Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>CC#N.C(Cl)Cl.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of compound 1I (3.3 g, 9.97 mmol) in 10% CH3CN in CH2Cl2 (50 mL) at rt was added NMO (3.0 g, 25.6 mmol) followed by tetrapropyl ammonium perruthenate (300 mg, 0.85 mmol). After a mild exotherm, the reaction was stirred at rt for 4 h. The reaction was diluted with hexane (50 mL), mixed well and filtered through a plug of silica gel (˜50 g). The silica plug was washed liberally with 30% EtOAc in hexane (500 mL). Solvents were removed under vacuum. Purification by flash chromatography (silica gel, 0-15% EtOAc in hexanes) provided the title compound (2.94 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23](C4C=CN=CC=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=NN([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)C=2)O1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(-c3ccccn3)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccncc3)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccccn3)c2)c2ccc(F)cc21
Yield: 62 %

Procedure:
Following the general method as outlined in Intermediate 10, starting from 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine (Intermediate 14; 485 mg; 1.80 mmol), 234 mg (62%) of the title compound was obtained as a yellow solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:67]([CH2:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]1)[CH2:68][CH3:69])[CH2:64][CH2:65][CH3:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][N:67]([CH2:63][CH2:64][CH2:65][CH3:66])[CH2:68][CH3:69])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCCCN(CC)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-butyl-N-ethyl-C-(piperidin-2-yl)-methylamine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:8]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Yield: 65.4 %

Procedure:
tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.2 g, 4.8 mmol) and methyl thiosalicylate (1.6 g, 9.9 mmol) were dissolved in toluene (10 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.2 g, 66%)
Reaction SMILES: C([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:5]1)(O)=O.S(Cl)(Cl)=O.[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:41]([O:37][C:22]([NH:21][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:17][CH:16]=2)[CH2:5]1)=[O:31])[C:40]1[CH:13]=[CH:4][CH:5]=[CH:38][CH:39]=1
Reactant: O=C(Nc1ccc(C(=O)N2CC(C(=O)O)Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To 3-carboxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.7 g) are added tetrahydrofuran (50 ml) and thionyl chloride (5 ml). The mixture is reacted at 60° C. for 1 hour. The reaction mixture is concentrated and to the residue is added acetone (20 ml). To the mixture is added dropwise a solution of sodium azide (1.0 g) in water (5 ml) under ice-cooling. The reaction mixture is stirred at the same temperature for 30 minutes and extracted with dichloromethane, dried over magnesium sulfate. The solvent is concentrated and to the resulting residue are added anhydrous toluene (30 ml) and benzyl alcohol (1.7 g). The mixture is refluxed for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl)-1,2,3,4-tetrahydroquinoline (3.7 g) as colorless amorphous.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH:15]([NH2:17])=[O:16].C(O)=O.O>C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][CH:15]=[O:16])=[CH:4][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: NC=O
Reactant: COc1ccc(C=O)cc1C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(CNC=O)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 9 h

Procedure:
A mixture of 5.8 g 3-trifluoromethyl-p-anisaldehyde, 8.6 ml formamide, and 13.6 ml formic acid was stirred at 130° C. for 9 hr. After cooling, water and ethyl acetate were added thereto. The ethyl acetate layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography to give 3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:30]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:30]=[C:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)cc1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.14 mg; 0.50 mmol) and methyl 4-[amino(hydroxyimino)methyl]benzoate (Maybridge; 97.10 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method A): 385.0 (M+H)+. HPLC (Method A) Rt 6.16 min (Purity: 98.5%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.[CH3:41][S:42]([CH2:45][CH2:46][O:47][C:48](ON1C(=O)CCC1=O)=[O:49])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[O:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CCOC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCOC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (64.1 mg) and triethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), 1-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (45.6 mg) was added, and the mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=95:5). Crystallization from diethyl ether/hexane gave the title compound (61.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:14])[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28].N>CCO.C(Cl)Cl.CO.C(Cl)Cl>[O:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])[CH:3]=2)[N:8]1[CH2:12][CH:13]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:14]
Reactant: CC(CN1C(=O)CCc2cc(N)ccc21)N1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(CN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (240 mg, 0.88 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (501 mg, 1.76 mmol) and stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (10 mL) and argon was bubbled through the solution for 20 minutes. The solution was partitioned between CH2Cl2 (100 mL) and saturated sodium carbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow which was subjected to flash chromatography on silica gel using 2% MeOH/CH2Cl2 then 5-10% 2M NH3 in MeOH/CH2Cl2. A yellow solid was obtained (200 mg, 59.4%). 1H-NMR (DMSO-d6) δ: 7.71 (d, J=3.6 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.08-7.06 (m, 2H), 6.72-6.71 (m, 2H), 6.41 (br s, 2H), 4.05 (dd, J=9.0, 13.8 Hz, 1H), 3.83 (dd, J=4.8, 13.8 Hz, 1H), 2.79-2.75 (m, 3H), 2.54-2.47 (m, 6H), 1.63 (br, 4H), 0.87 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(O)=O)[CH2:9][CH:8]([CH3:10])[CH2:7]1)=[O:5])[CH3:2].C([N:16](CC)CC)C.[Cl:21]C(OCC(C)C)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(OCC)C>[ClH:21].[CH2:1]([O:3][C:4]([C:6]1([NH2:16])[CH2:9][CH:8]([CH3:10])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)O)CC(C)C1
Reactant: CCN(CC)CC
Reactant: CC(C)COC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1(N)CC(C)C1
Product: Cl
Reaction time: 0.25 h

Procedure:
3-Methyl-cyclobutane-1,1-dicarboxylic acid ethyl ester (V. Prelog et al., Helv. Chim. Acta 65 (1982), 2622-2644; 200 mg, 1.074 mmol) was suspended in acetone (20 ml) and stirred in an ice bath. Triethylamine (152 mg, 1.50 mmol) and isobutyl chloroformate (191 mg, 1.40 mmol) were added, the mixture was stirred at 0° C. for 30 min, then sodium azide (129 mg, 1.99 mmol) as solution in water (10 ml) was added, and stirring was continued for 15 min. Then diethyl ether (50 ml) was added, the phases were separated. The organic layer was washed with water, dried over sodium sulfate, filtered and added to refluxing toluene in a flask with distillation bridge. The toluene solution was refluxed for 4 h, the volatiles were evaporated in vacuo, the residue was dissolved in dioxane, 2 N hydrochloric acid was added in excess, and the mixture was stirred until the isocyanate was completely decomposed (approximately 20 min). The volatiles were evaporated and the obtained amino acid ester hydrochloride was used without further purification.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](O)(=[O:24])[C:15]1[CH:23]=[C:21]([OH:22])[C:19]([OH:20])=[C:17]([OH:18])[CH:16]=1>S(=O)(=O)(O)O>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[C:15]1[CH:16]=[C:17]([OH:18])[C:19]([OH:20])=[C:21]([OH:22])[CH:23]=1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCOC(=O)c1cc(O)c(O)c(O)c1
Temperature: 55 °C

Procedure:
Lauryl alcohol in the amount of 294.4 g was heated in a flask of 1 L to a temperature of 60° C. One hundred grams (100 g) of gallic acid was added (purity 90%) together with 1 ml of sulfuric acid (96%) as a catalyst. The mixture was submitted to reaction in a Rotavapor at a temperature of approximately 160° C. and a vacuum of −0.4 bar. While reacting, the azeotropic water/lauryl alcohol was distilled off. Approximately 5 to 6 hours were needed for completion. The percent of remaining gallic acid was controlled by HPLC. When the remaining gallic acid was less than 1%, the process can be taken to the next step. The distilled azeotropic water/lauryl alcohol mixture was separated by means of a separation funnel and the lauryl alcohol can be re-used after quality control by GC. The remaining reaction mixture was cooled down to approximately 55° C., while stirring. In another flask of 2 L with reflux cooler and stirrer, 1 L of petroleum ether (Bp. 40-60° C.) was heated to approximately 55° C. When both the petroleum ether and the reaction mixture had the same temperature (approximately 55° C.), the reaction mixture was slowly added to the petroleum ether while stirring. The mixture of the reactants and the petroleum ether was cooled down over a period of approximately 5 hours to room temperature (hour 0, temp. 55° C.; h. 0.5, temp. 60° C.; h. 1, temp. 55° C.; h.2, temp. 45° C.; h3, temp. 35° C.; h. 4, temp. 25° C.; h. 5, temp. 25° C.). The lauryl gallate crystallized and was filtered via a vacuum sucked glass filter. Solid impure lauryl gallate and filtrate A (lauryl gallate, lauryl alcohol, petroleum ether) were obtained. The solid impure lauryl gallate was mixed again with 0.5 L of petroleum ether (Bp. 40-60° C.), but this time at room temperature. Again, this mixture was filtered by a vacuum sucked glass filter. This time pure lauryl gallate and filtrate B (lauryl gallate, lauryl alcohol, petroleum ether) were obtained. Filtrate A and B were combined and the petroleum ether was recovered via vacuum distillation with a Rotavapor (temp. 60° C., −0.4 Bar). After quality control, the petroleum ether could be re-used. The residue was also checked for remaining lauryl gallate and lauryl alcohol by HPLC and GC, it can be re-used at the start of a next batch. Drying of the pure lauryl gallate for 24 hours at approximately 60° C. and at a vacuum of −0.4 Bar in a vacuum oven, yields crystalline lauryl gallate. Lauryl gallate was obtained as a crystalline silver white powder with a purity of 81.35%. The conversion rate was rather good as only 0.2% of gallic acid was found remaining in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]([O:2][CH3:1])=[O:12])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1I
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
α-Bromo-benzeneacetic acid methyl ester (0.0123 mol) was added at room temperature to a mixture of intermediate (28) (0.0123 mol) and Na2CO3 (0.0123 mol) in DMF (50 ml). The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with diethyl ether and dried, yielding 5.8 g of 4-[4-[(2-iodobenzoyl)amino]phenyl]-α-phenyl-1-piperazine-acetic acid, methyl ester (intermediate 29).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:29]2[O:33]C(C)(C)O[C:30]2=[O:36])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:37][OH:38].O>CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@@H:13]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)=[O:15])[C@H:29]([OH:33])[C:30]([NH:37][OH:38])=[O:36])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(CCc3cccs3)CC2)[C@@H]2OC(C)(C)OC2=O)cc1
Reactant: NO
Solvent: CC(C)O
Solvent: O
Product: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(CCc3cccs3)CC2)[C@H](O)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of (5S)-5-[(1R)-4-(4-ethoxyphenyl)-1-({4-[2-(2-thienyl)ethyl]-1-piperazinyl}carbonyl)butyl]-2,2-dimethyl-1,3-dioxolan-4-one (101 mg, 0.20 mmol) in iPrOH (3 mL) was added a 50% aqueous solution of hydroxylamine (60 μL) and the resulting mixture was stirred at RT for 1 hour. Then water (12 mL) was added and the resulting mixture was purified by reverse-phase chromatography (using a mixture of water and iPrOH with a ratio from 4:1 to 1:1 as eluent) to give 40 mg (42%) of the title compound as a white powder. M−(ESI): 488.4; M+(ESI): 490.4. HPLC, Rt: 2.5 min (purity: 97.0%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1
Yield: 47.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 g, 14.8 mmoles), K2CO3(3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5 mmoles) in acetonitrile (60 ml) was heated at reflux for 4 hr. The solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (SiO2. 60 g; eluted with 1% methanol in dichloromethane, methane 1liter). The purest fractions were combined and gave 2.8 g, 48% of 1-[4-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propoxy)phenyl]ethanone, m.p.=111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2ccc(NC(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 65 °C
Yield: 20.6 %

Procedure:
A suspension of 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.10 mmol) obtained in Example 1, (3) in anhydrous tetrahydrofuran (10 mL) was added with phenyl isocyanate (27 μL, 0.25 mmol), the mixture was refluxed by heating at 65° C. for 4 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain the title compound (9 mg, yield 21%) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21](=[NH:23])[S:22][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSC(=N)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 23 %

Procedure:
{2-[2-(4-Bromo-phenyl)-ethylamino]-benzothiazol-6-yl}-thiourea (Example 39, 51.3 mg, 0.126 mmol) was dissolved in dry DMF (0.5 mL). Ethyl iodide (11 μl, 1.1 eq) was added and the yellow solution stirred at room temperature for 23 hours. The solution was diluted with ethyl acetate (10 mL) and extracted with ice water (2 mL) followed by ice cold brine (3×2 mL). The product was dried over MgSO4, filtered and concentrated to give a yellow oil. The product was purified by chromatography on silica gel (5% 2M ammonia/methanol in CH2Cl2) to give the isothiourea (12.5 mg, 23%). The product was dissolved in methanol (1.0 mL) and acidified with 1.0 M HCl in ether (4 mL). The orange precipitate was collected by filtration and washed with hexanes (6.0 mg, 10%). MS (M+1, 435, 437).