Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH2:3]1.[H-].[Na+].[CH2:21](Br)[CH3:22].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:9])[CH3:10])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][O:18][CH2:21][CH3:22])[CH3:15])[CH2:3]1
Reactant: CCBr
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCN(C)CCO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 19.3 %

Procedure:
2.57 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-hyd roxyethyl)-N-methylamine were dissolved in 100 ml of tetrahydrofuran. 0.48 g of a 50% strength sodium hydride dispersion was added at room temperature, and the reaction mixture was heated under reflux for 3 hours. A solution of 1.1 g of ethyl bromide in 20 ml of tetrahydrofuran was then added dropwise to the reaction solution at boiling temperature, and the reaction solution was heated under reflux for a further 6 hours. The reaction solution was worked up by adding 2 ml of water and concentrating the mixture under reduced pressure. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 0.55 g of oily N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-etho xyethyl)-N-methylamine was obtained. [α]D20 =-51.20° (c=1; methanol)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.Cl.[OH:34][CH:35]([C:37]1([OH:41])[CH2:40][NH:39][CH2:38]1)[CH3:36].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:39]2[CH2:40][C:37]([CH:35]([OH:34])[CH3:36])([OH:41])[CH2:38]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(O)C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (362 mg, 0.921 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (296 mg, 0.602 mmol, 65% yield): MS (EI) for C18H16F3IN2O3: 493 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SiH](CC)(CC)CC>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)OCC1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CCOCC2CCNCC2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
In a oven-dried flask, 4-[(phenylacetoxy)methyl]piperidine (53 mg, 0.23 mmol) and InBr3 (161 mg, 0.46 mmol) were dissolved in toluene (1.5 mL). After degassing and replacement of the atmosphere with Ar, Et3SiH (145 μL, 0.91 mmol, 4.0 equiv.) was added. The mixture was stirred at 90° C. for 4 h. After cooling to room temperature, the reaction was quenched with 1N HCl. The aqueous layer was washed with EtOAc, and its pH was raised to 9-10. After extraction with CH2Cl2, the organic layer was dried with Na2SO4. The solvent was removed to furnish 4-[(2-phenylethoxy)methyl]piperidine (30 mg, 59%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.22 (m, 5H), 3.61 (t, 2H, J=7.2 Hz), 3.26 (d, 2H, J=6.0 Hz), 3.07 (d, 2H, J=12.0 Hz), 2.87 (t, 2H, J=7.2 Hz), 2.59 (t, 2H, J=11.6 Hz), 2.31 (br, 1H), 1.70 (m, 3H), 1.09 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.Cl.[CH:13]1([C:16](=[NH:18])[NH2:17])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[NH:18][C:16]([CH:13]3[CH2:15][CH2:14]3)=[N:17][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N=C(N)C1CC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2cnc(C3CC3)[nH]2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 89.0 g (320 mmol) 2-bromo-1-(4-bromophenyl)ethanone in 2.0 L N,N-dimethylformamide were added cyclopropanecarboximidamide hydrochloride, 132.8 g potassium carbonate and the mixture was stirred at 23° C. overnight. After removal of the solvent, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by crystallisation to give 42.1 g (50%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[C:15]([C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Yield: 61.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzonitrile (350 mg, 1.45 mmol) and potassium carbonate (263 mg, 1.9 mmol) in anhydrous DCM (3 ml) was added dropwise phenyl chloroformate (0.91 ml, 7.3 mmol) as a solution in DCM (1.5 ml). The crude was purified by silica gel chromatography (DCM/EtOAc 6-50%) to afford phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (320 mg, 61%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 6.45 (s, 1H), 7.26-7.28 (m, 3H), 7.31-7.38 (m, 2H), 7.75-7.82 (m, 4H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCC2)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclobutylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31]C1C=C(N=C=O)C=CC=1.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1cccc(Cl)c1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 3-chlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 223°-227° C.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:7][CH2:8][NH2:9])[CH:2]([CH3:4])[CH3:3].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH:14](=[N:9][CH2:8][CH2:7][CH2:6][P:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)CP(CCCN)CC(C)C
Solvent: CCO
Product: CC(C)CP(CCCN=Cc1ccccc1)CC(C)C
Yield: 98 %

Procedure:
Under argon, a solution of 3-diisobutylphosphino-propylamine (428.5 mg, 2.11 mmol) and benzaldehyde (226.9 mg, 2.14 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless liquid (614.1 mg, 2.1 mmol, quantitative).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[CH:21]=2)[NH:16][CH:15]=1.C(OC(Cl)=O)C(C)C.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:35]1([NH:41][C:24](=[O:26])[CH2:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-[2-(1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (0.2 g) and triethylamine (0.061 g) in chloroform (10 ml) was treated with isobutylchloroformate (0.08 g) at -5°, resulting red solution stirred at the same temperature for 20 h and cyclohexylamine was added to the resulting anhydride (0.06 g). Reaction was allowed to warm up to ambient temperature and stirred for 1 h then the mixture was poured into dilute hydrochloric acid (2N, 20 ml) extracted with chloroform (3×10 ml), dried (MgSO4), solvent removed and residual oil purified by chromatography (silica Merck, 7734; 10 g; 1% methanol in dichloromethane as eluent). Product was obtained as an oil which on treatment with ethyl acetate/ether gave the title compound as a solid (0.09 g) m.p. 175°-6°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCc1cccc(Br)c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Brc1cccc(CNC2CCCCC2)c1
Reaction time: 18 h

Procedure:
Reaction of 1-bromo-3-(bromomethyl)benzene with cyclohexylamine following the method described in Example 9 except cesium carbonate was used as base and at 90° C. for 18 h gave N-(3-bromobenzyl)cyclohexylamine as a white solid. Yield (0.70 g, 65%): 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J=1.6 Hz, 1H), 7.38-7.41 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 3.73 (s, 2H), 2.38-2.46 (m, 1H), 1.92-1.95 (m, 2H), 1.70-1.78 (m, 2H), 1.58-1.66 (m, 1H), 1.06-1.30 (m, 5H).
Reaction SMILES: C([C:3]1[C:8]([Br:9])=[CH:7][C:6]([Br:10])=C[N:4]=1)#N.[C:11]([OH:14])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O>[Br:10][C:6]1[C:12]([C:11]([OH:14])=[O:13])=[N:4][CH:3]=[C:8]([Br:9])[CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(Br)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ncc(Br)cc1Br
Temperature: 140 °C

Procedure:
2-Cyano-3,5-dibromopyridine (prepared in the above (2)) 3.27 g is added to a mixture of acetic acid 14 ml, sulfuric acid 14 ml and water 14 ml, and the mixture is refluxed at 140° C. for 4 hours. The reaction mixture is cooled and water is added thereto. The resulting precipitate is filtered and washed with water. The precipitate is dissolved in ether, washed and dried. The solvent is removed in vacuo and crystallized from a mixture of ether and hexane to give 3,5-dibromopyridine-2-carboxylic acid. mp 170–171° C.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1.[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:11](=[O:13])[C@@H:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([I:10])=[CH:8][CH:9]=2)[CH2:30][CH2:29]1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2ccc(I)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.5 Boc-Phe(4-I)-OH replacing 2-phenoxyphenylboronic acid and piperazine-1-carboxylic acid butyl ester replacing intermediate 8.4.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[Cl:35]>CO.O1CCCC1>[Cl:35][C:7]1[CH:8]=[C:9]([NH:12][C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:11][C:6]=1[C:5]([OH:36])=[O:4]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCC2
Reaction time: 16 h

Procedure:
3 M Potassium hydroxide solution (2 ml) was added to a solution of crude 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester (0.097 g, 0.13 mmol) in MeOH (2 ml) and tetrahydrofuran (1 ml) and the mixture stirred for 16 hours. The organic solvent was evaporated and the solution neutralized with 3 M HCl solution (3 ml) forming a white precipitate. The precipitate was filtered and washed with heptane. The solid was then dried under vacuum to give 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, 0.037 g, as a red solid. LC @215 nm; Rt 2.06: 98%, m/z (ES+): 489.23 (M+H+.); δH (400 MHz; d6-DMSO) 13.18 (1H, br.s), 10.63 (1H, s), 8.22 (1H, d), 8.08 (1H, d), 7.83-7.91 (2H, m), 7.76 (1H, dd), 7.55-7.67 (2H, m), 7.43-7.48 (2H, m), 7.30 (1H, d), 3.84 (2H, m), 2.52 (2H, m), 1.62 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH2:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH:37][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Yield: 47.7 %

Procedure:
5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][Cl:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N(N)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(NCl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of a benzoylhydrazinecarboxylic acid tert-butyl ester (Example 7) in acetic acid (5 mL) is added N-chlorosuccinimide (1.2 eq.). After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (ethyl acetate/hexanes) to afford the corresponding chloro-benzoylhydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>CCOCC>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)cc1
Reaction time: 8 h

Procedure:
The product from (b) (2.9g;0.009 mole) was stirred in anhydrous ether (50ml) at room temperature and reacted with methanesulphonyl chloride (0.68ml) in the presence of triethylamine (1.2ml). The mixture was stirred overnight, then the ether was evaporated to give a solid which was partitioned between water/chloroform. The chloroform extract was washed with saturated sodium chloride solution and evaporated to give the desired compound as a highly crystalline solid which was recrystallised from ethyl acetate, m.p. 178° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:7]=O)[CH:2]=[CH2:3].[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc(CC=C)c1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCc1cc(C=C2SC(=S)NC2=O)cc(CC=C)c1O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
3,5-di-(2-propenyl)-4-hydroxybenzaldehyde (50.5 g), 36.6 g of rhodanine and 164 g of sodium acetate were heated together at reflux temperature in 1.25 liter of acetic acid for 14.5 hours. The resultant solution was cooled, poured into 2 liter of ice water to yield, upon separation, about 75 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl)-methylene]-2-thioxo-4-thiazolidinone, m.p. 157°-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].O=[CH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:14]([O:15][CH3:16])[C:12]=1[OH:13].OO.Cl>CCO>[OH:13][C:12]1[C:14]([O:15][CH3:16])=[CH:17][CH:18]=[CH:19][C:11]=1[C:10]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1cccc(C=O)c1O
Reactant: Nc1ccccc1S
Agent: Cl
Agent: OO
Solvent: CCO
Product: COc1cccc(-c2nc3ccccc3s2)c1O
Yield: 79 %

Procedure:
HMBT was synthesized according to a previous reported method with minor modifications (Guo et al., Chin. Chem. Lett. 2009, 20, 1408-1410. A solution of 2-aminothiophenol (0.3 mL, 4.2 mmol) and o-vanillin (0.48 g, 3.15 mmol) in EtOH (10 mL), aq H2O2 (30%, 18.9 mmol) and aq HCl (37%, 9.45 mmol) was stirred at room temperature for 90 min. The solution was quenched by 10 mL H2O. The precipitate was filtered, dried under vacuum and recrystallized from EtOH to afford the desired product as a light yellow solid (0.64 g, 79% yield). 1H NMR (CDCl3, 400 MHz), δ (ppm): 12.75 (s, 1H), 8.01 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.2 Hz), 7.51 (t, 1H, J=6.8 Hz), 7.42 (t, 1H, J=7.2 Hz), 7.33 (dd, 1H, J1=1.2 Hz, J2=8.0 Hz), 6.99 (dd, 1H, J1=1.2 Hz, J2=8.0 Hz), 6.91 (t, 1H, J=8.0 Hz), 3.96 (s, 1H). 13C NMR (CDCl3, 100 MHz), δ 169,74, 151.86, 149.13, 148.29, 136.47, 132.70, 126.80, 125.66, 122.36, 121.59, 120.11, 119.23, 116.86, 114.21, 56.36. ESI-FTMS m/z=258.0587 [M+H]+, calc. 258.0589 for C14H12NO2S.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][NH2:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([NH:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])=[N:15][CH:16]=1
Reactant: CCCCc1noc(C)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Temperature: 160 °C
Yield: 48.6 %

Procedure:
C-(3-Butyl-5-methyl-isoxazol-4-yl)-methylamine (320 mg, 1.90 mmol) was dissolved in DMSO (3 mL), methyl 6-chloronicotinate (326 mg, 1.90 mmol) and N,N-diisopropylethylamine (492 mg, 3.80 mmol) added, and the reaction mixture heated under microwave irradiation at 160° C. for 1 h. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (280 mg, 49%) as a white solid. MS: m/e=348.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>CN(C)C=O.O>[C:10]1([C:7]2[C:6]3[CH:16]=[C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]4=[CH:4][C:5]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Oc1cc2onc(-c3ccccc3)c2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1Oc2cc3onc(-c4ccccc4)c3cc2O1
Reaction time: 2.5 h
Yield: 55.3 %

Procedure:
A mixture of 5,6-dihydroxy-3-phenyl-1,2-benzisoxazole (2.9 g), potassium carbonate (10.7 g) and methyl dichloroacetate (3.7 g) in 50 ml of N,N-dimethylformamide was stirred at 90°-100° C. for 2.5 hours. After cooling, water (50 ml) was added to the mixture followed by stirring it at 90°-100° C. for 40 minutes. After cooling and acidifying the mixture with hydrochloric acid, the mixture was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was washed with methylene chloride, recrystallized from acetone/water to give 2.0 g of 3-phenyl-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 202.5°-203.5° C.