Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Reactant: C1CNCCN1
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1cscc1N2

Procedure:
A bomb charged with 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine, 8.6 g. of piperazine, and three drops of acetic acid is placed in an oil bath and heated at 155°-160°C. for 4 days. The bomb is then cooled and the contents are dissolved in 2N acetic acid. The solution is filtered and the filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extracts are dried, filtered and evaporated to give a yellow solid. Recrystallization from ethanol gives the product as light tan crystals which melt at 228°-231°C. (dec.).
Reaction SMILES: [H][H].BrC1C=C2C(C(C)(C)CCC2=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](OCC)=[O:26])[CH:21]=[CH:22][CH:23]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
In the preferred compounds of the invention the two R1 substituents are methyl, and the R2 and R3 substituents are hydrogen. Reaction Scheme 2 illustrates a synthetic process for preparing 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention. Thus, referring now specifically to Reaction Scheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL-H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Compound G is covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:17])[NH:9][N:10]2[C:14]([CH3:15])=NN=[C:11]2[CH3:16])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:20])C>>[C:14]([N:10]1[C:11]([CH3:16])=[N:17][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:20])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nnc(C)n1NC(=N)c1ccc(Cl)cc1
Product: CC(=O)n1nc(-c2ccc(Cl)cc2)nc1C

Procedure:
63.6 g (254.0 mM) 4-Chloro-N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)benzenecarboximidamide prepared in part B and 67 ml of acetic anhydride in a 300 ml round bottom flask equipped with a distillation head are heated to 170° in an oil bath. A solution forms from which acetic acid distills off in the first few minutes. The mixture is refluxed for 2.5 hours and the excess acetic anhydride is evaporated to dryness under vacuum to produce a residue comprising a mixture of the title compound and its 1-acetyl-5-(4-chlorophenyl)-3-methyl isomer. The residue is triturated with 120 ml of water at room temperature and filtered. The filter cake is dissolved in 1 liter of hot ethanol, filtered hot, and the product precipitated from the hot alcohol by adding 3 liters of cold water. The product is filtered off, wshed with water, and dried at 80° under vacuum to yield 37.6 g of the 1-acetyl-3-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole as a crystalline material (99% pure), m.p. 132°-133°.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CS(O[CH2:23][CH:24]1[CH2:27][C:26]([F:29])([F:28])[CH2:25]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1([F:29])[CH2:27][CH:24]([CH2:23][O:1][C:2]2[C:3]3[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:25]1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCC3CC(F)(F)C3)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.85 g (7.89 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A and 2.37 g (9.47 mmol) of (3,3-difluorocyclobutyl)methyl methanesulphonate Example 105A were initially charged in 104 ml of DMF, and 10.28 g (31.56 mmol) of caesium carbonate were added. The reaction mixture was stirred at 60° C. overnight. After cooling, the reaction mixture was filtered, the solid was washed thoroughly with ethyl acetate, the filtrate was concentrated and about 150 ml of water were added to the residue. The solid formed was filtered off and dried under high vacuum. This gave 2.51 g (89% of theory; purity 95%) of the title compound.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.N[C@H](C(N[C@@H](C(NC[C:65]([NH:67][C@H:68]([C:76]([OH:78])=[O:77])[CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=O)=O)C)=O)CC1C=CC(O)=CC=1.[NH2:79][C@H:80]([CH2:85][OH:86])[CH2:81][CH2:82][S:83][CH3:84]>C1COCC1.C(O)(=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([N:67]([CH3:65])[C@H:68]([C:76]([OH:78])=[O:77])[CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:79][C@H:80]([CH2:85][OH:86])[CH2:81][CH2:82][S:83][CH3:84]
Reactant: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: CSCC[C@H](N)CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
1.23 g of Boc-Tyr-(D)Ala-Gly-OH is dissolved in 30 ml of THF and cooled to 15°. 0.38 ml of ethylmorpholine are added with stirring followed by 0.39 ml of chloroformic acid iso-butyl ester and stirring continued for 10 minutes. A cold solution of 14 g of TFA.H-MePHe-methioninol and 0.45 ml of N-ethylmorpholine in 12 ml of TFA are added with stirring at -15°. The mixture is stirred for 20 hours at 0°, diluted with 250 ml of acetic acid and washed repeatedly with water, 1 N citric acid, 10% KHCO3 and 30% NaCl solution. The liquid is dried over Na2SO4 and evaporated. The residue is purified chromatographically on kieselgel using a mixture of methanol/CH2Cl2 /50% acetic acid, whereby the title compound is obtained. Decomp. 160°.
Reaction SMILES: CC[N:3](CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].N[C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][C:18]1[C:19](=[O:39])[O:20][C:21]2[CH:31]=[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[C:29]([Cl:38])=[CH:28][C:22]=2[C:23]=1[CH2:24][C:25](=[O:27])[NH2:26]>C(Cl)Cl>[C:25]([CH2:24][C:23]1[C:22]2[CH:28]=[C:29]([Cl:38])[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:31][C:21]=2[O:20][C:19](=[O:39])[C:18]=1[CH:17]([NH2:3])[C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([S:9]([CH3:8])(=[O:11])=[O:10])[CH:15]=1)(=[O:27])[NH2:26]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CC(N)=O)c2cc1Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc2oc(=O)c(C(N)c3cccc(S(C)(=O)=O)c3)c(CC(N)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Et3N (13 μL, 0.093 mmol) and methanesulfonyl chloride (3.6 μL, 0.050 mmol) were added to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester (20 mg, 0.047 mmol) in methylene chloride (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (5.0 mg, 22%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:31]([O:30][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]([CH3:14])[C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:26][CH:25]=1)([CH3:28])[CH3:29])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)O)cc2)c1Sc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 2-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)propan-2-ol (Example 73, 300 mg, 0.69 mmol) in 4 mL of pyridine and 4 mL of acetic anhydride was added catalytic amount of DMAP. After stirring at 60° C. for 2 hr, the reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness to afford 1-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)-1-methylethyl acetate which was used in the next step without further purification.
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10](O)[CH:11]=2)N=CN=1)C.C[O:17]C1C=CC=CC=1O.[Cl:25][CH2:26][C:27](Cl)=[O:28]>>[Cl:25][CH2:26][C:27]([O:28][C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:17]
Reactant: COc1ccccc1O
Reactant: O=C(Cl)CCl
Reactant: CCc1ncnc2cc(OC)c(O)cc12
Product: COc1ccccc1OC(=O)CCl
Yield: 75 %

Procedure:
4-ETHYL-7-METHOXYQUINAZOLIN-6-OL.--2-Methoxyphenol was esterified by reaction with chloroacetyl chloride to give in 75% yield, 2-methoxyphenyl chloroacetate, m.p. 60°-61.5°. This material was acylated with propionic acid in the presence of polyphosphoric acid to produce 2-methoxy-5-propionylphenyl chloroacetate in 75% yield, m.p. 77°-79.5° C. This ester was hydrolyzed with sodium acetate in methanol to yield 1-(3-hydroxy-4-methoxyphenyl)-1-propanone, m.p. 91°-92°, yield 90%. Benzylation of the later by treatment in acetone with benzyl chloride and potassium carbonate yielded 1-(3-benzyloxy-4-methoxyphenyl)-1-propanone, m.p. 83°-85°, yield 96%. The latter was then nitrated by treatment with 1:3 nitric acid/acetic acid at 18°-20° to yield 1-(2-nitro-4-methoxy-5-benzyloxyphenyl)-1-propanone, m.p. 120.5°-123°, yield 65%. Reduction of this material with hydrazine hydrate and Raney nickel yielded 1-(2-amino-4-methoxy-5-benzyloxyphenyl)-1-propanone. The latter was cyclized by treatment with formic acid and formamide to yield 6-benzyloxy-4-ethyl-7-methoxyquinoline, yield 80%, m.p. 132°-134°. Catalytic hydrogenation of the latter resulted in debenzylation to yield 4-ethyl-7-methoxyquinolin-6-ol in 85% yield, m.p. 200°-202°.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+]>O>[F:10][C:11]([F:15])([F:14])[CH2:12][O:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-chloronicotinonitrile (0.30 g, 2.2 mmol) was a mixture of 2,2,2-trifluoroethanol (0.19 mL, 2.6 mmol) and potassium tert-butoxide (1M solution in THF, 2.5 mL, 2.5 mmol) added at 0-5° C. The resulting mixture was stirred at ambient temperature for 1 hour. Water was added (20 mL) followed by extraction with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuum affording 6-(2,2,2-trifluoroethoxy)nicotinonitrile, 0.42 g (96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=2.26 Hz, 1 H) 8.28 (dd, J=8.53, 2.26 Hz, 1 H) 7.21 (d, J=8.78 Hz, 1 H) 5.0 (q, J=8.95 Hz, 2 H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24](Cl)=[O:25].O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24]([NH:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:25]
Reactant: NC1C(=O)Nc2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC1C(=O)Nc2ccccc21)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under argon atmosphere and ice cooling, a solution of 16.5 g of triethylamine in 50 ml of methylene chloride was added dropwise to a stirred mixture of 15.05 g of 3-amino-2,3-dihydro-1H-indol-2-one hydrochloride and 17.20 g of 3,4-dichlorobenzoyl chloride suspended in 300 ml of methylene chloride. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with 100 ml of water, and the whole was stirred for additional 2 hours. The resulting precipitates were collected by filtration, washed and then recrystallized from dimethylformamide-water to afford 22.9 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1H-indol-3-yl)benzamide as colorless needle crystals. Melting point: 283° to 285° C. (decomposed), IR (Nujol) (cm-1) : 3280, 3160, 3100, 1710, 1690, 1635, MS (m/z): 322 & 320 (M+), 147 (base).
Reaction SMILES: [C:1](=[O:22])([O:12]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]([OH:12])=[O:2].[C:32]1([N:38]2[CH2:43][CH2:42][N:41]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 14 h
Yield: 11.7 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 1.58 g, 5.1 mmol) was dissolved in DMF (25 mL). DIPEA (0.87 mL, 5.0 mmol) and 4-phenyl-piperazine (807 mg, 0.76 mL, 5.0 mmol) were added and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated in vacuo. The residue was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-100%) to give 2-(4-methyl-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate formate (113 mg, 6.7%) as a yellow oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1C(F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:11]([N:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:13][CH2:12]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: CN1CCCNCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C

Procedure:
36.2 g of sodium bicarbonate and 28.7 mL of N-methylhomopiperazine are added to a solution of 15 g of 4,5-difluoro-2-nitroaniline in 120 mL of anhydrous DMF. The reaction medium is heated to 80° C. using an oil bath for 2H30. The reaction medium is cooled to ambient temperature, then poured into 500 mL of water. The mixture is cooled using an ice bath and stirred, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with water. The solid is dried in an oven at 40° C. 21.2 g of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenylamine are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 2.22 (s, 3H); 2.45 (m, 4H); 3.17 (m, 4H); 6.42 (d, J=8.0 Hz, 1H); 7.34 (broad s, 2H); 7.63 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=254: M+. (base peak)—m/z=239: (M−CH3)+—m/z=234: (M−HF)+.−m/z=183: (M−C4H9N)+—m/z=70: C4H8N+—m/z=43: C2H5N+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=34)[S:21]2(=[O:33])=[O:32])[CH2:14][CH2:13]1.[H-].[Na+].[CH3:36]I.O>CN(C)C=O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:36])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=34)[S:21]2(=[O:32])=[O:33])[CH2:16][CH2:17]1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1cc(CC2CCN(CCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2cc(F)ccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) in dimethylformamide (40 cc) is added in the course of 15 minutes to a 50% strength dispersion of sodium hydride (0.27 g) in liquid paraffin, under a stream of argon, while the temperature is maintained in the region of 20° C. The reaction medium is stirred for 1 hour at a temperature in the vicinity of 20° C. and a solution of methyl iodide (0.4 cc) in dioxane (20 cc) is then added in the course of 15 minutes. Stirring is maintained for 15 hours at a temperature in the vicinity of 20° C. The reaction mixture is taken up with distilled water (25 cc) and the organic phase is extracted with dichloromethane (4×50 cc), then washed with distilled water (25 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column under a stream of argon at moderate pressure (0.5-1.5 bar) with dichloromethane and then a mixture of ethyl acetate and methanol (97:3 by volume) as eluent. 2-{2-[4-((5-Fluoro-1-methyl-3-indolyl)methyl)piperidino]ethyl} naphtho[1,8-cd]isothiazole 1,1-dioxide (0.8 g) is obtained in the form of a yellow oil, which is converted to an acid oxalate, m.p. 150°-152° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[S:10][C:11]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[CH:17]=3)=[C:12](NC)[N:13]=2)[CH2:3]1.[CH2:24]([N:26]([CH2:29]C)CC)[CH3:25].C(OC(=O)C)(=[O:33])C>ClCCl>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[S:10][C:11]([C:16]3[CH:17]=[C:18]([CH3:23])[N:19]=[C:20]([CH3:22])[CH:21]=3)=[C:12]([CH2:29][NH:26][C:24](=[O:33])[CH3:25])[N:13]=2)[CH2:5]1
Reactant: CNc1nc(N2C[C@@H](C)O[C@@H](C)C2)sc1-c1cc(C)nc(C)c1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCc1nc(N2C[C@@H](C)O[C@@H](C)C2)sc1-c1cc(C)nc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A mixture of Intermediate 5 (150 mg, 0.45 mmol) and triethylamine (0.063 mL, 0.54 mmol) was stirred in dichloromethane (6 mL) at room temperature. Acetic acid anhydride (0.051 mL, 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with a potassium carbonate solution. The organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC (RP Shandon Hyperprep C18 BDS—8 μm, 250 g, 5 cm; mobile phase (0.25% NH4HCO3 solution in water, MeOH+CH3CN)), yielding 100 mg (59%) of Compound 60.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[Br:28][C:29]1[CH:33]=[N:32][N:31]([CH3:34])[C:30]=1[NH2:35]>C(OCC)C>[Br:28][C:29]1[CH:33]=[N:32][N:31]([CH3:34])[C:30]=1[NH:35][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12]
Reactant: Cn1ncc(Br)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(Br)cnn3C)c2o1
Yield: 6.4 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 4-bromo-2-methyl-2H-pyrazol-3-ylamine (93 mg). Purification by column chromatography on silica eluting with 1-5% methanol in dichloromethane afforded, after trituration with diethyl ether, the title compound as a white solid (7 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:31][CH:30]=1>>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)=[O:19])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: COc1ccc(N(C(=O)c2cccc(C(F)(F)F)c2)C(C)C(=O)O)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1cccc(C(F)(F)F)c1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(m-trifluoromethylbenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(m-trifluoromethylbenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(m-trifluoromethylbenzoyl)2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 119° to 121°).
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(Cl)([Cl:18])=O.[CH3:20]O>>[ClH:18].[CH3:20][O:14][C:13](=[O:15])[CH:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: COC(=O)C(N)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
50 g of DL-tryptophan available from Nakarai Chemicals, Kyoto, Japan, was suspended in 500 ml of methanol and 40 ml of thionyl chloride was dropwise added thereto while vigorously stirring. The reaction was exothermic and the reaction mixture was allowed to be refluxed for 10 hours while stirring. Then, the solvent was distilled off and the resultant residue was washed with diethylether. Thus, DL-tryptophan methylester hydrochloride was obtained in the form of white crystals.