Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: COc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2ccc(Br)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (100 mg, 0.465 mmol) in DCM (2 mL) were added (3-methoxyphenyl)methanamine (70.2 mg, 0.512 mmol), DIEA (0.244 mL, 1.395 mmol) and HATU (212 mg, 0.558 mmol) at RT. The reaction was stirred under argon at RT for 1 h. The crude product was purified by normal phase chromatography. 58A was obtained as white solid (155 mg, 0.464 mmol, 100% yield). LCMS (ESI) m/z: 336.0 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.30-7.24 (m, 1H), 6.92 (dd, J=7.6, 0.6 Hz, 1H), 6.88 (t, J=1.8 Hz, 1H), 6.84 (dt, J=8.1, 1.3 Hz, 1H), 6.38 (br. s., 1H), 4.60 (d, J=5.7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH3:13][C@H:14](N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@H:14]([CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](C1=Cc2ccc(Cl)cc2CC1)c1ccccc1

Procedure:
To a stirred solution of 6-chloro-2-tetralone (1.0 equiv., 100.0 mmol., 18.06 g) in toluene (300 ml) was added (S)-(-)-α-methylbenzylamine (1.0 equiv., 100.0 mmol., 12.9 ml). The mixture was heated at reflux for 3 hrs with the azeotropic removal of water (Dean-Stark). The cooled reaction mixture was concentrated in vacuo to give the enamine, (S)-6-chloro-2-(α-methylbenzyl)-3,4-dihydronaphthalene, as a purple oil. The oil was taken up in chloroform (150 ml) and saturated aqueous sodium bicarbonate was added (150 ml). The vigorously stirred mixture was treated with acryloyl chloride (1.05 equiv., 105.0 mmol., 8.5 ml) dropwise over 5 min. The reaction mixture was allowed to stir at ambient temperature for 20 min., then diluted with chloroform and the layers separated. The aqueous layer was extracted with chloroform (1×). The combined organics were washed with brine (1×), dried (Na2SO4), and concentrated in vacuo to give 37.9 g of a black oil. The crude oil was subjected to HPLC on silica gel (gradient elution with hexanes increasing to 25% ethyl acetate/hexanes) to give 19.03 g of a purple oil which was further purified by flash chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give 17.96 g, 53% yield of the title compound as a brown glass which was homogeneous by HPLC analysis (reverse phase, C18, mobile phase: 60% acetonitrile/0.5% aqueous ammonium acetate buffer),thin layer chromatography (Silica gel, Rf =~0.5, developed with 40% ethyl acetate/hexanes), and 300 MHz 1H NMR analysis. FDMS: m/e=337. α[D]589 =-24.75 (c=1.0, CHCl3).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: C=CCOc1ccc(F)cc1-c1ccccc1-c1ccccc1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(F)cc(-c2ccccc2-c2ccccc2)c1O
Yield: 96 %

Procedure:
A solution of 2-allyloxy-5-fluoro-2′-phenylbiphenyl (6.4 g, 21.0 mmol) in mesitylene (200 mL) was refluxed for 72 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes afforded 6.2 g (96%) of 3-allyl-5-fluoro-2′-phenylbiphenyl-2-ol as a pale yellow oil.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>CO>[C:6]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11]
Reactant: COCOc1cccc(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc(O)c1-c1ccccc1
Yield: 98.9 %

Procedure:
A solution of 16 (400 mg, 1.46 mmol) in MeOH (12.0 mL) at room temperature was treated dropwise with 3 M HCl (430 μL, 11.7 mmol), then heated to reflux for one hour. Water (15 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 17 as an orange amorphous solid (269 mg, 99%): 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, J=7.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.46-7.44 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 2H), 4.84 (s, 1H), 4.83 (s, 1H).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=[C:10]([NH2:17])[C:9]=2[N:8]=[C:7]1[CH2:18][CH2:19][CH3:20].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[CH3:22].Cl.N1C=CC=CC=1>CO>[NH2:17][C:10]1[C:9]2[N:8]=[C:7]([CH2:18][CH2:19][CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][O:2]/[N:1]=[C:21](/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)\[CH3:22])[C:14]=2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCO/N=C(\C)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of 1-[3-(aminooxy)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.64 g, 2.3 mmol) and acetophenone (325 μL, 2.76 mmol) in methanol (23 mL) was stirred overnight at room temperature, then heated at 50° C. for 4 hours. Pyridine hydrochloride (100 mg) was added to the solution and stirring was continued at 50° C. overnight. Additional pyridine hydrochloride was added and the solution was heated at reflux for 5 hours. The solvent was removed under reduced pressure and the resulting off-white solid was partitioned between chloroform (100 mL) and saturated aqueous sodium carbonate (30 mL). The aqueous layer was extracted with chloroform (3×30 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 5-30% CMA in chloroform) to yield a solid that was triturated with acetonitrile and dried under vacuum at 70° C. overnight to provide 105 mg of (1E)-1-phenylethanone O-[3-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]oxime as a white powder, mp 125.0-127.0° C. Anal. Calcd for C22H29N5O: C, 69.63; H, 7.70; N, 18.45. Found: C, 69.41; H, 7.73; N, 18.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[Na].[CH2:10](O)C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH3:10]
Reactant: CCO
Reactant: COC1=CC(=O)NC1
Agent: [Na]
Product: CCOC1=CC(=O)NC1
Yield: 65 %

Procedure:
A solution of 4-methoxy-3-pyrrolin-2-one (3 g; 26.52 mmols) in absolute ethanol (60 ml) is treated with sodium ethoxyde (2.17 g; 31.82 mmols) under nitrogen atmosphere. The solution is refluxed for 2 hours and then poured into a 30% NaH2PO4 solution (200 ml) The resulting mixture is extracted with ethyl acetate (3×150 ml) and the organic phase is shacked with brine, dried over sodium sulphate and evaporated to dryness to obtain 4-ethoxy-3-pyrrolin-2-one (2.19 g; 17.24 mmols). Yield: 65%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:23][CH2:24][N:25]([C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCNCC2)C3)cc1F
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(=O)OC)CC2)C3)cc1F
Temperature: 25 °C
Yield: 5.3 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6-(piperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (90 mg, 0.17 mmol) and DIPEA (30 μL, 0.17 mmol) in Dioxane (5 mL) was added methyl chloroformate (14 μL, 0.19 mmol). Reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (low pH) to afford an orange gum. This was then further purified using a TsOH cartridge to remove residual formic acid from HPLC (loaded in MeOH eluted with 2M methanolic ammonia). This gave a creamy pink solid (4.9 mg, 0.009 mmol, 5.3%).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24](OC)[O:25]C)[C:19]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:30])[N:9]=[N:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:45][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24]=[O:25])[C:19]=2[C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[N:9]=[N:8]1
Reactant: COC(Cc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=CCc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combine [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2-dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone (1 eq) in acetone/H2O (4:1) and p-toluenesulfonic acid (1 eq) with stirring. Attach a reflux condensor and stir overnight in a 60° C. oil bath. Neutralize with saturated aqueous NaHCO3, extract with ethyl acetate, dry over MgSO4, filter, and concentrate under vacuum. 1H NMR (CDCl3): δ 9.84 (s, 1H), 7.83 (s, 1H), 7.56-7.09 (m, 11H), 5.43 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Br:1][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A solution of N-bromosuccinimide (0.24 g, 1.3 mmol) in DMF (1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (0.41 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (0.34 g, 68%). LCMS calculated for C21H22BrFN2O2Na(M+Na)+: m/z=455.1. Found: 455.0.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[CH2:4][N:5]1[CH2:9][CH:8]=[CH:7][N:6]1O.P(Br)(Br)([Br:18])=O>C(Cl)(Cl)Cl>[Br:18][C:9]1[N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[N:6]=[CH:7][CH:8]=1
Reactant: ON1C=CCN1Cc1c(F)cccc1F
Reactant: O=P(Br)(Br)Br
Solvent: ClC(Cl)Cl
Product: Fc1cccc(F)c1Cn1nccc1Br
Temperature: 25 °C
Yield: 96.3 %

Procedure:
2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole (81.2 mg, 0.386 mmol, 1.0 eq) and 5 ml of anhydrous CHCl3 were combined in a flame-dried 25 mL round-bottom flask under argon and cooled in an ice/water bath. A solution of POBr3 (398.1 mg, 1.39 mmol, 3.60 eq) in 3 mL of CHCl3 was added using a syringe in aliquots over an hour period with stirring. The reaction solution was warmed to room temperature and stirred for 16 hours. The CHCl3 was removed in vacuo and the resulting orange mixture was neutralized with saturated aqueous NaHCO3 and extracted with 3×30 mL of diethyl ether. The combined ether fractions were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 101.5 mg (96.7% yield) of 5-bromo-1-(2,6-difluorobenzyl)-1H-pyrazole as a hygroscopic orange-tan colored solid. 1H NMR (CDCl3 300 MHz) δ 7.51 (d, 1H), 7.34 (m, 1H), 6.94 (t, 2H), 6.29 (d, 1H), 5.50 (s, 2H). LC/MS (ES) M+1=273.1, 275.1
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.[Cl:35][C:36]1[S:37][C:38]([CH2:41]Cl)=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:41][C:38]2[S:37][C:36]([Cl:35])=[CH:40][CH:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-chloro-5-(chloromethyl)thiophene (2.39 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 45%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:15][O:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>O1CCCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:15]([O:16][CH3:17])[C:45](=[O:47])[CH3:46])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CC(=O)Cl
Reactant: CCCC1(NOC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC1(N(OC)C(C)=O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of Example 9 (15 mg, 0.029 mmol) in tetrahydrofuran (200 μL) was added N,N-diisopropylethylamine (11 μL, 0.062 mmol) and acetyl chloride (5 μL, 0.070 mmol) and stirring was continued overnight. The solution was concentrated and taken up in H2O (1 mL) and 1N NaOH (0.5 mL). This solution was stirred at room temperature for 2 hours and 1N HCl was added slowly until the solution became acidic. This aqueous solution was extracted with ethyl acetate (3×2 mL), the organic extracts combined, dried over Na2SO4, the drying agent filtered off, the solvent removed in vacuo, and the crude product was purified by column chromatography on silica gel (5% methanol/chloroform) to give the title compound as a colorless solid: 1H NMR (d6-DMSO) δ 13.81 (s, 1H), 10.18 (s, 1H), 8.10, 8.07 (d, 1H), 7.71-7.45 (m, 7H), 4.07 (s, 3H), 3.06 (s, 3H), 2.03 (br s, 3H), 1.30-1.05 (br s, 1H), 1.24 (br s, 2H), 0.75-0.50 (br s, 1H), 0.74-0.65 (t, 3H); MS (ESI) m/z 563 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][O:32][CH3:33]>C(OCC)(=O)C>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:3]1[C:2]([O:1][CH2:30][CH2:31][O:32][CH3:33])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCOc1c(O)cc([N+](=O)[O-])cc1C(=O)OC
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1cc([N+](=O)[O-])cc(C(=O)OC)c1OCCOC
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a mixture of methyl 3-hydroxy-2-{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate (4.4 g, 16.2 mmol), potassium carbonate (4.5 g, 33 mmol) and acetonitrile (100 mL) was added 1-bromo-2-(methyloxy)ethane (2.5 mL, 24 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide to give methyl 2,3-bis{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate, (4.9 g, 14.8 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): 8.27-8.26 (d, 1H), 7.92-7.91 (d, 1H), 4.37-4.35 (m, 2H), 4.27-4.25 (m, 2H), 3.94 (s, 3H), 3.83-3.81 (m, 2H), 3.77-3.74 (m, 2H), 3.45 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc(Cl)cc(C(=O)O)n1
Reactant: C1COCCN1
Product: O=C(O)c1cc(N2CCOCC2)cc(C(=O)O)n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-chloro-pyridine-2,6-dicarboxylic acid (0.025 mol, 5.0 g) is slowly added under stirring to a solution of morpholine (0.250 mol, 21.6 g) at room temperature. Care is taken to avoid a too-fast addition leading to local temperature increase. Precipitation of a solid is observed. The reaction mixture is heated at 120° C. for 2 hr. By gradually heating the reaction mixture becomes solid. After cooling at 60° C., H20 (80 ml) is added and the mixture is stirred for 30 min. until the solid is completely dissolved. The solution is then acidified with 2M HCl until pH=1. The formed precipitate is filtered, washed twice H2O and dried overnight at 70° C. (70%)
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[K+].O1[CH2:31][CH2:30][NH:29]C1=O>>[O:10]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:31][CH2:30][NH2:29])=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NCCO1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: NCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
Mesitylene (24 mL) was added into a round bottom flask containing 4-phenoxyphenol (5.00 g, 26.85 mmol). Potassium methoxide (25% in methanol) (0.79 mL, 2.685 mmol) was added and stirred for 15 minutes. 2-oxazolidinone (2.34 g, 26.85 mmol) was then added, and the reaction mixture was heated to reflux temperature and stirred for 16 h. After cooling the reaction mixture to room temperature, the reaction mixture was filtered over Celite® and the solvent evaporated under reduced pressure. The crude reaction product was isolated by flash column chromatography to yield 2.75 g (45%) of the amine. 1H NMR (MeOD, 400 MHz) δ 8.21-8.11 (m, 2H), 8.35-7.91 (m, 1H), 7.83-7.67 (m, 6H), 7.02-6.96 (m, 2H), 4.71 (dd, 2H, J=5.9, 5.9 Hz), 3.68 (dd, 2H, J=5.8, 5.8 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:5]2[O:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:21]1=[O:22])[CH3:33]
Reactant: c1ccc2occc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2cc3ccccc3o2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To benzo[b]furan (76.4 mg, 2.1 eq) in anhydrous THF (2 mL) at −40° C. (bath temperature) was added n-BuLi (0.423 mL, 1.53 M in hexanes, 2.1 eq). The resulting light yellow coloured solution was stirred for 30 minutes, after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added. Stirring was continued at −40° C. for 9 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1%-2% MeOH in CHCl3) to give the title compound as a yellow oil (29.0 mg, 21%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCc1sc(C(=O)OC)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg, 1.204 mmol), potassium carbonate (832 mg, 6.02 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (326 mg, 1.565 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (301 mg, 1.204 mmol, 100% yield) as a brown oil: LCMS (ES) m/e 251 (M+H)+.