Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C.NO>[Fe].O>[N:13]1([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: [Fe]
Agent: NO
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
1-(4-Nitro-benzenesulfonyl)-piperidine (30 g) was mixed with iron powder (50 g), ammonium chloride (50 g), ethanol (200 ml) and water (50 ml). The mixture was heated under reflux conditions for 2 h. LCMS showed that the reduction goes through a hydroxylamine intermediate. The mixture was filtered through Celite while hot and the iron residues washed with warm ethanol, ethyl acetate, water and dichloromethane. All volatiles were removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic solution was separated and washed with brine, dried over MgSO4 concentrated to give 4-(piperidine-1-sulfonyl)-phenylamine, 23 g. 1HNMR CDCl3 7.43 (2H, d), 6.67 (2H, d), 3.33 (2H, bs), 2.84 (4H, t), 1.53 (4H, m), 1.31 (2H, m)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[S:16][CH3:17])[NH:5][C:4]=2[CH:3]=1.S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[S:16][CH3:17])[NH:5][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CSc1cccc2c1Sc1ccc(O)cc1N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Yield: 50.5 %

Procedure:
2-Methoxy-6-methylthiophenothiazine (m.p. 152°-154°C.; 20.1 g.) is prepared by methylation of 2-hydroxy-6-methylthiophenothiazine (37.8 g.) by means of dimethyl sulphate (22.2 g.) in the presence of sodium carbonate (30.1 g.) in acetone.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)C.[O-]CC.[Na+].C(OC(C)C)(C)C>CN(C=O)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>[CH3:31][CH:28]1[CH2:29][CH2:30][CH:25]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]4[S:12][C:8]([C:5]5[CH:6]=[CH:7][C:2]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:3][CH:4]=5)=[N:9][N:10]=4)=[CH:14][CH:15]=3)[CH2:20][CH2:21]2)[CH2:26][CH2:27]1
Reactant: CCOC=O
Reactant: CC1CCC(N2CCN(c3ccc(-c4nnc(-c5ccc(I)cc5)s4)cc3)CC2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nnc(-c3ccc(N4CCN(C5CCC(C)CC5)CC4)cc3)s2)cc1

Procedure:
To a suspension of 1-[4-[5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl]phenyl]-4-(4-methylcyclohexyl)piperazine (2 g) in DMF (40 ml) was successively added ethyl formate (0.56 ml), dichlorobis(triphenylphosphine)palladium(II) (0.52 g) and 20% sodium ethoxide ethanol solution (4.43 ml) with stirring and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was added diisopropyl ether (600 ml). The resulting precipitate was collected by filtration. The precipitate was dissolved THF (200 ml), insoluble materials were filtered off and solution was concentrated in vacuo. The resulting residue was washed with acetonitrile, and dried to give ethyl 4-[5-[4-[4-(4-methylcyclohexyl)-1-piperazinyl]phenyl]-1,3,4-thiadiazol-2-yl]benzoate (1.07 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(N)c1N
Reaction time: 36 h
Yield: 100.1 %

Procedure:
To a slurry of 2-amino-4-methyl-3-nitropyridine (10.0 g, 65.3 mmol) in 350 mL of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours. Filtration and evaporation gave 8.05 g of a black solid which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.CC1C=CC(S(O[CH2:21][C@@:22]2([CH3:25])[CH2:24][O:23]2)(=O)=O)=CC=1.C(OCC)(=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:21][C@:22]2([CH3:25])[CH2:24][O:23]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Yield: 67.8 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.51 g, 10.17 mmol) and (R)-2-methyloxiran-2-ylmethyl 4-methylbenzene sulfonate (3.70 g, 15.25 mmol) were suspended in acetonitrile (150 ml). Benzyl(triethyl)ammonium chloride (0.23, 1.02 mmol) was added to this suspension, and the resulting mixture was stirred under reflux for 10 hours. After the reaction mixture was allowed to return to room temperature, ethyl acetate was added to the solution. The resulting mixture was washed with an aqueous sodium hydrogencarbonate, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (40 ml). DBU (1.57 ml, 10.17 mmol) was added to the solution with cooling on ice-bath, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3) to afford (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole (1.50 g, yield 68%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH3:23])[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2c(C)n(C)c3cc(Cl)ccc23)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.0752 g, 0.23 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide solution (0.500 mL, 0.5 mmol, 1.0M in hexanes) was added. After 1 hour, iodomethane (11 μL, 0.18 mmol) was added and the reaction was allowed to warm to room temperature over 30 minutes then submitted to aqueous workup. Purification by silica gel chromatography (0-100% EtOAc in hexanes) provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][CH2:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Br:1])=[CH:15][CH:14]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNCc2cc(Cl)ccc2Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.70 g, 6 mmol) in ACN (10.0 mL) was added p-methoxybenzyl amine (0.91 g, 6.6 mmol) and potassium carbonate (2.08 g, 15.0 mmol) and the overall mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was diluted with water (10 mL) and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (10 mL×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was washed with hexanes to obtain the desired product N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine as a pale yellow solid. MS m/e 340 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[N:10]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]([C:19]1([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.[NH4+].[Cl-]>[CH3:15][O:16][C:17]([C:19]1([C:25]2[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([O:31][CH2:2][C:3]3[CH:12]=[C:11]4[C:6]([C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[N:10]4)=[CH:5][CH:4]=3)[CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: COC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Reactant: Clc1cc(Cl)c2ccc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Bromomethyl-2,4-dichloro-quinoline (1.4 g, 4.8 mmol), 4-(3-Fluoro-5-hydroxy-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (5a, 1.2 g, 4.8 mmol), and cesium carbonate (3.1 g, 9.6 mmol) were suspended in DMF (20 mL) and stirred overnight at room temperature. The mixture was diluted with EtOAc and saturated NH4Cl, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 5b.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: C1COCCN1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(N3CCOCC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C

Procedure:
A mixture of 4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3689 mmol), morpholine (321.7 uL, 3.689 mmol), DIPEA (642.6 uL, 3.689 mmol) in DMF (4 mL) were mixed in sealed tube under an atmosphere of argon and heated at 90° C. for 4 days. The crude material was purified by MDP directly under basic conditions the desired product. MS (ES+): m/z 278.24 (100) [MH+]; HPLC: tR=0.81 min (UPLC, analytical).
Reaction SMILES: [K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[F:14][C:15]([F:27])([C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH2:16][OH:17].[O-]Cl.[Na+].S(=O)(=O)(O)[OH:32]>CC#N.O>[F:14][C:15]([F:27])([C:18]([F:25])([F:26])[C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])[C:16]([OH:32])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C

Procedure:
5.2 ml water, 19 ml MeCN, 0.34 g KBr, TEMPO (0.12 g), and 6 g of 2,2,3,3,4,4,5,5-octafluoro-pentan-1-ol were placed in a 100 mL glass flask equipped with a dropping funnel and stirrer. 45 mL of 15% (wt) aq. NaOCl buffered to pH 8-9 were added via the dropping funnel in 3 portions over two days while stirring at room temperature. Then concentrated sulphuric acid were added to render the reaction mixture acidic. (pH 1-2). The reaction mixture was extracted three times with diethyl ether and the combined organic phases were dried over magnesium sulphate. The solvent was evaporated to give a colorless liquid (8.98 g), which was distilled using a water pump (15 mmHg, 73° C.) to give 5.13 g of the acid. Yield: 80%. 1H NMR (CDCl3): 6.08 (tt, J=52 Hz, J=5.3 Hz, 1H); 8.6 (s, 1H); 19F NMR (CDCl3): −120.6 (t, J=9.2 Hz, 2F); −125.81 (m, 2F); −130.61 (m, 2F); −138.4 (dm, J=52 Hz, 2F).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccccc1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine (which was obtained in Intermediate 23) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp>205° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.70 (m, 9 H), 3.70-4.00 (m, 7 H), 4.95 (brs, 1 H), 6.64-6.94 (m, 3 H), 7.01(d, J=8.9 Hz, 2 H), 7.27-7.30(m, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 262.0 ((M+2H)2+, 100%); 523.0 (MH+, 10%); HRMS Calcd. for C27H35N6O3S (MH+): 523.2491. Found: 523.2511.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].CCCC(C)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Trans-(4-Formyl-cyclohexyl)carbamic acid tert-butyl ester (3.27 g, 14.38 mmol) and aniline (1.98 mL, 15.81 mmol) are dissolved in dichloromethane (60 mL) at room temperature. Sodium triacetoxyborohydride (4.57 g, 21.57 mmol) is added in one portion and the mixture is stirred at room temperature for 2.5 hours. 1N sodium hydroxide solution (20 mL) is added and the mixture is stirred at room temperature for a further 10 minutes. The DCM layer is separated and washed successively with water and saturated brine, dried (MgSO4), filtered and evaporated to give a colourless solid. This is slurried with iso-hexane, filtered and dried to give a colourless solid; [MH+ 305]
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:25]1C=CC(S(OC)(=O)=O)=CC=1)([O-])=O.O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:8]([CH3:25])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)cc2ccc(Br)cc12
Reactant: COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Cl)c2)cc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
7-Bromo-3-(3-chlorophenyl)isoquinolin-1(2H)-one (Intermediate 23A) (0.1 g, 0.299 mmol) was dissolved in THF (4 mL), under an atmosphere of nitrogen. Sodium hydride (0.018 g, 0.448 mmol) was added and reaction stirred for 30 minutes. The reaction was then cooled using an ice bath and methyl 4-nitrobenzenesulfonate (0.065 g, 0.299 mmol) was added. The reaction was allowed to warm to room temperature and left to stir overnight. Water was added to the reaction mixture and extracted with EtOAC (×2). The organics were combined and washed with brine, dried (MgSO4) filtered and concentrated under reduced pressure. The mixture was purified on silica (25 g column on Isolera 4) eluting with 0-10% methanol in dichloromethane to afford 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1(2H)-one (51 mg, 0.15 mmol).
Reaction SMILES: C([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7](CCCC)[C:5]1=[O:6])C=C.[BH4-].[Na+]>O.C1COCC1.[OH-].[Na+].C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[NH:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[NH:7][C:5]1=[O:6]
Reactant: C=CCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Hg+2]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reaction time: 0.17 h

Procedure:
16 g (0.050 mole) of mercury (II) acetate are dissolved in 250 ml water. 12.4 g (0.05 mole) of 1-allyl-3-butyl xanthine (prepared as described above from 1-butyl-5-formylamino-6-aminouracil and allyl bromide) dissolved in 250 ml of THF are added dropwise with stirring over a period of 10 minutes. After a few minutes, a precipitate is formed. Stirring is continued for 30 minutes, after which the mixture is cooled in an ice bath. 68 ml of 3 N NaOH are added, followed by the dropwise addition of 60 ml of a freshly prepared 0.5 M solution of NaBH4 in 3 N NaOH. On completion of the addition, stirring is continued for another 15 minutes. The solution is neutralized to pH 4-5 with 6 N HC1 (approximately 60 ml), saturated with NaC1 and the xanthine extracted with dichloromethane (3×200 ml). The organic extract is dried and the solvent is evaporated: 12.9 g of crude product containing 20% of starting product. The products are separated by passing the mixture through a column of silica using chloroform as eluent for the starting product and chloroform/methanol (95/5) for the hydroxylated xanthine (9.5 g) . The xanthine is recrystallized twice from water: 8.5 g (64%); Mp. 157-158° C.
Reaction SMILES: [B:1]([OH:28])([OH:27])[C@@H:2]([NH:7][C:8]([C@@H:10]([NH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:26]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.NCC[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1.P(O)(O)([O-])=O.[Na+].[OH-].[Na+]>>[B:1]([OH:28])([OH:27])[C@@H:2]([NH:7][C:8]([C@@H:10]([NH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:26]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:35]1([C:37](=[CH:39][CH:40]=[CH:33][CH:34]=1)[OH:38])[OH:36]
Reactant: NCCc1ccc(O)c(O)c1
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B(O)O
Agent: Cl
Agent: O=P([O-])(O)O
Product: Oc1ccccc1O

Procedure:
Bortezomib and dopamine hydrogen chloride were dissolved separately in d6-DMSO 0.2 M concentration. The two solutions were mixed to give a stock solution of DA-BTZ conjugate at 0.1 M in DMSO. A solution of 0.1 M monosodium phosphate in D2O was used to dilute the DA-BTZ stock to 1 mM, and pH of such solutions were adjusted with 4N NaOH in D2O to 5.5, 6.5, 7.4 and 8.5. These solutions were analyzed on AVANCE III 500 MHz (FIG. 6) and peak integrals in the range of 7.2 to 5.5 ppm were used for quantifying the degree of dissociation of DA-BTZ presented in FIG. 3B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(N)cccc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-(2-Amino-6-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.53 mmol) in CH2Cl2 was treated with 62 L (0.80 mmol, 1.5 eq) of methanesulfonyl chloride and 148 L (1.06 mmol, 2 eq) of triethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc (40 mL) and sat. NaHCO3 (20 mL) were added. The organic layer was separated and washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and concentrated. Column chromatography (silica, 0-5% acetone/CH2Cl2) provided 145 mg (70%) of 4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 5% acetone/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C16H24ClN3O4S, 389.12; m/z found, 388.1 (negative). 1H NMR (400 MHz, CDCl3): 7.41 (dd, J=8.2, 1.6 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 4.25-3.91 (m, 2H), 3.66-3.52 (m, 2H), 3.01 (s, 3H), 3.01-2.84 (m, 2H), 2.70-2.56 (m, 2H), 2.55-2.43 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7]C[S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:10](=[O:12])[CH2:9][CH:8]3[CH2:7][S:5][C:4]4[S:13][CH:14]=[CH:15][C:3]=4[C:2]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1CC2CSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 33.2 %

Procedure:
A mixture of 3.7 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 2.6 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 6.5 hours. Then, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in 40 ml of acetic acid and the mixture is further refluxed under heating for 1.5 hours. After cooling, the mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.7 g of 2-(4-chlorophenyl)-4,4a, 5,6-tetrahydrothieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 134°-135° C.