Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:16].[Na+]>OS(O)(=O)=O.O>[OH:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CS(=O)(=O)c1cc(N)cc(C(=O)O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(O)cc(C(=O)O)c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
3-Amino-5-methylsulphonylbenzoic acid (D12) (7.24 g) was dissolved in a mixture of conc H2SO4 (100 ml) and water (300 ml) and cooled to 5° C. sodium nitrite (5.1 g) in water (15 ml) was added dropwise and the mixture was thereafter stirred in the cooling bath for 15 min and with the cooling bath removed for 40 min. It was then heated at 90° C. for 1 h. The heating was removed and the reaction was allowed to stand overnight. The mixture was partially neutralised (˜pH1) with solid sodium bicarbonate until a solid precipitate formed. The mixture was extracted 3 times with ethyl acetate and the combined extracts were washed with water and brine, dried (Mg SO4) and evaporated to a solid which was triturated with ether to give D13 (2 crops, 4.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Yield: 104.7 %

Procedure:
To a solution of methyl 2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g). The reaction was allowed to stir for two hours, then the reaction mixture was washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CO>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:3](=[O:5])[CH2:2][C:1]([OH:9])=[O:8]
Reactant: Nc1ccccc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)Nc1ccccc1Br
Temperature: 180 °C
Yield: 57.3 %

Procedure:
Diethyl malonate (101 mL, 0.989 mol) and 2-bromoaniline (50.g, 0.291 mol) were combined and heated at 180° C. for six hours. A Dean-Stark trap was used to collect the volatiles. The reaction was allowed to cool to ambient temperature overnight; a precipitate formed. The precipitate was isolated by filtration and combined with methanol (160 mL), water (800 mL), and solid sodium carbonate (105 g). The mixture was heated at reflux for two hours, allowed to cool to ambient temperature, and then cooled to 0° C. The mixture was adjusted to pH 2 with the addition of 3 N hydrochloric acid; a white precipitate formed. The precipitate was isolated by filtration, washed with water, and dried overnight on the filter funnel to provide 43 g of N-(2-bromophenyl)malonamic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=C.[O:12]=[O+][O-]>CO>[CH3:11][O:10][C:3]([O:2][CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:12]
Reactant: O=[O+][O-]
Reactant: C=CC(CCCC)(OC)OC
Solvent: CO
Product: CCCCC(C=O)(OC)OC

Procedure:
1 liter of a solution of 237 g (1.5 moles) of n-butylacrolein dimethylacetal in methanol is reacted with ozone analogously to the procedure indicated in Example 1 and is then hydrogenated. The absorption of H2 is 29 standard liters.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C>[C:24]([O:23][N:22]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)ON=C(CN)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To 162 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(tert-butoxyimino)ethyl]phthalimide in 10 ml of ethanol, 40 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (25 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 89 mg of the desired crude product as a colorless oil. The oil was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[OH:17])[CH2:14]2.C(N(CC)CC)C>C1COCC1>[Cl:6][CH2:5][CH2:4][O:3][CH2:2][O:17][CH:8]1[CH:7]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]1[CH2:10]3)[CH2:14]2
Reactant: ClCCOCCl
Reactant: OC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCCOCOC1C2CC3CC(C2)CC1C3
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of 2-chloroethyl chloromethyl ether obtained in Example 1 (1), 1.52 g (10 mmol) of 2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 2-adamantanol was converted by 97.6% and that 2.35 g (9.6 mmol, isolation yield: 96.2%) of a colorless liquid which was the intended product was obtained at a selectivity of 98.6%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH:8]1[C:18]2[C:17](=[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH2:14][S:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:8]1[C:18]2[C:17](=[C:19]3[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH2:14][S:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc2c(c1)CSc1ccccc1C2=C1CCNCC1
Reactant: CC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1

Procedure:
A solution of 10 g of 5-bromo-2-pentanone in 40 cc of chloroform is added dropwise within 10 minutes to a mixture of 14.7 g of 4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidine and 12.7 g of potassium carbonate in 200 cc of chloroform, and the mixture is heated at reflux for 18 hours. After cooling, filtration is effected, the filtrate is washed with water, dried over magnesium sulphate, and the solvent is completely removed by distillation. The oily residue is then chromatographed on 200 g of silica gel with a mixture of chloroform/ethanol 9:1, and the so purified title compound is converted into the hydrogen fumarate form. M.P. 215°-218° from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]=[C:5]([CH3:14])[CH:4]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)(=O)C>[CH:14]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][N:6]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C)ncc1CCC(C)C
Reactant: O=Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=Cc2ccccc2)ncc1CCC(C)C

Procedure:
The starting substance can be manufactured by dissolving 26 g of 4-methoxy-5-isoamyl-2-picoline in 78 ml of benzaldehyde and 86 ml of acetic anhydride and heating the reaction mixture for 16 hours under reflux. After cooling, the mixture is evaporated, treated with 2 N sodium hydroxide solution and extracted with ether. Distillation of the ether residue in a bulb tube in a high vacuum at a temperature of 180°-200° yields 2-styryl-4-methoxy-5-isoamyl-pyridine.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH:17][CH:18]1[CH:26]2[CH:21]([CH:22]3[CH2:27][CH:25]2[CH:24]=[CH:23]3)[C:20](=O)[O:19]1>C1C=CC=CC=1>[O:17]=[C:18]1[C@H:26]2[C@H:21]([C@@H:22]3[CH2:27][C@H:25]2[CH:24]=[CH:23]3)[C@@H:20]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[O:19]1
Reactant: O=C1OC(O)C2C3C=CC(C3)C12
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1

Procedure:
A mixture of 5.2 g of benzyl L-leucinate, 4 g of (3RS, 3aRS,4RS,7RS,7aRS) 3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one and 40 ml of anhydrous benzene was refluxed for 90 minutes while azeotropically distilling off the water of reaction formed and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered to obtain 2.3 g of benzyl (αS,3S,3aS,4R,7S,7aR) α-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)-amino]isohexanoate melting at 95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[CH:11][CH:10]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:23][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Reactant: O=C1CCC(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Reaction time: 4 h
Yield: 20.8 %

Procedure:
A mixture of 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl (28 mg, 0.082 mmol), succinic anhydride (8.2 mg, 0.083 mmol) and 10% Pd/C (4.4 mg) in THF (3 mL) was hydrogenated at 45 psi for 4 hrs. The reaction mixture was filtered and evaporated. The crude product was purified by flash chromatography with a 0-50% gradient of ethyl acetate in hexanes to yield 7 mg (20.7%) of N-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenyl]-succinamic acid as a solid. LC-MS (ES) calculated for C23H19F2NO4, 411.41; found m/z 410.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21]([O-])=[O:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)c(Cl)c1
Product: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)c(Cl)c3)cc2)cc1

Procedure:
Compound 617 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 3-chloro-4-morpholinobenzoate. [M+H]+ calcd for C24H23ClN3O3: 436.14; found: 435.97.
Reaction SMILES: BrC1C=C2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4](C(O)=O)C=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NCC(OC(C)(C)C)=O>>[C:16]1([NH:15][C:8](=[O:11])[CH2:7][CH2:6][C:5]#[CH:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(Br)cc2c1CCC2=O
Reactant: Nc1ccccc1
Agent: CC(C)(C)OC(=O)CN
Product: C#CCCC(=O)Nc1ccccc1

Procedure:
The procedure for Example 41 was used, substituting 4-pentynoic acid for 6-bromo-4-carboxy-1-indanone and aniline for t-butyl glycinate to provide Example 645. MS (ESI): m/z 174 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].[CH:17]([N:20]=[C:21]=[S:22])([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([NH:20][C:21]([NH:16][NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[N+:1]([O-:3])=[O:2])=[O:14])=[S:22])([CH3:19])[CH3:18]
Reactant: NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Reactant: CC(C)N=C=S
Solvent: CN(C)C=O
Product: CC(C)NC(=S)NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Yield: 85.6 %

Procedure:
To a suspension of 3-nitro-1H-indole-5-carbohydrazide (1.2 g, 5.454 mmol) in DMF (5 mL) was added isopropyl isothiocyanate (661 mg, 6.545 mmol) in one lot and the reaction was heated to reflux for 4 h. The mixture was quenched with water (20 mL) to get a pale yellow precipitate. The precipitate was filtered, washed with water (2×10 mL) and dried. The crude product was treated with 20% EtOAc in petroleum ether (2×20 mL) to afford N-isopropyl-2-(3-nitro-1H-indole-5-carbonyl)hydrazinecarbothioamide (1.5 g, 88%) as pale yellow solid. MS (ESI, pos. ion) m/z: 322.1 (M+1); 1H-NMR (300 MHz, DMSO-d6): δ 12.90 (brs, 1H), 10.43 (brs, 1H), 9.19 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7.87-7.93 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.4 Hz), 4.40-4.53 (m, 1H), 1.11 (d, 6H, J=6.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)c(F)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-4,5-difluoro-benzoic acid. LC-MS (basic): tR=0.94 min; [M+H]+=502.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[Cl:26][CH2:27][C:28]1[N:29]([CH3:35])/[C:30](=[N:33]/[CH3:34])/[S:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.CCOCC>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([CH2:27][C:28]3[N:29]([CH3:35])/[C:30](=[N:33]/[CH3:34])/[S:31][CH:32]=3)[CH2:23][CH2:24]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: C/N=c1\scc(CCl)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/N=c1\scc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1C
Yield: 121.4 %

Procedure:
A suspension of 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (2.5 g) obtained in Example 3a), N-((2Z)-4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine hydrochloride (2.2 g) and potassium carbonate (2.4 g) in DMF (50 mL) was mixed at 65° C. for 3 hours. The solvent was distilled off under reduced pressure, the residue was diluted with an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The product, which was obtained by the purification of the residue with a basic silica gel column, was dissolved in ethyl acetate. A solution of hydrogen chloride in ether was added thereto, and the mixture was concentrated and dried to give the title compound (2.4 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.ClC(Cl)(Cl)S(O[CH2:52][C:53]([F:56])([F:55])[F:54])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][N:20]([CH2:52][C:53]([F:56])([F:55])[F:54])[C:18]=3[N:19]=2)=[N:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1nnn2CC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
150 mg (0.415 mmol) of the compound from example 53 and 113 mg (0.0415 mmol) of BEMP were initially charged in 7 ml of dimethylformamide, and a solution of 117 mg (0.415 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate in 2.5 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at RT for 16 h. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.05% trifluoroacetic acid, gradient 10:90→90:10). 22 mg of the title compound were obtained (11% of theory).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][O:25][C:24]1=[O:28])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])C1C=CC=CC=1>O1CCCC1.[Pd]>[C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][O:25][C:24]1=[O:28])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:10])[CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH3:20]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H]1CCOC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC(CCC)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H]1CCOC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.9 %

Procedure:
(S)-3-[[N-Benzyloxycarbonyl-(L)-phenylalanyl]amino]tetrahydrofuran-2-one (1.5 g) was dissolved in tetrahydrofuran (35 ml) followed by addition of palladium-on-carbon (5%, 0.8 g) and the catalytic hydrogenation was carried out at room temperature and atmospheric pressure. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (DMF) (35 ml). Then, valproic acid [(C3H7)2CHCOOH](0.622 g) and 1-hydroxybenzotriazole (HOBt) (0.66 g) were added, after which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.902 g) was added under ice-cooling and the whole mixture was stirred at room temperature for 14 hours. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid, water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned and dried (MgSO4) and the solvent was distilled off to give (S)-3-[[N-valproyl-(L)-phenylalanyl]amino]tetrahydrofuran-2-one (chemical formula below) (0.55 g, 38%). This product was recrysallized from dichloromethane-ether. Colorless prisms, m.p. 203°-205° C. Optical rotation [α]D -39.3° (c=0.52, CHCl3). ##STR32##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([F:12])[C:3]=1[I:13].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:12])[C:3]=1[I:13]
Reactant: CC(=O)Nc1ccc(Cl)c(I)c1F
Agent: Cl
Solvent: CO
Product: Nc1ccc(Cl)c(I)c1F
Temperature: 25 °C

Procedure:
To a mixture of N-(4-chloro-2-fluoro-3-iodophenyl)acetamide (20.0 g, 64 mmol) in MeOH (80 mL) is added concentrated HCl (60 mL). The mixture is stirred at reflux for 18 hours before cooling to room temperature and removal of the solvent under reduced pressure while maintaining the water bath below 45° C. The residue is cooled with an ice bath and a 1N NaOH solution is added to adjust the pH between 9 and 10. The aqueous phase is extracted with ether and dried over MgSO4. The solvent is removed and the residue is purified through a flash chromatographic column with a gradient of hexanes/ether to give 4-chloro-2-fluoro-3-iodoaniline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:6]1[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2ccnc2n1
Solvent: ClCCl
Product: Cc1cc(Cl)n2ccnc2n1
Yield: 52 %

Procedure:
A mixture of 0.893 g (5.99 mmol) 7-Methylimidazo[1,2-a]pyrimidin-5-ol and 17 mL (182.1 mmol) of phosphorus oxychloride were refluxed for two hours. At the end of the reflux, a clear red solution is obtained, which is rotovaped to remove excess phosphorus oxychloride. The residue thus obtained was titurated with methylene chloride followed by filtration of the slurry to isolate the desired compound as a solid. Further washes with methylene chloride followed by drying of the solid under reduced pressure resulted in the chlorinated product. Yield 522 mg (52% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([OH:18])[CH:16]=2)[N:11]=[CH:10][NH:9]1.CS(O[C@H:26]1[CH2:31][CH2:30][C@H:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]2)[CH2:28][CH2:27]1)(=O)=O.O>CN1CCCC1=O>[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([O:18][C@H:26]3[CH2:27][CH2:28][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]4)[CH2:30][CH2:31]3)[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Reactant: CN1CCN([C@H]2CC[C@H](OS(C)(=O)=O)CC2)CC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1
Reaction time: 20 h

Procedure:
2.4 g sodium carbonate are added to 2 g of 3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline (VII) in 16 ml N-methyl-2-pyrrolidinone at 130° C. Then six times 600 mg (in total: 2.4 g) (trans)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane (II) are added stepwise at 130° C. within 4 h and the mixture is kept at 130° C. for 20 h. After 10 days, 25 ml of water are added and the mixture is extracted with 25 ml isopropyl acetate, 50 ml of dichloromethane and 25 ml of dichloromethane. The organic phases are evaporated down and the residue is separated off by preparative HPLC. 500 mg of the product are obtained.