Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH:13]=O)[C:8]#[N:9].[C:15](=[O:20])([O:17][CH2:18][CH3:19])[NH2:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:12]([CH:13]([NH:16][C:15](=[O:20])[O:17][CH2:18][CH3:19])[NH:16][C:15](=[O:20])[O:17][CH2:18][CH3:19])=[C:5]([F:4])[CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: CCOC(N)=O
Agent: [Ca+2]
Agent: [Cl-]
Product: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1F
Temperature: 150 °C
Reaction time: 3 h

Procedure:
In a three-necked round bottom flask equipped with a drying tube filled with calcium chloride and an inlet for nitrogen, 3-fluoro-4-formylbenzonitrile (5.00 g, 33.5 mmol) and ethyl carbamate (6.57 g, 73.7 mmol) are heated at 150° C. The flask is being purged with a flow of nitrogen, and concentrated sulfuric acid (200 μL) is added drop by drop within 10 min. The mixture is heated at 150° C. for 6 h and then cooled at room temperature. The mixture is ground, treated with water (400 mL) and then stirred for 3 h. The precipitate is filtered and dried. Yield: 6.50 g; ESI mass spectrum: [M+Na]+=332; Retention time HPLC: 0.58 min (Z011_S03).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 4-aminobutanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 2 of European Patent Application 136,883 to give (±)-4-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]butanoic acid, methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12](CC)[N:11]([CH2:16][CH3:17])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Cl[O-].[Na+]>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:10][N:11]([CH2:16][CH3:17])[N:12]=[CH:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCN1CC(NC(=O)c2ccc(N)cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc(N)cc2)C=N1

Procedure:
In accordance with the procedure of Example 2, 4-amino-N-(1,2-diethyl-4-pyrazolidinyl)benzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([N:19]5[C:20](=[O:29])[C:21]6[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:27]5=[O:28])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:31]=1
Reactant: CC(c1ccc2c(c1)ncn2-c1cccc(Br)c1)N1C(=O)c2ccccc2C1=O
Reactant: OB(O)c1cccnc1
Product: CC(c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1)N1C(=O)c2ccccc2C1=O

Procedure:
This was prepared analogously from 2-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-isoindole-1,3-dione and 3-pyridineboronic acid
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F>CN(C=O)C>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 98.9 %

Procedure:
Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved in 25 mL of anhydrous DMF. This solution was cooled to 0° C. under an atmosphere of nitrogen. Sodium hydride (1.04 g, 26 mmol, 60% by weight in mineral oil) was slowly added to the solution. The resulting mixture was allowed to stir for 3 minutes at 0° C., and then at room temperature for 10 minutes. 2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quickly added and the mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and a saturated aqueous solution of sodium chloride. The layers were separated and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organics were concentrated to yield diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g, 99%) as a pale yellow oil which was used without further purification. Retention time 1.86 min.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15][C:16]1([O:19][CH2:18]1)[CH3:17]>CN(C)C=O.O>[CH3:15][C:16]([OH:19])([CH3:18])[CH2:17][O:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1
Reactant: CC1(O)CCC2(CC1)OCCO2
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COC1(C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (4.01 g) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (960 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To this mixture was added isobutylene oxide (2.52 g), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless oil (1.81 g, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:19][C:20](=[O:22])[CH3:21])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1cncc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CSc1cncc(Br)c1

Procedure:
5-Bromo-pyridine-3-thiol (0.880 g, 4.63 mmol) in THF (100 mL) was cooled to 0° C. and Hünig's base (2.4 mL, 13.89 mmol) was added. Chloroacetone (0.371 mL, 4.63 mmol) was added and the ice bath was removed. After 15 minutes the reaction mixture was concentrated, diluted with EtOAc, and washed with H2O/brine. After drying over MgSO4 the mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:34][C:35]([F:39])([F:38])[CH2:36]I>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:27](=[O:32])[CH2:28][CH2:29][C:30]4=[O:31])[CH2:20][CH2:19]3)[N:11]=2)=[CH:3][C:2]=1[O:1][CH2:36][C:35]([F:39])([F:38])[F:34]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Reactant: FC(F)(F)CI
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC(F)(F)F

Procedure:
Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and 1,1,1-trifluoro-2-iodoethane as starting compounds.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](N(CC)CC)C.IC>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.18 mmol) and triethylamine (49 μL, 0.35 mmol) in DMF (1 mL) at −78° C., iodomethane (177 μL, 0.17 mmol, 1.0M in DMF) was added. The reaction was allowed to stir for 1 h while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 30 mg (34%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (dd, 1 H), 3.75 (dd, 1 H), 3.37-3.26 (m, 1H), 2.98 (dd, 1H), 2.70-2.65 (m, 2H), 2.56-2.50 (m, 1H), 2.47-2.30 (m, 1H), 2.26-2.18 (m, 2H), 2.14 (s, 3H), 2.11-2.01 (m, 1H), 1.61 (t, J=10.5 Hz, 1H); LC-MS [M+H]+=495, RT=2.10 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1)=[O:10])(C)(C)C.CCOC(C)=O.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:7][CH2:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCC(=O)c1cc2ccccc2s1
Reaction time: 8 h
Yield: 94.7 %

Procedure:
(2-Benzo[b]thiophen-2-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (544 mg, 1.867 mmol) was dissolved into 3 mL of EtOAc and 10 mL of 4.0 M HCl in dioxane was added. The mixture was allowed to stir overnight with a white precipitate forming. The precipitate was triturated with 3×10 mL of EtOAc and dried under vacuum to give 400 mg, 94.7% of crude 2-amino-1-benzo[b]thiophen-2-yl-ethanone HCl salt. The material was carried on without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 113 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1) and pyridin-3-ylboronic acid to afford a white solid. HPLC (Condition 4) tR=4.68 min, UPLC-MS (Condition 7) m/z=487.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87-1.10 (m, 6H) 1.53-1.80 (m, 2H) 1.96-2.12 (m, 1H) 3.00-3.20 (m, 3H) 3.24-3.33 (m, 1H) 4.25 (s, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.46 (dd, J=7.82, 5.08 Hz, 1H) 7.74-7.89 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.55 (dd, J=4.69, 1.56 Hz, 1H) 8.61 (d, J=1.56 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: N12CCN(CC1)CC2.[SH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH2:20][OH:21])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.[CH2:24]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH3:25]>>[CH2:24]([O:26][C:27]([CH:28]1[CH:20]([OH:21])[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[N:12]=[CH:11][C:10]=2[S:9][CH2:29]1)=[O:30])[CH3:25]
Reactant: COc1ccc2ncc(S)c(CO)c2c1
Reactant: C=CC(=O)OCC
Agent: C1CN2CCN1CC2
Product: CCOC(=O)C1CSc2cnc3ccc(OC)cc3c2C1O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
1,4-diazabicyclo[2.2.2]octane (1.04 g, 9.26 mmol) is added at room temperature to a stirred solution of (3-mercapto-6-methoxy-quinoline-4-yl)-methanol and its corresponding dimer (2.02 g) in acrylic acid ethyl ester (21.7 mL, 203.72 mmol). The reaction mixture is heated under reflux for 2 hours, cooled down to room temperature and concentrated to afford 4-hydroxy-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester as a dark brown solid (1.47 g, 99.5% yield).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1.[C:16]([C:18]1[O:22][C:21]([C:23](Cl)=[O:24])=[CH:20][CH:19]=1)#[N:17].CCN(C(C)C)C(C)C>>[F:15][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:23]([C:21]2[O:22][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Nc1ccccc1N1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2ccccc2N2CCC(F)(F)CC2)o1
Yield: 36.2 %

Procedure:
Using a procedure similar to Example 3, step (d), 2-(4,4-difluoro-piperidin-1-yl)-phenylamine (76 mg, 0.35 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (62 mg, 0.40 mmol) in the presence of DIEA (134 μL, 0.770 mmol) to afford 42 mg (36%) of the title compound as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.44 (dd, 1H, J=1.3, 8.1 Hz) 7.32 (d, 1H, J=3.8 Hz), 7.27-7.21 (m, 3H), 7.18-7.13 (m, 1H), 3.07-3.04 (m, 4H), 2.29-2.21 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C17H15F2N3O2, 332.1 (M+H), found 332.1.
Reaction SMILES: CO[C:3](=[NH:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:33])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[NH3:35]>>[C:3]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[O:33])=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)(=[NH:34])[NH2:35]
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: N
Product: N=C(N)c1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1

Procedure:
3-{3-[4-(4-Sulfamoylbenzylcarbamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (370 mg) was dissolved in methanolic ammonia solution (5 ml, 7 M) and refluxed for 4 h. The mixture was filtered, the filtrate concentrated in vacuo and diethylether was added. The resulting precipitate (300 mg) was filtered off. 100 mg were suspended in ethyl acetate/methanol/ammonia, filtered off, washed with ethyl acetate and ether and dried in vacuo to yield 60 mg of 4-[3-(3-carbamimidoylphenyl)-ureido]-N-(4-sulfamoylbenzyl)-benzamide.
Reaction SMILES: [H-].[Na+].C(S)C.[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][N:10]1[C:26](=[O:27])[C:25]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:28]C)[CH:22]=4)[NH:17][C:16]=3[C:15]([CH2:30][O:31][CH3:32])=[CH:14][C:13]=2[C:11]1=[O:12]>CN(C)C=O>[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][N:10]1[C:26](=[O:27])[C:25]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:28])[CH:22]=4)[NH:17][C:16]=3[C:15]([CH2:30][O:31][CH3:32])=[CH:14][C:13]=2[C:11]1=[O:12]
Reactant: COCc1cc2c(c3c1[nH]c1ccc(OC)cc13)C(=O)N(CCN(C)C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COCc1cc2c(c3c1[nH]c1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
520 mg of 60% sodium hydride was suspended in 10 ml of N,N-dimethylformamide. Thereto was dropwise added a solution of 0.87 ml of ethanethiol dissolved in 5 ml of N,N-dimethylformamide, in 5 minutes with stirring at room temperature. Then, thereto was added 90 mg of N-(2-dimethylaminoethyl)-6-methoxy-1-methoxymethylcarbazole-3,4-dicarboximide. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=40/1 to 20/1), followed by recrystallization from n-propanol to obtain 30 mg (yield: 35%) of N-(2-dimethylaminoethyl)-6-hydroxy-1-methoxymethylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:33])=[CH:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(=O)C>O1CCCC1>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]([CH3:25])([CH3:24])[CH:22]=[C:21]([F:33])[CH2:20][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:31][CH:30]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Yield: 22.5 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.19 g), tetrahydrofuran (2 ml) and magnesium (22 g), and 4-(4-chlorophenyl)-2-fluoro-4-methylpent-2-enyl acetate (Example 13) (0.12 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 3 ml/min; to give the title compound (38 mg, 22%).
Reaction SMILES: [C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])=[N+](C)C)C>C1COCC1>[C:18]([O:20][N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 18 h
Yield: 29 %

Procedure:
To a solution of mono-tert-butyl octadecanedioate (1,00 g, 2.7 mmol) in dry THF (8 ml), was added DIPEA (0,555 ml, 3.2 mmol) followed by TSTU (1,00 g, 3.2 mmol). The reaction mixture was stirred under nitrogen for 18 h. The solvent had evaporated. AcOEt was added to the residue and the resulting suspension was filtered. The filtrate was washed with cold 0.1 M HCl (2×) and water, dried and concentrated to give succinimidyl tert-butyl octadecandioate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][CH:17]=O)[O:8][C@H:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.C([O:29][C:30]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:31])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:13])[CH3:14])[C:10](=[O:15])[C@@H:9]([CH2:16]/[CH:17]=[CH:32]/[C:30]([OH:31])=[O:29])[O:8][C@H:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N1C(=O)[C@@H](CC=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)[C@@H](C/C=C/C(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
In toluene (20 ml) was dissolved trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde (1.5 g). To the solution was added (ethoxycarbonylmethylene)-triphenylphosphorane (2.0 g), and the mixture was stirred for 3 hours at 90° C. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl ester of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-crotonic acid (1.28 g) as prisms, m.p.126°-127° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH:12]([CH2:29]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([OH:34])(=[S:33])[CH3:32]>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:17])=[O:18])[CH2:13][CH:12]([CH2:29][S:33][C:31](=[O:34])[CH3:32])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=S
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CC(CO)CC(COCc2ccccc2)C1
Product: CC(=O)SCC1CC(COCc2ccccc2)CN(S(=O)(=O)c2ccc3ccccc3c2)C1

Procedure:
(3SR,5RS)-[5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanol (1.35 g) was reacted with thioacetic acid (see Mitsunobu reaction described in Example 17) to obtain thioacetic acid (3SR,5RS)-S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-ylmethyl] ester (0.92 g) as a syrup, MS: 484 (MH+).
Reaction SMILES: O=[C:2]([CH2:8]CC)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[CH3:7][C:6]1([CH:11]=[CH2:12])[O:5][C:3](=[O:4])[CH2:2][CH2:8]1
Reactant: CCCC(=O)C(=O)OCC
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC1(C)CCC(=O)O1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of ethyl 2-ketopentanoate (10 mL, 71 mmol) in 100 mL of THF at −78° C. was added dropwise a solution of 1.0 M vinyl magnesium bromide (80 mL, 80 mmol). After completion of the addition, the mixture was stirred for two more hours, the cooling bath was removed and the mixture was gradually warmed to ambient temperature. After the removal of the most of the solvent, the residue was poured to 2N HCl aqueous solution, extracted with ethyl acetate and dried over MgSO4 Purification by lash column chromatography on silica gel with DCM as elute afforded 4.80 grams of 5-methyl-5-vinyl-dihydro-furan-2-one. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.824-5.917 (dd, 1H); 5.29 (d, 1H); 5.13 (d, 1H); 2.50-2.56 m, (2H); 2.07-2.18 (m, 2H); 1.48 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1[CH:9]=[C:8]([CH:10]([NH2:14])[C:11]([OH:13])=[O:12])[S:7][CH:6]=1>CO>[NH2:14][CH:10]([C:8]1[S:7][CH:6]=[CH:5][CH:9]=1)[C:11]([O:13][CH3:1])=[O:12]
Reactant: CC(=O)Cl
Reactant: NC(C(=O)O)c1cccs1
Solvent: CO
Product: COC(=O)C(N)c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.8 %

Procedure:
To dry MeOH (1000 mL) stirring at room temperature was added acetyl chloride (40.3 g, 513 mmol) over a 5 minute period. A mild exothermic reaction resulted. The mixture was stirred for 10 minutes and DL-α-amino-2-thiopheneacetic acid (40.5 g, 257 mmol) was added. The brown mixture was heated to reflux and stirred overnight. After cooling to room temperature, the mixture was concentrated to a volume of 400 mL and poured into Et2O (1500 mL). The precipitated white solid was collected and dried in vacuo to afford 49.2 g (92%) of the title compound as its hydrochloride salt. The 1H NMR spectrum was consistent for the title compound. An analytical sampie was recrystallized from EtOAc-hexane. Mpt.=182° C.