Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CN(C)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (77 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dimethyl-1,2-ethanediamine (23 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (14 mg, yield 21%).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7](F)=[N:8][CH:9]=1>O>[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:1])=[N:8][CH:9]=1
Reactant: [OH-]
Reactant: Fc1cc(Cl)cnc1F
Agent: [Na+]
Solvent: O
Product: Oc1ncc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was removed by filtration and dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78%) and was used without additional purification. The product was characterized by 1H NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])OCC3C=CC=CC=3)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[N+]([C:28]1C=C2C(NC(=O)OCC3C=CC=CC=3)COCC2=N[CH:33]=1)([O-])=O.Br.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:10]2[CH:11]([NH:14][C:15](=[O:24])[CH2:28][CH3:33])[CH2:12][O:13][CH2:6][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(NC1COc2cc([N+](=O)[O-])cnc2C1)OCc1ccccc1
Reactant: O=C(NC1COCc2ncc([N+](=O)[O-])cc21)OCc1ccccc1
Agent: Br
Agent: CCC(=O)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1COCc2ncc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of benzyl 3,4-dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-ylcarbamate and benzyl 6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridine-5-ylcarbamate (6.54 g, 26.23 mmol) in CH2Cl2 (55 ml) was stirred at 0° C. and 33% HBr in acetic acid (45 ml) was added. The solution was further stirred at 0° C. for 1 h then at room temperature for 2 h. The solvents were then removed. The crude mixture was dissolved in CH2Cl2/H2O 1/1 (80 ml) and the aqueous mixture adjusted to pH˜10 with 2N NaOH solution. After separation of the layers, the organic phase was washed with H2O (×2), dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (400 ml) and the solution cooled to 0° C. Propionyl chloride (4.54 ml, 52 mmol) and triethylamine (7.22 ml, 52 mmol) were added and then the mixture was allowed to reach 20° C. and stirred for 4.5 h. The solution was washed successively with 1 N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. Immediate recrystallization in acetone gave a pure fraction of N-(6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridin-5-yl)propionamide (2.2 g, 33% for two steps) as a white solid. The remaining mixture was subjected to chromatography on silica gel (heptane:ethyl acetate, 1.5:3.5 then CH2Cl2:CH3OH, 95:5) to afford another portion of N-(6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridin-5-yl)propionamide (1.15 mg, 17% for two steps) and N-(3,4-dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (445 mg, 7% for two steps) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11](I)=[CH:10]3)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:29]([NH2:27])=[O:30])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 13-bromo-4-iodo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (5.0 g, 0.013 mol) in DMF (50 mL) was added hexamethyldisilazane (16 mL, 0.077 mol) and Pd(PPh3)2Cl2 (0.45 g, 0.639 mmol). After being purged with CO three times, the mixture was heated at 70° C. for 3 h. After removal of the solvent, water (100 mL) was added. The solid was collected by filtration, washed with water and dried in vacuo to afford 13-Bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (3.75 g, 95% yield) as a yellow solid. LCMS (ESI) m/z: 309.1 [M+H+]
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(-c2cc(O)no2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: Cc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 80.7 %

Procedure:
3-Hydroxy-5-(4-methylphenyl)isoxazole (1.5 g) and 2-(N-tert-butoxycarbonylamino)ethanol (1.5 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (2.2 g, 82%) as a colorless powder.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3ccccc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (25 mg, 83%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 304 (base, M+H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[Se:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([N:32]([CH2:35][CH2:36][NH:37][NH2:38])[CH2:33][CH3:34])[CH3:31].Cl>CN(C)C=O.CC(O)C>[ClH:1].[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:35][CH2:36][N:37]1[C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]3[Se:7][C:8]4[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:38]1)[CH3:31]
Reactant: CCN(CC)CCNN
Reactant: O=c1c2ccc(O)cc2[se]c2c([N+](=O)[O-])ccc(Cl)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)[Se]c1cc(O)ccc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 1.59 g (0.004 mole) of 1-chloro-6-hydroxy-4-nitro-9H-selenoxanthen-9-one in 12 ml of N,N-dimethylformamide with 0.85 ml of diisopropylethyl amine is added 0.85 ml of 2-(diethylaminoethyl)hydrazine. The cooling bath is removed and the mixture is stirred at 25° C. for 2.5 hours. Concentration of the reaction in vacuo leaves an orange solid. Trituration of the solid with boiling 2-propanol gives an orange powder which is dried in vacuo at 80° C. to afford 1.66 g of the dry product as a salt with 1.0 equivalents of hydrogen chloride; mp 255°-257° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:19])[CH2:14][Si](C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:11][O:12][C:13](=[O:19])[CH2:14][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Br)cnc1[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-Bromo-2-nitro-pyridine (2.33 g, 11.5 mmol) and trimethylsilanyl-acetic acid methyl ester (1.8 g, 12.0 mmol) in THF (12 mL) is added at −78° C. a solution of dried TBAF (3.0 g, 11.5 mmol), obtained by drying TBAF×3 H2O (7.5 g) for 18 h at 70° C. under high vacuum, in a mixture of acetonitrile (6 mL) and THF (6 mL). The resulting deep red solution is stirred for 1 h at −40° C. TLC analysis indicated complete consumption of starting material. The reaction mixture is cooled to −78° C. and DDQ (2.6 g, 11.5 mmol) is carefully added. The black solution is slowly warmed to RT. Since TLC analysis indicated that no further changes occurred, the reaction mixture is partitioned between EtOAc and a saturated aq. NH4Cl solution. The layers are separated and the organic layer is washed with a saturated aqueous NH4Cl solution, brine, dried over Na2SO4 and concentrated at reduced pressure. The crude product is purified by FCC (cyclohexane/EtOAc 9:1 to 8:1) to afford the title compound as yellow needles. 1H NMR (CDCl3, 400 MHz): δ 3.94 (s, 3H), 4.17 (s, 2H), 8.20 (s, 1H), 8.78 (s, 1H).
Reaction SMILES: C1(SC2C3C=CC=CC=3SC=2I)C=CC=CC=1.[C:18]1([S:24][C:25]2[C:26]3[CH:38]=[C:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[CH:31][C:27]=3[S:28][C:29]=2I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:23]1[C:18]2[S:24][C:25]3[C:26]4[CH:38]=[C:37]5[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]5)=[CH:31][C:27]=4[S:28][C:29]=3[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: Ic1sc2cc3ccccc3cc2c1Sc1ccccc1
Agent: Ic1sc2ccccc2c1Sc1ccccc1
Product: c1ccc2cc3c(cc2c1)sc1c2ccccc2sc31
Yield: 91 %

Procedure:
Except that 3-(phenylsulfenyl)-2-iodobenzo[b]thiophene was replaced with 3-(phenylsulfenyl)-2-iodonaphtho[2,3-b]thiophene, the reaction was implemented in the same way as in Example 3. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that a yellow solid was produced (yield: 91%).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[C:26]1[C:31](C(Cl)=O)=[CH:30][CH:29]=[C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:27]1.[N:40]1[C:49]2[C:44](=[CH:45][C:46]([NH2:50])=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([C:31]2[C:26](=[O:25])[O:27][C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)=[O:17])[C@H:12]([C:22]([NH:50][C:46]2[CH:45]=[C:44]3[C:49](=[CH:48][CH:47]=2)[N:40]=[CH:41][CH:42]=[CH:43]3)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: Nc1ccc2ncccc2c1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)Nc2ccc3ncccc3c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=553.4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[CH3:16][CH:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH:18]=[CH2:19]>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([C:22](=[O:23])[CH2:21][O:20][CH:17]([CH:18]=[CH2:19])[CH3:16])[CH:7]=1
Reactant: C=CC(C)OCC(=O)N(C)OC
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=CC(C)OCC(=O)c1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 230 %

Procedure:
1,5-Dibromo-2,4-difluorobenzene (1.16 g, 4.28 mmol) was dissolved in Et2O (2 mL) and the solution was cooled to −78° C. nBuLi (1.26 mL 2.5M solution in hexanes) was added dropwise, maintaining the internal temperature below −70° C. Immediately after addition of nBuLi is complete, a solution of (±)-2-(but-3-en-2-yloxy)-N-methoxy-N-methylacetamide (0.5 g, 2.85 mmol) in Et2O (2 mL) was added dropwise, keeping the internal temperature below −70° C. The reaction was stirred at −78° C. for 15 minutes before quenching with saturated NH4Cl. The mixture was extracted with DCM (×3), dried (MgSO4) and concentrated in vacuo. The reaction was repeated a further 5 times on the same scale. The residues from all six reactions were combined and purified by column chromatography (Biotage SNAP 25 g 0-10% EtOAc in hexane) to leave the desired compound as a yellow oil (2 g). 1H NMR (400 MHz, CDCl3) δ ppm: 8.20 (t, J=7.46 Hz, 1H), 6.98 (dd, J=7.95, 10.15 Hz, 1H), 5.76 (ddd, J=7.70, 10.09, 17.42 Hz, 1H), 5.16-5.26 (m, 2H), 4.51-4.69 (m, 2H), 3.93-4.04 (m, 1H), 1.34-1.40 (m, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[Br:11].C([Sn](CCCC)(CCCC)[CH:18]=[CH:19][O:20]CC)CCC.O.C1C(=O)N([Br:39])C(=O)C1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:19](=[O:20])[CH2:18][Br:39])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(I)ccc1Br
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)CBr)ccc1Br
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
To the solution of 2-bromo-5-iodo-benzoic acid methyl ester (4.33 g, 12.7 mmol) and tributyl(ethoxyvinyl)stannane (4.79 g, 13.3 mmol) in dioxane (56 ml) was added PdCl2(PPh3)2 (322 mg). The mixture was heated at 80° C. for 17 hours and was cooled to 0° C. Water (19 ml) was added, followed by slow addition of NBS (2.33 g, 12.9 mmol) over 10 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc=2/1) gave 2-bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester (3.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:35][C:33](=[O:34])[NH:32][CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cccc(Cl)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc(Cl)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 8.6 %

Procedure:
A mixture of 1-(3-chlorophenyl)-2-phenylethanone (450 mg, 1.95 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (411 mg, 1.95 mmol), and urea (350 mg, 5.83 mmol) in anhydrous EtOH (15 mL) was added concentrated HCl solution (0.5 mL), the reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed that about 30% of starting materials were consumed, and the reaction mixture was concentrated. The residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 37 as a yellow solid (78.1 mg, yield: 8.6%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.20-7.25 (m, 2H), 7.02-7.7.13 (m, 5H), 6.85 (d, J=6.8 Hz, 2H), 5.25 (d, J=2.8 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]([CH:45]=[CH:46][CH:47]=2)[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([C:40]3[CH:44]=[CH:43][O:42][N:41]=3)[CH2:24]C(N3[C@@H](CC4C=CC=CC=4)COC3=O)=O)=[CH:19][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:50]O.[Li+].[OH-].Cl.C1[CH2:59][O:58]CC1>O>[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:13]=[C:14]([CH:45]=[CH:46][CH:47]=2)[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([C:40]3[CH:44]=[CH:43][O:42][N:41]=3)[CH2:24][C:59]([OH:58])=[O:50])=[CH:19][CH:18]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(C[C@@H](c1ccc(OCc2cccc(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCc2cccc(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1
Reaction time: 5 h

Procedure:
To a solution of the oxazolidinone (33.1) (106 mg, 0.154 mmol) dissolved in THF (7 mL), was added a 30% hydrogen peroxide solution (175 μL, 1.54 mmol) followed by a 2 M LiOH solution (383 μL, 0.765 mmol). The resulting slurry was stirred for five hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (3×30 mL), and the organic layer was washed with an acidic sodium sulfite solution (1×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 33 (52.0 mg). MS ESI (pos.) m/e: 532.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.22 (1 H, d, J=1.6 Hz), 8.00 (2 H, d, J=8.2 Hz), 7.94 (1 H, s), 7.83 (1 H, d, J=7.8 Hz), 7.70 (2 H, d, J=8.6 Hz), 7.59 (1 H, d, J=7.8 Hz), 7.48 (1 H, t, J=7.6 Hz), 7.12 (2 H, d, J=9.0 Hz), 6.82 (2 H, d, J=8.6 Hz), 6.00 (1 H, d, J=1.6 Hz), 5.00 (2 H, s), 4.48 (1 H, t, J=7.6 Hz), 3.27 (1 H, dd, J=16.8, 7.8 Hz), 2.90 (1 H, dd, J=16.6, 7.6 Hz).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:9][N:8]([C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH2:7]1)C.O.[NH2:17][NH2:18]>C(O)C>[CH:12]1([C:10]([N:8]2[CH2:9][CH:6]([CH2:5][C:4]([NH:17][NH2:18])=[O:3])[CH2:7]2)=[O:11])[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC1CN(C(=O)C2CC2)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CC1CN(C(=O)C2CC2)C1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In a round bottom flask equipped with reflux condenser under nitrogen, a solution of ethyl[1-(cyclopropylcarbonyl)-3-azetidinyl]acetate (0.433 g, 2.097 mmol) and hydrazine monohydrate (1.3 mL, 41.9 mmol) in ethanol (10 mL) was stirred at 80° C. for 16.5 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was then concentrated down from methanol and then toluene. The residue was dissolved in dichloromethane, filtered through sodium sulfate, and concentrated in vacuo to a colorless oil. The oil still looked wet and was too heavy, so it was dissolved again in dichloromethane and filtered through sodium sulfate, rinsing with additional dichloromethane. The combined organics were concentrated in vacuo and then concentrated under high vacuum pressure to yield the crude title product as a yellow oil (0.316 g, 86% pure, 66% yield). MS(ES)+ m/e 198.1 [M+H]+, 395.1 [2M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]1C=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[S:28][C:27]=1[C:35]([O:37][CH3:38])=[O:36].C(#[N:41])C>>[C:31]([C:29]1[S:28][C:27]([C:35]([O:37][CH3:38])=[O:36])=[C:26]([CH2:25][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)[C:2]=2[CH3:1])[N:41]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CBr
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1sc(C(C)(C)C)nc1CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (466.2 mg, 2.0 mmol) and cesium carbonate (782.0 mg, 2.4 mmol) were suspended in anhydrous acetonitrile (20 mL) and the mixture was cooled to 0° C. Methyl 3-(bromomethyl)-5-tert-butylthiophene-2-carboxylate (109c) (584.4 mg, 2.0 mmol) was then added. The resulting mixture was allowed to gradually warm to room temperature, then stirred at 40° C. overnight. The reaction mixture was filtered through Celite®, and the filtrate was concentrated. The residue was purified on silica eluted with a gradient of 0 to 10% Ethyl acetate in heptane to afford methyl 2-tert-butyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)thiazole-5-carboxylate (109d) (501.6 mg, 56%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[O:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCC1COc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
12.20 g (64 mmol) of p-toluenesulphonyl chloride are added at room temperature and while stirring to a solution of 10.81 g (60 mmol) of 2-(2-hydroxyethyl)benzo-1,4-dioxan in 35 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 15.50 g (77.2%) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan, which melts at 82°-84°, are obtained.