Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C:7](=[O:19])[C@H:6]([OH:20])[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:19])[C@H:6]([OH:20])[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](O)[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](O)[C@H]1c1ccccc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
0.2 g (0.6 mmol) of (8R,9R)-10-acetyl-8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one is dissolved in 15 ml of methanol and admixed with 40 mg (1.1 mmol) of sodium borohydride in portions with ice cooling. After 10 min, hydrolysis is effected using saturated sodium hydrogencarbonate solution and extraction using dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether. 0.16 g (80%) of the title compound is isolated as a colourless solid (m.p. 260-261° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:19]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)([CH3:18])[CH2:9][O:10][C:11]([C:16]#[N:17])([CH2:14][F:15])[CH2:12][F:13])[C:5]([F:32])=[CH:4][N:3]=1.C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:18])[CH2:9][O:10][C:11]([CH2:14][F:15])([CH2:12][F:13])[C:16]([NH2:17])=[N:19]2)[C:5]([F:32])=[CH:4][N:3]=1
Reactant: CC(COC(C#N)(CF)CF)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(c2cc(Br)ncc2F)COC(CF)(CF)C(N)=N1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A solution of N-[1-(2-bromo-5-fluoro-pyridin-4-yl)-2-(cyano-bis-fluoromethyl-methoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide (840 mg, 1.563 mmol), N-acetyl-L-cysteine (510 mg, 3.13 mmol) and K2CO3 (432 mg, 3.130 mmol) in abs. EtOH (10 ml) was stirred at 85° C. for 18 h. N-acetyl-L-cysteine (250 mg, 1.533 mmol) and K2CO3 (210 mg, 1.519 mmol) was added and stirring at 85° C. was continued for 18 h. The reaction mixture was concentrated to ⅓ of its volume, quenched with 10% aq. K2CO3 soln. and 3× extracted with TBME. The combined org. phases were washed with sat. aq. NaHCO3 soln, brine, dried over Na2SO4, filtered and concentrated to leave the crude title compound that was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 68:30:2 to 0:65:35),
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13]C(N)=[CH:11][CH:10]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CI.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:31]([N:30]([CH3:33])[CH3:29])=[CH:13][CH:14]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1
Reactant: CCOC(=O)c1cc(C)cc(-c2ccc(N)cc2)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1cc(C)cc(-c2ccc(N(C)C)cc2)n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-methyl-6-(4-aminophenyl)-2-pyridinecarboxylate hydrochloride (3.5 g), anhydrous potassium carbonate (8.8 g), dimethylformamide (30 ml) and methyl iodide (10 ml) is agitated at 50° C. for 30 minutes and further at 130° C. for 3 hours. After cooling, the reaction mixture is filtered to remove potassium carbonate. The filtrate is concentrated under reduced pressure in order to distill off the solvent. To the resulting residue is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water and dried, and ethyl acetate is distilled off to give ethyl 4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxylate (2.2 g). M.P. 143°-144° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[C@H:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:22][CH:23]=2)=[CH:16][N:17]=1)=O)(C)(C)C.CO>CCOCC>[CH3:52][O:51][C:49](=[O:50])[NH:48][C@H:41]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:40](=[O:53])[N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:32]1[NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:21]3[N:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][CH:16]=4)=[CH:19][N:20]=3)=[CH:25][CH:26]=2)=[CH:34][N:33]=1
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cold (0° C.) 4 NHCl in dioxanes (4 mL) was added via syringe to (S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-pyrimidin-5-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shaped flask followed by MeOH (0.5 mL). The homogeneous mixture was stirred at room temperature for 15 min before a precipitate was observed. After stirring further for 1.75 h, the suspension was diluted with ether and hexanes. Suction-filtration of a small portion of the suspension yielded the title compound as a yellow solid which was used for characterization purposes. The balance of the suspension was concentrated down to dryness and placed under high vacuum for 16 h. There was isolated the rest of the title compound also as a yellow solid (137.7 mg, 123%) which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[Br:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cc(F)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
Potassium carbonate (2.61 g, 18.8 mmol) was added to a solution of 2-bromo-5-fluorophenol (3.0 g, 15.7 mmol) in DMF (15.7 mL) and the mixture was stirred in a nitrogen stream at room temperature for 15 minutes. To this solution, benzyl bromide (2.69 g, 15.7 mmol) was added dropwise at the same temperature and the mixture solution was stirred at the same temperature overnight. To the reaction mixture was added a potassium hydrogensulfate aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography (developing solution=n-hexane) to obtain the title compound (4.31 g, 98%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([O:28][C:29](=[O:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)C>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][C:29]([OH:45])=[O:28])[CH:35]=5)[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: O=C(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid ethyl ester to give 152. MS(ESI+) 477.0. 1H NMR (400 MHz, DMSO) δ 13.61-12.69 (br, 1H), 8.31-8.26 (m, 2H), 8.25 (s, 1H), 7.99 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.95 (s, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>O>[Cl:18][CH:12]1[NH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][CH:10]=[C:11]1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(-c2ccc(Cl)cc2)[nH]c1=O
Solvent: O
Product: CC1=CN=C(c2ccc(Cl)cc2)NC1Cl
Yield: 92 %

Procedure:
2-(4-Chloro-phenyl)-5-methyl-3H-pyrimidin-4-one (570 mg, 2.58 mmol) was suspended in phosphorus oxychloride (2 ml) and heated to reflux for 2 hours. The mixture was cooled before being stripped to dryness in vacuo. The resulting crude product was solubilised in water (10 ml) and ethyl acetate (10 ml) and the biphasic mixture separated. The aqueous layer was further extracted with ethyl acetate (10 ml) before the combined organics were dried with magnesium sulphate, filtered and stripped to dryness in vacuo to give 6-Chloro-2-(4-chloro-phenyl)-5-methyl-1,6-dihydro-pyrimidine as a white solid (567 mg, 2.38 mmol, 92% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:11]([CH2:21][S:22][C:23]1[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=1)=[N:10][CH:9]=[CH:8]2.[C:32]([O:38][CH2:39]Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][C:17]([F:19])([F:20])[F:18])[C:11]([CH2:21][S:22][C:23]1[N:24]([CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=1)=[N:10][CH:9]=[CH:8]2
Reactant: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OCC(F)(F)F
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccnc(CSc3nc4ccccc4n3COC(=O)C(C)(C)C)c2cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of 30.8 mg of 60% NaH (0.77 mmol) in 5 ml of dry DMF was added 293.6 mg of 2-{[6-methoxy-7-(2,2,2-trifluoroethoxy)isoquinolin-1-yl]methylthio}benzimidazole (Ia-7) (0.7 mmol) and the mixture was stirred for 10 min. at room temperature. The mixture was mixed with 126.5 mg of chloromethyl pivalate, stirred for 2 hr. at room temperature and allowed to stand overnight. After DMF was distilled off in vacuo, the residue was mixed with water and extracted with CH2Cl2. The CH2Cl2 layer was dried over anhydrous sodium sulfat4e and concentrated. The residue was subjected to silica gel column chromatography, eluting with CH2Cl2 -AcOEt. Crude product was washed with cyclohexane to give 344.7 mg of the objective compound 2-{[6-methoxy-7-(2,2,2-trifluoroethoxy)isoquinolin-1-yl]methylthio}-1-pivaloyloxymethylbenzimidazole (Ib-10) (Yield: 92.3%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Brc1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(Br)cc3)CC2)c(OC)nc1C
Yield: 64 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:28])([F:29])[F:30])=[CH:24][C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
A N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (253 mg, 0.54 mmol) was treated with 4 N HCl solution in dioxane (4.0 mL) at room temperature. The solution was stirred for 2 h as a white solid was formed. The mixture was concentrated and the residue was dissolved in methanol. After removal of methanol, the residue was dried under high vacuum to obtain 221 mg (100% yield) of 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt as an amorphous white solid. ES-LRMS m/z 369.3 (M+H), 410.3 (M+CH3CN). h) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21

Procedure:
4-Bromo-1-(benzenesulfonyl)-1H-indole was prepared from 4-bromoindole and phenylsulfonyl chloride according to Method 4 to afford 3.1 g (91%) of a light purple solid: 1HNMR (CDCl3) δ 7.94 (d, J=8 Hz, 1H), 7.89–7.84 (m, 2H), 7.62 (d, 4 Hz, 1H), 7.57–7.51 (m, 1H), 7.46–7.37 (m, 3H), 7.19–7.13 (m, 1H), 6.72 (dd, J=1, 4 Hz, 1H); MS (ESI) 419.9+421.9 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[CH3:27][C:28]([NH2:41])([CH3:40])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.[BH4-].[Na+].O>C(O)C.ClCCl>[CH3:40][C:28]([NH:41][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:27])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)Cc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(Cc1cccc(C(F)(F)F)c1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 217 mg (1 mmol) 1,1-dimethyl-2-(3-trifluoromethyl-phenyl)-ethylamine are stirred for 3 hours in 5 mL ethanol at 65° C. The mixture is cooled to ambient temperature, 113 mg (3 mmol) of sodium borohydride are added and the mixture is stirred overnight. It is combined with 2 mL water, stirred for 30 minutes and then diluted with 10 mL dichloromethane. The solution is filtered through kieselguhr and washed with dichloromethane. The eluate is freed from solvent and the residue is dissolved in 5 mL ethanol and hydrogenated at 2.5 bar and ambient temperature with palladium on charcoal (10%) as catalyst. Then the catalyst is separated off and the crude product is purified by chromatography (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Beige solid. Yield: 169 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]+=425.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11].S(=O)(=O)(O)[OH:13].[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[NH2:10])=[CH:4][C:3]=1[NH2:11]
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1ccc(N)c(N)c1

Procedure:
To 1.03 g. of 1,2-diamino-4-cyanomethylbenzene (1.03 g.) was slowly added concentrated sulphuric acid (7 ml.). The mixture was heated at 90° for 90 minutes, then poured onto 50 ml. of water and ice and adjusted to pH 8 with NaOH. The precipitate which formed on cooling was discarded and the aqueous phase was concentrated to drynes. The residue was extracted with acetone, the extracts were concentrated and chromatographed on silica gel using CH2Cl2 /MeOH 9:1 to 8:2 v/v to give 1,2-diamino-4-carbamoylmethylbenzene (0.65 g.) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])(=O)=O>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][N:12]1[C:11](=[O:14])[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)=[N:13]1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCc1ccccc1Cl
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CCc2ccccc2Cl)c1=O
Yield: 59.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-(2-chlorophenyl)ethanol methanesulfonate were reacted to yield the title compound as a pale yellow solid (yield: 59.8%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1.Br[C:21]1[N:25]([CH3:26])[N:24]=[N:23][N:22]=1>C(O)C>[CH3:26][N:25]1[C:21]([NH:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)=[N:22][N:23]=[N:24]1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Reactant: Cn1nnnc1Br
Solvent: CCO
Product: Cn1nnnc1NCC(O)COc1cccc(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
A solution of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (1.19 g) and 5-bromo-1-methyl-1H-tetrazole (0.735 g) in absolute ethanol (6 ml) was heated in an autoclave at 125° for 18 h. The mixture was cooled, evaporated, saturated with sodium carbonate solution (30 ml) and ethyl acetate (30 ml) added. The mixture was stirred for 15 min. and filtered to give a white solid (830 mg) which was recrystallised from ethyl acetate (20 ml) to give the title compound (0.58 g) as white micro-crystals, m.p. 156°-7°.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:37]=[N+:38]=[N-])(C)C.N(OC(C)(C)C)=O>C(#N)C.O>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]=[N+:37]=[N-:38])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1N=[N+]=[N-])-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1.75 g of 20b in 40 ml of acetonitrile was added dropwise at 0° C. 0.54 g of trimethylsilyl azide, followed by 0.6 gr of tertbutyl nitrite. The reaction was stirred for ½ hr at ambient temperature, and then diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The remainder was chromatographed on silicagel (using a gradient of heptane/ethyl acetate as eluent), to provide 1.14 g of 20c. LCMS-ESI: [M+1] 476.17.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH2:31])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH:31][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1ccc2ccccc2c1
Yield: 95.6 %

Procedure:
142 mg (0.825 mmol) of 2-naphthoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 138 μl (0.991 mmol) of triethylamine to give the title compound (272 mg, 96%). ##STR83## TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.73, FD-MS: (M+H)+ =516, 518, 520, IR: 3420, 1625 cm-1.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:5]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][C:2]([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2ccccc2)cc1
Yield: 41 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 4-biphenylcarbonyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=7.2 Hz, 2H), 7.39-7.69 (m, 7H), 4.12 (q, J=6.9 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.30(t, J=7.5 Hz, 2H), 1.76 (m, 2H), 1.65 (m, 2H), 1.40 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[C:10]1[CH3:11]>CC(C)=O>[C:1]1([NH:8][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:15])=[O:16])[CH:2]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1cccc(N)c1
Solvent: CC(C)=O
Product: C/C(=C/C(=O)Nc1cccc(NC(=O)/C=C(/C)C(=O)O)c1)C(=O)O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A 3-liter, 3-neck round bottom flask was charged with 54 g (0.5 mole) of m-phenylenediamine and 500 ml of reagent acetone and flushed with nitrogen. The flask was fitted with a reflux condenser, mechanical stirrer and thermocouple. The solution was stirred as 112 g (1.0 mole) of citraconic anhydride in 500 ml of reagent acetone was added dropwise over about 11/2 hours as the temperature was allowed to rise to reflux the acetone. The reaction mixture was refluxed for an additional hour, cooled to room temperature and suction filtered to give 166 g of N,N'-(m-phenylene)bis citraconamic acid as shown by NMR analysis, as a tan mustard-colored solid melting at 152°-156° C.