Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][S:10][CH2:11][CH:12]([OH:24])[CH2:13][S:14][CH2:15][CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].CN(C1C=CC=CN=1)C>>[C:25]([O:24][CH:12]([CH2:13][S:14][CH2:15][CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][S:10][CH2:9][CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: OC(CSCCSc1ccccc1)CSCCSc1ccccc1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccccn1
Product: C=CC(=O)OC(CSCCSc1ccccc1)CSCCSc1ccccc1

Procedure:
An excess of 2-(phenylthio)ethanethiol is reacted with epichlorohydrin to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol. In the final step, the 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol is reacted with a acryloyl chloride in the presence of a tertiary alkyl amine and dimethylaminopyridine to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-yl acrylate.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.CCN(C(C)C)C(C)C.C[Si]([N:35]=[N+:36]=[N-:37])(C)C>C1COCC1.CCO>[N:35]([C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2)=[N+:36]=[N-:37]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Temperature: 25 °C

Procedure:
(Z)-1,3-Dihydro-4-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (576 mg, 2.0 mmol) (from Example 42 above) was suspended in THF/EtOH (15 mL/8 mL). Hunig's base (diisopropylethyl amine, 5 mL, 30 mmol) (Aldrich) and trimethylsilyl azide (2.6 mL, 20 mmol) (Aldrich) were successively added at r.t. The mixture was heated at reflux for 3 h 20 min. The heterogeneous reaction mixture was cooled to r.t. and the orange suspension was collected by suction filtration. The precipitate was washed with ethanol and dried in a vacuum oven overnight. (Yield 490 mg, 79%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CNCCO
Solvent: O
Product: CN(CCO)c1nc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2-chlorobenzothiazole (8.5 g) and 2-methylaminoethanol (20 ml) was heated at 120° C. under pressure in a sealed, glass lined, stainless steel reaction vessel for 18 hours. After cooling, the oil was added to water (100 ml), extracted with dichloromethane (2×100 ml), the organic extracts were dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residual oil on silica-gel in 21/2% methanol in dichloromethane gave the title compound which was used in Preparation 1 without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:56])[C@H:10]([CH2:35][CH2:36][CH2:37][NH:38]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[N:11]([C:13](=[O:34])[C@H:14]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH:15]C(OC(C)(C)C)=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66]>CN(C)C=O>[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66].[CH2:1]([NH:8][C:9](=[O:56])[C@H:10]([CH2:35][CH2:36][CH2:37][NH2:38])[N:11]([C:13](=[O:34])[C@H:14]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH2:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H](N)Cc1cccc2ccccc12)[C@@H](CCCN)C(=O)NCc1ccccc1

Procedure:
Boc-β-(1-Naphthyl)alanyl-Nδ-Fmoc-Nα-methylornithine benzylamide (B) (28 mg) was deprotected in teo steps-i) 20% piperidine in dimethylformamide and ii) trifluoroacetic acid exposure to afford a white solid: HPLC (method A); 1H NMR (400 MHz, D2O) δ1.59 (m, 2H), 1.77 (m, 1H), 1.89 (m, 1H), 2.38 (s, 3H), 3.0 (t, 2H), 3.60 (dd, 1H), 3.82 (dd, 1H), 4.39 (d, 2H), 4.92 (t, 1H), 5.01 (dd, 1H), 7.36-7.50 (m, 12H), 7.75 (m, 2H), 7.99 (t, 1H),8.10 (d, 1H), and 8.18 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[CH3:8][C:3]1[C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccnc1C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), to afford 74 g of the title compound as colorless crystals.
Reaction SMILES: OS(O)(=O)=O.[C:6](=[O:22])([O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:6](=[O:22])([O:20][CH3:21])[O:7][C:8]1[CH:13]=[C:12]([N+:23]([O-:25])=[O:24])[C:11]([Br:14])=[CH:10][C:9]=1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)Oc1ccc(Br)cc1C1CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Temperature: -10 °C
Yield: 72.4 %

Procedure:
Concentrated H2SO4 (115 mL) was added to 4-bromo-2-cyclopentylphenyl methyl carbonate (26.09 g, 87.21 mmol) and the mixture stirred and cooled to −10° C. KNO3 (13.22 g, 130.80 mmol) was then added in portions with continuous stirring. The reaction was stirred at −10° C. for 1 h then quenched with ice resulting in precipitation of an off-white solid. The solid was filtered, washed with water and dried to provide the product. The water phase was extracted with dichloromethane (3×10 mL) and the combined organic extracts dried over Na2SO4. Purification by silica gel chromatography (5-20% ethyl acetate/hexane) provided additional 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (combined 21.72 g, 72% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.88 (s, 1H), 3.88 (d, J=5.7 Hz, 3H), 3.13 (dd, J=9.4, 17.2 Hz, 1H), 1.96-1.92 (m, 2H), 1.80-1.75 (m, 2H), 1.68-1.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(OP([N:34]=[N+:35]=[N-:36])(=O)OC2C=CC=CC=2)C=CC=CC=1.N1CCCN2CCCCCC=12>C1(C)C=CC=CC=1>[N:34]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:35]=[N-:36]
Reactant: OCc1cncc(Cl)c1COC1CCCCO1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cncc(Cl)c1COC1CCCCO1

Procedure:
A solution of [5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methanol (1.3 g, 4.9 mmol), phosphorazidic acid diphenyl ester (1.4 mL, 6.4 mmol) and 2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine (0.96 mL, 6.4 mmol) in toluene (0.15 mL) was stirred at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexanes/EA 3:1) to give the title compound. MS (m/z): 282.9 [M+H+].
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)N.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=O)[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C:16]3[C:8]4[CH:7]=[CH:6][CH:5]=[N:4][C:3]=4[NH:1][C:17]=3[C:18]([CH3:21])([CH3:22])[C:19]=2[CH:20]=1
Reactant: NNc1ccccn1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3ncccc3c1C2
Temperature: 190 °C
Reaction time: 48 h

Procedure:
2-Hydrazinopyridine (1.3 g, 11.8 mmol) and 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.4 g, 11.8 mmol) were dissolved in NMP (60 mL), and stirred at 190° C. for 48 hr. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the target compound (white solid, 101 mg, 3%).
Reaction SMILES: C([C:9]1[CH:10]=[C:11]2[CH:17]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:22]=1)(=O)C1C=CC=CC=1.[C:23](=[O:26])([O-])[O-].[K+].[K+].[C:29](O)(=O)[C:30](O)=O>CO.O>[C:23]([C:22]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:11]2=[CH:10][CH:9]=1)(=[O:26])[C:30]1[CH:29]=[CH:11][CH:10]=[CH:9][CH:22]=1
Reactant: O=C(O)C(=O)O
Reactant: COC(=O)C1CCCCn2cc(C(=O)c3ccccc3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2n1CCCCC2C(=O)O
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of methyl 2-benzoyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-9-carboxylate (1.00 g., 0.0034 moles) in methanol (30 ml.) and water (10 ml.) containing potassium carbonate (0.940 g., 0.0068 moles) was heated at reflux temperature, in a nitrogen atmosphere, for 2 hours. The solvent was removed in vacuo, water (25 ml.) was added and the solution was extracted with ether (2×50 ml.). The aqueous phase was cooled to 5°, oxalic acid (2.55 g., 0.02 moles) was added, and after agitation for 0.5 hours the product was extracted into ethyl acetate (3×100 ml.). The extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue, on crystallization from ethylacetate/hexane gives 3-benzoyl-5,6,7,8-tetrahydro-9H-pyrrolo[1,2-a]azepine-9-carboxylic acid in 73% yield, m.p. 163°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].F[C:16](F)(F)[C:17](OC(=O)C(F)(F)F)=[O:18].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[C:17]([C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:18])[CH3:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(OC)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(C)=O)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.00 g portion of methyl 2,4-dimethoxybenzoate was suspended in 0.58 ml of acetic acid, and 1.44 ml of dry trifluoroacetic acid anhydride was added under ice-cooling, followed by stirring at room temperature for 12 hours. Under ice-cooling, a saturated sodium bicarbonate aqueous solution and ethyl acetate were added, and then insoluble matter was removed by celite filtration. The thus obtained filtrate was extracted with ethyl acetate, washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-80:1) to give 0.99 g of methyl 5-acetyl-2,4-dimethoxybenzoate.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][CH:14]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3](O)=[O:4].[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C=CC=CC1=O.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C=O)C>[N:1]1([C:10]([O:12][CH2:13][CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:11])[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3]([NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:4]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)[C@H]1C[C@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=c1ccccn1O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)[C@H]1C[C@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
1.4 g of Fmoc-D-Hyp-OH are dissolved in 25 ml of dry acetonitrile and then 1.05 g of H-Gly-OtBu and 0.445 g of N-hydroxypyridone are added. Then 1.31 g of O-[(cyano(ethoxycarbonyl)methylidene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) are introduced in/portions within 10 minutes, as well as 1.03 ml of diisopropylethylamine in 15 ml of DMF dropwise over the course of 15 minutes. After 1 h, the mixture is concentrated, the residue is taken up in ethyl acetate and extraction with sodium chloride solution is carried out. The organic phase is dried over sodium sulfate and evaporated to dryness. The remaining oil is taken up in a little ether and added dropwise to petroleum ether while stirring. The flocculent precipitate is filtered off with suction and dried in vacuo.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][C:14]([CH3:16])=O.[CH3:17][C:18]([CH3:20])=O.N1C=CC=CC=1.Cl[C:28]([O:30][CH:31]([Cl:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:28](=[O:29])([O:6][C@H:5]1[C@@H:3]2[O:4][C:14]([CH3:16])([CH3:13])[O:1][C@@H:2]2[O:8][C@H:7]1[C@@H:9]1[CH2:11][O:12][C:18]([CH3:20])([CH3:17])[O:10]1)[O:30][CH:31]([Cl:33])[CH3:32]
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)O[C@H]1[C@@H]2OC(C)(C)O[C@@H]2O[C@H]1[C@@H]1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of diacetone-D-glucose (1.56 g, 6 mmol) and pyridine (1.09 g, 1.12 mL, 13.8 mmol) in methylene chloride (6 mL) at −78° C. was added slowly a solution of 1-chloroethyl chloroformate (970 mg, 732 μl, 6.78 mmol) in methylene chloride (4 mL). After addition, the reaction mixture was allowed to stir at −78° C. for 1.5 h. Then the cold bath was removed and the reaction mixture was warmed up to room temperature. The reaction mixture was concentrated in vacuo and taken up in diethyl ether. The precipitate was filtered and the solid was washed thoroughly with diethyl ether. The filtrate and washing solutions were combined and concentrated to give 2.135 g of 1-chloroethyl (3aS,5S,6R,6aS)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yl carbonate as clear light yellow thick oil, which was used directly without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19](C3C=CC=C(C(F)(F)F)C=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-:46]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19]([Br:46])[CH:18]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as a white gum (0.976 g, 58%) from N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-hydroxy-benzamide using a procedure similar to Example 191. 1H NMR (DMSO-d6) δ 9.84 (s, 1H); 8.42 (t, 1H); 8.04 (d, 1H); 7.85-7.67 (m, 5H); 7.26-7.10 (m, 5H); 3.21 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.26 (m, 8H); IR (KBr) 3330, 2950, 2850, 1620, 1550, 1495, 1470, 1330, 1220, 1170, 1120, 1100, 1080 cm−1; mass spectrum [(+)APCI], m/z 549 (M+H)+; Anal. Calcd. for C28H29F3NO2: C, 61.32; H, 5.33; N, 2.55, Found: C, 61.02; H, 5.29; N, 2.51.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13]C)=O)[CH2:6]1)(=[O:3])[CH3:2].[NH3:15]>>[C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([NH2:15])=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)[C@H]1CCC[C@H](NC(C)=O)C1
Product: CC(=O)N[C@H]1CCC[C@H](C(N)=O)C1
Temperature: 70 °C
Yield: 57.1 %

Procedure:
Methanolic ammonia (20 ml) was added to trans-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 1.75 mmol), taken in a steel bomb and heated at 70° C. for 18 h. The reaction mixture was concentrated, washed with n-pentane and dried under reduced pressure to afford 200 mg (57.1%) of trans-3-acetamidocyclohexanecarboxamide as white color solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH:19]([N:22]=[C:23]=S)([CH3:21])[CH3:20].C(N(CC)CC)C.C(Cl)(Cl)=O>CC(C)=O.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)ccc2N1
Temperature: 60 °C
Yield: 38.3 %

Procedure:
To a suspension of 2-amino-5-bromobenzenesulfonamide (0.8 g; 3.2 mmol) and potassium carbonate (0.54 g; 3.9 mmol) in acetone (20 ml) was added isopropyl isothiocyanate (0.387 g; 3.84 mmol). The mixture was heated to 60° C. and after 16 hr cooled, concentrated in vacuo and the crude residue was taken up in tetrahydrofuran (50 ml) and cooled to 0° C. To the cooled mixture was added triethylamine (0.648 g; 6.4 mmol) followed by the addition of phosgene in toluene 1.9M (1.82 ml) over 2 min. After 1 hr at 0° C. the mixture was concentrated in vacuo. The crude product was taken up in water (10 ml) and pH was adjusted to 6 with sodium bicarbonate. The precipitated product was collected by filtration and dried in vacuo at 50° C. for 16 hr giving 390 mg (38.3%) of the title compound; m.p. >220° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
tert-Butyl [2-(4-hydroxyphenyl)ethyl]carbamate (3.45 g, 14.54 mmol) was dissolved in dry DCM (70 mL) and cooled in an ice-water bath. Methanesulfonyl chloride (1.99 g, 17.45 mmol) was added followed by TEA (2.21 g, 21.80 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was washed with saturated aqueous NaHCO3, and the organic phase was dried with MgSO4, filtered and evaporated. Column chromatography of the crude product (ISOLUTE SI, (20 g), eluated with Heptane/EtOAc (90:10), Heptane/EtOAc (70:30)) afforded the title compound (4.06 g, 88.5%). 1H NMR (500 MHz, CD3OD): δ 1.43 (s, 9H), 2.80 (t, 2H), 3.20 (s, 3H), 3.29 (q, 2H), 7.25 (d, 2H), 7.31 (d, 2H).
Reaction SMILES: [ClH:1].C[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1.Cl.[Br:28]C1C=CC=C2C=1NC=C2CCN>Cl>[ClH:1].[Br:28][C:10]1[CH:11]=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3Cc1cccc2ccccc12
Reactant: NCCc1c[nH]c2c(Br)cccc12
Agent: Cl
Product: Brc1cccc2c3c([nH]c12)C(Cc1cccc2ccccc12)NCC3
Temperature: 25 °C
Yield: 11.2 %

Procedure:
A suspension of azalactone (prepared as described in Example 5) (55 g, 6.53 mmol) and 7-bromotryptamine hydrochloride (1.50 g, 5.44 mmol) in 1N HCl (100 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The brown solid was triturated with isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50 mL). Recrystallization from ethanol afforded 260 mg of desired product as the hydrochloride salt. (mp=231°-233° C., dec.)
Reaction SMILES: N[C@H:2](C(O)=O)CC1C=CC=CC=1.[NH2:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16]([OH:18])=[O:17].[ClH:22].[CH3:23][OH:24]>>[ClH:22].[CH3:23][O:24][C:19](=[O:21])[C@H:14]([CH2:15][C:16]([O:18][CH3:2])=[O:17])[NH2:13]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C[C@H](N)C(=O)OC

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that the L-phenylalanine was replaced with 133.1 g of L-aspartic acid and that 133.1 g of methanol and 64 g of hydrochloric acid were used. Following cooling to deposit the crystals, the latter were collected by filtration and then dried to obtain 160.5 g (78.4 yield) of L-aspartic acid dimethyl ester hydrochloride having a purity of 96.5% and containing 0.2% of water and 2.6% of the total of L-aspartic acid and α- and β-monomethyl esters of L-aspartic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23]([O:25]CC)=O)[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:30][NH2:31].O.NN>C(O)C>[NH:30]([C:23]([C:21]1[S:20][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:29][CH:28]=3)[C:16]=2[CH:22]=1)=[O:25])[NH2:31]
Reactant: NN
Reactant: CCOC(=O)c1cc2c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)n[nH]c2s1
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN)cc34)cc2)CC1
Yield: 36.5 %

Procedure:
Ethyl 3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate (0.5 g, 1.03 mmol, 1 eq.) and ethanol (2 mL) are placed in a 15 mL round-bottomed flask, and a 1 M hydrazine solution (3.09 mL, 3.09 mmol) and 2 mL of hydrazine monohydrate are added. The reaction mixture is stirred at reflux for 5 hours, the solvent is then evaporated off and the residue is taken up in water. The white precipitate is filtered off, washed with water and then dried at a temperature in the region of 80° C. under vacuum. N-(5-Hydrazinocarbonyl-1H-thieno[2,3-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (0.15 g, 49%), Rf=0.32 (methanol/dichloromethane 10/90 (v/v)) is thus obtained, which product is used directly in the following step. Ethyl 3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate may be obtained by deprotection of ethyl 1-(1-ethoxyethyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate according to example 28.