Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[C:30](=[O:32])[CH2:29][CH2:28][CH:27]4[CH3:26])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C#N)CC2)c(C)c1
Yield: 92.3 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1 g) described in Preparation Example 187 and 5-methylpyrrolidin-2-one (372 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (965 mg) was obtained.
Reaction SMILES: O1CCCC1.C([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19]2)C1C=CC=CC=1>[Pd].CO>[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19]2
Reactant: COC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2cccc(O)c2n1C
Yield: 101.6 %

Procedure:
In a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol was dissolved 2.31 g (7.82 mmol) of methyl 7-benzyloxy-1-methyl-2-indolecarboxylate. After 0.5 g of 10% palladium/carbon was added to the solution, catalytic hydrogenation was performed at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.63 g (>99%) of methyl 7-hydroxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[C:5]([OH:17])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH2:15]Cl>Cl>[Cl:3][C:4]1[C:13]2[O:12][CH:15]=[C:9]([CH2:10][C:11]([OH:14])=[O:1])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:17]
Reactant: O=c1cc(CCl)c2ccc(O)c(Cl)c2o1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1coc2c(Cl)c(O)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1N NaOH (56.7 mL) and 8-chloro-4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (2.78 g) was stirred at 100° C. for 1 h. After cooling, the reaction mixture was acidified with 6N HCl (10 mL). The precipitate was collected by filtration to give the title compound (1.65 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OC(c1cccc(Br)n1)C(F)(F)F
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(O)C(F)(F)F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanol (123 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].O.Cl.[C:10]([NH2:16])(=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:16][C:10](=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:3]
Reactant: CC(C)CC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC(=N)CC(C)C
Yield: 93.3 %

Procedure:
78.8 parts of methyl chloroformate and a mixture of 46.8 parts of potassium hydroxide in 215 parts of water are added via two inlets to a mixture of 113.8 parts of isovaleramidine hydrochloride in 530 parts of methylene chloride, at from 0° to 10° C., in the course of 25 minutes, while stirring. The mixture is stirred at 25° C. for 30 minutes, the phases are separated and the aqueous phase is extracted once with methylene chloride. The solvent is removed from the organic extract to give 123 parts (93.3% of theory) of N-methoxycarbonylisovaleramidine of melting point 82°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:62])[CH2:5][N:6]([C:8](=[O:61])[C@@H:9]([NH:25][C:26](=[O:60])[C@@H:27]([NH:52]C(OC(C)(C)C)=O)[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:62])[CH2:5][N:6]([C:8](=[O:61])[C@@H:9]([NH:25][C:26](=[O:60])[C@@H:27]([NH2:52])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:45])([CH3:46])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:35])=[O:36])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@@H](N)CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Compound E (7.4 g, 8.2 mmol) in DCM (24 mL) was treated with 4 M HCl in dioxane (24 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h. DCM and most of the dioxane were removed in vacuo to a total volume of ˜15 mL, and Et2O (300 mL) was added. Precipitated product was filtered off, washed with Et2O (150 mL) and hexane and finally dried in vacuo to afford compound F (6.34 g, 100% yield) as a cream solid. LC-MS [M+H] 811.4 (C34H50N8O11S2+H, calc: 811.94). Purity >95% (UV/254 nm). Compound F was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-methoxyphenylacetic acid (1.16 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 163° C.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: C=CCN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A solution of 3.3. g of allyl isocyanate in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 6.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride, with stirring. When the exothermic reaction has subsided, stirring of the reaction mixture is continued at 20° to 25° C. for a further hour and the solvent is then evaporated off. The residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 13.2 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-allylurea are obtained. Melting point: 187°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].C1COCC1.Cl[C:46]([O:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55]C)=[O:54])=[CH:51][CH:50]=1)=[O:47]>O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:46]([O:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=2)=[O:47])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 192 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 157 mg of sodium hydrogen carbonate were added 3 mL of THF and 1.5 mL of water, followed by addition of 133 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). It was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 228 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([O-:22])(=O)=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2].[Na+].P(Cl)(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([Cl:26])(=[O:22])=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)[O-])ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reaction time: 1 h

Procedure:
The 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride was prepared by dropwise treatment of a suspension of dry sodium 5-acetamido-1-acetoxynaphthalene-2-sulfonate in 100 ml. phosphoryl chloride with 5.5 ml. dry dimethylformamide in a nitrogen atmosphere. The reaction mixture was stirred 1 hour and then poured over 600 ml. of crushed ice. The crude product was filtered and dissolved immediately in 500 ml. chloroform. The solution was treated with activated charcoal and dried over anhydrous magnesium sulfate to give 10.8 g. (44%) of a resinous yellow product which showed a single spot on a thin-layer chromotography.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][CH:24]1[CH:29]([CH3:30])[CH2:28][CH2:27][CH2:26][CH:25]1[NH2:31]>>[CH3:23][CH:24]1[CH:29]([CH3:30])[CH2:28][CH2:27][CH2:26][CH:25]1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: CC1CCCC(N)C1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC(C)C2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2,3-dimethylcyclohexanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.75-0.76 (m, 3H), 0.85-0.95 (m, 3H), 1.55-1.74 (m, 8H), 1.86-1.97 (m, 4H), 2.07 (s, 3H), 3.10-3.18 (m, 1H), 4.43 (bs, 2H), 7.20-7.26 (m, 1H), 7.50-7.57 (m, 1H), 7.67-7.73 (m, 1H), 8.60-7.68 (m, 1H); MS (ESI) m/z 340.4 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Product: Cc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
19.77 g of 6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 100 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added chloroform and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 19.90 g of 3-chloro-6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxii) of the present invention).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[N:6][CH:7]=1.[NH4+].[Cl-].CCOC(C)=O>O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2cnc(Br)cn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnc(Br)cn2)c(N)c1
Temperature: 65 °C
Yield: 74.1 %

Procedure:
Into a 250 mL 3-necked roundbottom flask, was placed a solution of methyl 4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) (5.0 g, 14.2 mmol) in TI-IF (75 mL). This was followed by the addition of a solution of NH4Cl (3.8 g, 71 mmol) in H2O (25 mL). To the above was added Fe (4.0 g, 71 mmol) in several batches, while warming to a temperature of 65° C. The resulting solution was allowed to react for 3 hours at 65° C. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Undissolved material was removed by filtration. The filtrate was extracted three times with 200 mL of EtOAc and the organic layers were combined and dired (Na2SO4). After removal of the solvent, the residue was separated by silica gel chromatography eluting with a mixture of PE/EtOAc (starting at 10:1 and proceeding through 5:1, 3:1, and 2:1, v/v) to afford the product methyl 3-amino-4-(5-bromopyrazin-2-ylamino)benzoate (xi) (3.4 g, yield 74%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.1 g of 4-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 6.08 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 2.74 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-dimethylaminobenzoyl)piperazine having a melting point of 133°-134° is thus obtained.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([OH:53])=[O:52])[CH:48]3[CH2:49][CH:44]4[CH2:45][CH:46]([CH2:50][CH:42]2[CH2:43]4)[CH2:47]3)=[O:39])[CH:15]=1.[OH-].[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59]>CO>[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59].[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH3:4])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([O-:53])=[O:52])[CH:42]3[CH2:43][CH:44]4[CH2:45][CH:46]([CH2:47][CH:48]2[CH2:49]4)[CH2:50]3)=[O:39])[CH:15]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
A solution of 1 ml of DCM containing 0.05 g of the compound obtained in EXAMPLE 1' and 0.025 ml of a 45% solution of choline hydroxide in MeOH are left stirring for 15 minutes at 35° C. and the mixture is then concentrated under vacuum. The residue is triturated in 5 ml of ether and the precipitate formed is drained. 0.03 g of the expected product is obtained, m.p.=150° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:14]([O:18][C:19]([NH:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 20 h

Procedure:
63.6 ml of an N aqueous NaOH solution and 1.28 g of MgO are introduced, at 0° C., into 50 ml of dioxane containing 5 g of trans-4-(aminomethyl)cyclohexylcarboxylic acid, followed, slowly, by 6.94 g of di(t-butyl)carbonate in solution in 20 ml of dioxane. After 20 hours at room temperature, the mixture is filtered, the solvent is removed and the residue is taken up in 100 ml of H2O and the aqueous phase is washed with (C2H5)2O before acidifying it up to pH 2 by addition of KHSO)4 ; it is then extracted in CH3COOC2H5 to yield 7.3 g of trans-N-(t-butoxycarbonyl)-4-(aminomethyl)cyclohexylcarboxylic acid which melts at 125° C.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:33]([CH3:34])[CH3:35])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCCCCC[NH-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that discribed in Example 1, using as starting materials 81 mg of BOC-Phe-His-OH, 79 mg of H-Leu-Val-7-tert.-butoxycarbonyl-heptyl amide, 28 mg of HOBt and 57 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system: methylene chloride/methanol/concentrated ammonia 800:50:1). Rf (methylene chloride/methanol/concentrated ammonia 500:50:1)=0.33.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.CN(C)[CH:19]=[O:20].Cl>O1CCCC1.C(OCC)(=O)C>[NH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:19]=[O:20])=[N:11][N:10]=[N:9]1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of 5-phenyl-1H-tetrazole (500 mg, 3.42 mmol) in 10 mL of dry tetrahydrofuran was added dropwise s-butyllithium (1.04 mol/L, 6.6 mL, 6.9 mmol) under nitrogen at −78° C. After the reaction mixture was stirred at the same temperature for 30 min, N,N-dimethylformamide (2 mL, 30 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 10 min, 1M HCl (10 mL) was added. The solution was allowed to warm up to room temperature, diluted with ethyl acetate, and extracted. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by recrystallization (hexane 2.5 mL, ethyl acetate 2.5 mL) to obtain the title compound (390 mg, 99%).