.72 (d, 4J=2.0 Hz, 0.5H, pyr-C6-H, diastereomer 1); 8.78 (d, 4J=2.0 Hz, 0.5H, pyr-C6-H, diastereomer 2). 13C-NMR (CDCl3, 100 MHz): δ=10.9, 11.0 (thiazole-CH3, two diastereomers); 13.8, 14.4 (CHCH3, two diastereomers); 14.4 (double peak, thiazole-CH3, two diastereomers); 36.3, 36.5 (S—CH3, two diastereomers); 60.5, 61.2 (CHCH3, two diastereomers); 117.9, 118.0 (Ar, two diastereomers); 119.4, 119.5 (pyr-C, 2 diastereomers); 131.4, 132.1 (Ar, two diastereomers), 137.1, 137.4 (pyr-C, 2-diastereomers); 141.7, 141.9 (Ar, two diastereomers) 149.3, 149.4 (pyr-C, 2-diastereomers); 161.4, 161.7 (thiazole, two diastereomers); CF3, not detected. HPLC-MS (ESI+): mass calc'd for C14H17F3N3OS2 (M+H+): 364.1, found 364.5, HPLC-MS (ESI+) mass calc'd for C14H15F3N3OS2 (M−H+): 362.1, found 361.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=C(C2C=CC=C(B3OCC(C)(C)CO3)C=2)C=CC=1.Cl[C:39]1[CH:48]=[CH:47][N:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:51])[F:50])=[N:44]2>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:39]3[CH:48]=[CH:47][N:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:50])[F:51])=[N:44]4)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(Br)c2)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Agent: COc1cccc(-c2cccc(B3OCC(C)(C)CO3)c2)c1
Product: COc1cccc(-c2cccc(-c3ccnc4nc(C(F)(F)F)ccc34)c2)c1
Yield: 13 %

Procedure:
3-Bromo-3′-methoxybiphenyl (prepared as described in patent WO 0130764) was converted to 2-(3′-methoxybiphenyl-3-yl)-5,5-dimethyl[1,3,2]-dioxaborinane using the procedure described in Example 7 part f). The crude product of this transformation (83 mg, 0.28 mmol) was coupled to 5-chloro-2-trifluoromethyl[1,8]-naphthyridine (50 mg, 0.22 mmol) as described in Example 7 part g), affording 5-(3′-methoxybiphenyl-3-yl)-2-trifluoromethyl[1,8]naphthyridine (11 mg, 13%). δH (360 MHz, CDCl3) 3.87 (3H, s), 6.95 (1H, m), 7.14-7.25 (2H, m), 7.40 (1H, t, J 7.9), 7.47 (1H, d, J 7.7), 7.56-7.69 (3H, m), 7.77-7.83 (2H, m), 8.59 (1H, d, J 8.8), 9.29 (1H, d, J 4.2). m/z (ES+) 381 [MH]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:53][C:54]3[CH:64]=[CH:63][C:62]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=4)[C:68](O)=[O:69])=[CH:61][C:55]=3[C:56]=2[C:57](=[O:60])[NH:58][CH3:59])=[CH:48][CH:47]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:68]([C:67]2[CH:66]=[C:65]([C:62]3[CH:63]=[CH:64][C:54]4[O:53][C:52]([C:49]5[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=5)=[C:56]([C:57]([NH:58][CH3:59])=[O:60])[C:55]=4[CH:61]=3)[CH:73]=[CH:72][CH:71]=2)=[O:69])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccc(Cl)cc4)c3)cc12
Reaction time: 1 h
Yield: 57.4 %

Procedure:
2-(4-chlorophenyl)propan-2-amine (21 mg, 0.123 mmol) was added to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol), and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (32 mg, 57%). 1H NMR (500 MHz, DMSO-d6) d ppm 8.64 (1H, s), 8.47-8.55 (1H, m), 8.14 (1H, s), 7.99-8.04 (2H, m), 7.92 (1H, s), 7.74-7.89 (4H, m), 7.57 (1H, t, J=7.78 Hz), 7.37-7.45 (4H, m), 7.34 (2H, d, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz), 1.69 (6H, s). LC-MS retention time: 1.95 min; m/z (MH+): 541. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.18 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.66 min, purity=99%.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Br[CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>C(OCC)C.CCOC(C)=O>[CH3:18][CH:17]([CH3:19])[C:16](=[O:20])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)CBr
Reactant: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(=O)CSc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of thiophenol (4.44 mL; 43.4 mmol) in diethyl ether (29 mL) was added pyridine (17.2 mL; 0.21 mol), followed by the drop-wise addition of a solution of compound 563-B (7.18 g; 43.5 mmol) in diethyl ether (15 mL), at ambient temperature, and the reaction was stirred for 72 h. The reaction was diluted with EtOAc, washed with 2N HCl, H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford compound 563-C as an oil. 1H-NMR (CDCl3): δ 1.09-1.10 (d, 6H), 2.90-2.97 (m, 1H), 3.75 (s, 2H), 7.18-7.35 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11](N)[CH:10]=[N:9]1.N([O-])=O.[Na+].[ClH:23]>[Cu]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:23])[CH:10]=[N:9]1
Reactant: Cl
Reactant: CC(C(=O)O)c1ccc(-n2cc(N)cn2)c(Cl)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Temperature: -3 °C
Reaction time: 1 h

Procedure:
2.65 g (10 mmoles) of 2-[3-chloro-4-(4-aminopyrazol-1-yl)phenyl]propionic acid are dissolved in 10 ml of 25% strength hydrochloric acid, the solution is cooled to -3° C., and 1.04 g (15 mmoles) of sodium nitrite (dissolved in 5 ml of water) are added. After 10 minutes the reaction mixture is stirred into a solution of 2 g (20 mmoles) of copper(I) chloride. Heating to 100° C. ist then effected for 1 hour, followed by cooling, extraction with chloroform and purification through chromatography on silica gel (benzene/cyclohexane/glacial acetic acid 2:1:1). 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, m.p. 102°-103° C., is obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]=[C:41]([C:43]3[C:47]([CH2:48][CH2:49][CH3:50])=[C:46]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[O:45][N:44]=3)[O:40][N:39]=2)=[CH:34][CH:33]=1)[OH:31].CCN(C(N1N=NN(C2C(Cl)=CC=CC=2)C1=O)=O)C1CCCCC1>CS(C)=O.CO>[OH:31][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]=[C:41]([C:43]3[C:47]([CH2:48][CH2:49][CH3:50])=[C:46]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[O:45][N:44]=3)[O:40][N:39]=2)=[CH:34][CH:33]=1)[CH2:29][N:8]1[CH2:7][CH2:6][NH:5][CH:4]([C:1]([OH:3])=[O:2])[CH2:9]1
Reactant: O=C(O)C1CNCCN1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCNC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-carboxypiperazine (47 mg, 0.36 mmol) in 0.5 mL dry DMSO was added tetrabutylammonium hydroxide (0.360 mL, 360 μmol, 1M in THF) and the reaction mixture was stirred at rt for 15 min. 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was dissolved in 0.5 mL DMSO and added and the reaction was agitated at 400 rpm on an INNOVA® platform shaker at 80° C. for 1.5 hours. The reaction was diluted with 250 μL of MeOH and purified by HPLC (MeOH—H2O-TFA) to give 4-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperazine-2-carboxylic acid. MS (m+1)=504. HPLC RT=2.06 min Waters Masslynx instrument equipped with a 19×100 mm 5 uM C18 column and a method of 0-100% B solvent over 15 min at a flow rate of 20 mL/min. Solvent A is 5:95 acetonitrile/water; solvent B is 95:5 acetonitrile/water and both contain 0.5% TFA.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([O:8][C:9](=[O:26])[CH:10]([CH2:24][CH3:25])[C:11]([O:13][CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[O:12])[CH2:5][C:4]([CH3:28])([CH3:27])[NH:3]1.[H-].[Na+].[CH3:32][C:33]1[C:40]([OH:41])=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=[C:37]([CH3:46])[C:34]=1[CH2:35]Cl>CN(C)C=O>[CH3:21][C:18]1([CH3:20])[CH2:19][CH:14]([O:13][C:11](=[O:12])[C:10]([CH2:24][CH3:25])([CH2:35][C:34]2[C:37]([CH3:46])=[CH:38][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[C:40]([OH:41])[C:33]=2[CH3:32])[C:9]([O:8][CH:6]2[CH2:7][C:2]([CH3:1])([CH3:29])[NH:3][C:4]([CH3:28])([CH3:27])[CH2:5]2)=[O:26])[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: CCC(C(=O)OC1CC(C)(C)NC(C)(C)C1)C(=O)OC1CC(C)(C)NC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Cc1c(C)cc(C(C)(C)C)c(O)c1C)(C(=O)OC1CC(C)(C)NC(C)(C)C1)C(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To 24.6 g (0.06 mole) of ethylmalonic acid-bis(2,2,6,6-tetramethyl-4-piperidinyl)ester in 80 ml of dimethylformamide there are added 2.5 g of NaH dispersion (55-60%) followed by 13.6 g (0.06 mole) of 2,6-di-methyl-4-tert. butyl-3-hydroxybenzyl chloride in 40 ml of DMF. The reaction mixture is stirred for 20 hours at 90°-100° C. and is then poured into ice-water; the aqueous solution is extracted with ether, the ethereal solution is dried over Na2SO4, and after removal of the solvent in vacuo there is obtained ethyl-(2,6-dimethyl-4-tert.butyl-3-hydroxybenzyl)malonic acid-bis (2,2,6,6-tetramethyl-4-piperidinyl)ester in the form of an oily yellowish residue (No. 43).
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:4][CH:3]=[N:2]1.[CH2:12]([N:14]1[C:26]2[CH:25]=[C:24](C=O)[CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13].[BH3-][C:30]#N.[Na+].C(Cl)Cl>O1CCCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:30][C:23]3[CH:24]=[CH:25][C:26]4[N:14]([CH2:12][CH3:13])[C:15]5[C:20]([C:21]=4[CH:22]=3)=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:7]2)=[CH:4][CH:3]=[N:2]1
Reactant: c1cc(C2CCCNC2)[nH]n1
Reactant: CCn1c2ccccc2c2ccc(C=O)cc21
Reactant: [BH3-]C#N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4ccn[nH]4)C3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.2 %

Procedure:
A 100-mL 3-necked round-bottom flask was charged with a solution of 3-(1H-pyrazol-5-yl)piperidine (1.8 g, 11.31 mmol, 1.00 equiv, 95%) in tetrahydrofuran (THF) (100 mL). To this was added 9-ethyl-9H-carbazole-2-carbaldehyde (2.66 g, 11.32 mmol, 1.02 equiv, 95%) and Ti(OiPr)4 (4.24 g, 14.76 mmol, 1.25 equiv, 99%). The resulting solution was allowed to stir at room temperature overnight. To the mixture was then added NaBH3CN (3 g, 47.26 mmol, 4.00 equiv, 99%). The resulting mixture was allowed to stir at room temperature overnight. The progress was monitored by TLC (DCM; MeOH=10:1). Upon completion, the reaction was quenched by the addition of saturated aqueous Na2CO3 (150 mL). The resulting mixture was extracted with ethyl acetate (5×200 mL). Combined organic layers were dried over MgSO4, filtered off and concentrated on a rotary evaporator to give a residue that was purified by silica gel column chromatography eluted with DCM/MeOH (50:1) affording 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as a white solid (0.211 g, 5%). LCMS: [M+H]+: 359.2. 1H NMR (CDCl3,300 MHz) δ 8.11 (m, 1H), 8.00 (s, 1H), 7.48-7.36 (m, 5H), 7.24 (m, 1H), 6.03 (s, 1H), 4.37 (m, 2H), 3.93 (br, 2H), 3.76 (s, 2H), 3.15-2.60 (m, 5H), 1.67-1.56 (m, 4H), 1.43 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:38])[N:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[NH:20][C:19]4[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=4[CH:13]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 94 °C
Reaction time: 72 h
Yield: 26.6 %

Procedure:
9a (25 mg) was suspended in THF (2 ml) in a pressure tube, 4-fluorophenyl isocyanate (200 mg) was added and the mixture was stirred at 94° C. for 3 days. After cooling to room temperature, the mixture was evaporated to almost dry and the solid was filtered and washed with ether (two peaks shown in HPLC, rt=8.0 min, rt=11.6 min). The solid was stirred with DCM, the solid (rt=8.0 min) was removed and the mother liquid was collected. After removal of the solvent, the residue was purified by column (14 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 98:2) to give the product (11a) (9 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. 1H NMR (DMSO, d6): 0.83-0.95 (m, 6H), 1.53-1.75 (m, 4H), 3.26 (s, 3H), 3.60 (t, 2H), 3.87 (t, 2H), 4.17 (t, 2H), 6.85 (s, 1H), 7.16 (t, 2H, J=8.7 Hz), 7.48 (m, 3H), 8.30 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.95 (d, 1H, J=2.4 Hz), 10.87 (s, 1H), 12.50 (s, 1H). MS: m/z 523 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>[Cl-].[Cl-].[Zn+2]>[OH:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=[CH:5][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)c1ccc(O)c(C)c1O
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-benzene-1,3-diol, acetic anhydride and ZnCl2 was heated at 150-60° C. for 3.5 h, and processed as reported in the literature. (Pearson. D. E. et. al., Synthesis, 533, 1972 and the references cited therein). The crude was purified using flash chromatography (silica gel, 0-5% CH3CN in chloroform) to obtain the title compound. Yield, 73%; mp, 65-66° C. (EtOAc-PE 60-80° C.); MS (CI): 195 (M++29), 169 (M++1); analysis: C9H10O3 requires C, 65.05; H, 6.07; found C, 65.44; H, 6.62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[ClH:1].[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[CH:15]=2)[CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1ccnc(Cl)c1
Product: Cl
Product: Clc1cccc(-c2cc(Cl)ccn2)c1
Yield: 71.1 %

Procedure:
Following general procedure F, 2,4-dichloropyridine (4.0 g, 27 mmol) was reacted with (3-chlorophenyl)boronic acid (4.6 g, 30 mmol), followed by formation of the hydrochloride salt to afford the title compound (5.0 g, 71%) as a white solid. MW=260.55. 1H NMR (CDCl3, 500 MHz) δ 8.92-8.79 (m, 1H), 8.16-8.09 (m, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.74-7.64 (m, 1H), 7.58-7.52 (m, 2H); APCI MS m/z 224 [M+H]+.