Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(OCC)(=O)C>[ClH:23].[ClH:23].[CH3:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(NC2CCNCC2)c1C

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) (under an atmosphere of nitrogen for 10 minutes) was added 2,3-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) portionwise with stirring. The stirring was continued at ambient temperature for a further 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to as afford a transparent viscous liquid which was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (98%) of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (m, 2H), 4.1 (m, 2H), 3.5 (m, 1H), 3.0-2.9 (t, 2H), 2.3 (s, 3H), 2.1 (m, 2H), 2.0 (s, 3H), 1.5 (s, 9H), 1.4 (m, 2H). A solution of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.45 g, 0.00476 mole) in ethyl acetate.HCl (15 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 1.1 g (83) of (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 95.98%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.3 (m, 3H), 3.7 (m, 2H), 3.3 (d, 2H), 3.1 (bs, 1H), 2.9 (m, 2H), 2.3 (d, 6H), 2.1 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>C(OCC)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 142b. Melting Point: 202-205° C. (diethylether)
Reaction SMILES: Cl.[NH2:2]O.[CH:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (0.766 g, 11.03 mmol) was added to a solution of compound 11 (1.888 g, 5.51 mmol) in pyridine (5.5 mL). The solution was heated to 90 degrees for 10 minutes and then cooled to room temperature. Acetic anhydride (3.23 mL, 34.2 mmol) was then added to the solution. It was then stirred at room temperature for 30 minutes and then at 80 degrees for 1 hour. The reaction was concentrated to half the volume under reduced pressure and then diluted with 300 mL of water, extracted into ethyl acetate (3×), washed with brine, dried over Na2SO4, filtered and then concentrated. The resulting yellow oil was then purified by silica gel chromatography through a 40M Biotage column with gradient of 12-24% ethyl acetate in hexanes to give compound 12 (1.39 g, 74%) as a white crusty solid. LRMS (ESI): calc. 339.13; found 338.1 (M-H)−.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24](N)[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])([O:4]P(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:34].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C(C)=CC=CC=1>[CH:27]1[NH:28][C:29]2[N:20]([C@@H:18]3[O:19][C@H:15]([CH2:14][O:13][P:1]([OH:2])([OH:4])=[O:3])[C@@H:16]([OH:31])[C@H:17]3[OH:30])[CH:21]=[N:22][C:23]=2[C:24](=[O:34])[N:26]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1C
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Escherichia coli cells containing the recombinant DNA collected in Example 2 (3) were suspended (cell concentration was 100 g wet cell weight/ml) in 100 mM Tris-hydrochloride buffer (pH 8.0) containing 10 mM ATP, 10 mM inosine and 5 mM magnesium sulfate. Xylene was added to the suspension in a concentration of 10 ml/l. After thoroughly stirring, the mixture was allowed to stand at 30° C. for an hour. The reaction solution was analyzed by HPLC and an amount of 51 -IMP in the reaction solution was quantitatively determined. Almost all transformants did not produce 5'-IMP but 5'-IMP-producing bacteria were obtained in a proportion of 1 out of 50,000 samples, The thus obtained 5'-IMP-producing bacteria are transformants carrying a recombinant DNA containing inosine guanosine-kinase gene.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[NH2:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1.C(N(CC)CC)C>C(#N)C.CN(C=O)C>[CH2:4]([O:3][C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1)=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: NCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCCNC(=O)OCc1ccccc1)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.84 g (3.01 mmol) of N-carbobenzyloxy-ε-aminocaproic acid, 0.39 g (2.89 mmol) of 1-hydroxybenzotriazole hydrate, and 0.59 g (2.86 mmol) of DCC in 3 mL of acetonitrile and 6 mL of DMF is stirred at room temperature under nitrogen for 20 minutes. A quantity of 0.50 g (2.88 mmol) of tyramine hydrochloride followed by 0.40 mL (2.88 mmol) of triethylamine are added and the mixture is stirred for 2 days at room temperature. The mixture is filtered and the filtrate is evaporated. The residue is taken-up into EtOAc, refiltered, and evaporated to give a yellow oil. Purification via silica gel chromatography eluting with 9:1 CHCl3 -MeOH gives crystalline product; wt 0.98 g (88%); mp 107.8°-108.4° C.; MS (CI) 385 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:26][C:27]([F:30])([F:29])[F:28]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (33.0 g, 0.18 mol) and potassiuin carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:27](=[O:28])[NH:26][CH2:23][CH2:24][CH3:25])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CCCN=C=O
Product: CCCNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 83 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are reacted with n-propyl isocyanate according to the method described in Example 44. The crude product is recrystallized from ethanol. Thus, 0.63 g (83%) of the title compound are obtained. M.p.: 186°-187° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.[OH-].[K+].C(N)CC(C)C>CCO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (370 mg, 0.814 mmol), KOH (457 mg, 8.14 mmol), and isoamylamine (1.892 mL, 16.28 mmol) in EtOH (15 mL) was stirred at 100° C. under microwave irradiation for 2 hr. The reaction mixture was diluted with CH2Cl2. The mixture was filtered through SiO2 pad. The SiO2 cake was washed with a mixture of CH2Cl2/MeOH (c.a. 6/1). The organic solution was concentrated and purified by silica gel flash column chromatography [(5% 2,2,2-trifluoroethanol in CH2Cl2)/MeOH=1/0 to 85/15] to give the title compound. 1H NMR (400 MHz, DMSO-d6, with about 5 μL TFA) δ ppm 11.01 (br. s., 1H), 8.05 (s, 1H), 7.67 (br. d, J=8.30 Hz, 1H), 7.62 (br. d, J=8.30 Hz, 1H), 7.26 (t, J=2.80 Hz, 1H), 6.79 (s, 1H), 6.43 (dd, J=1.80, 2.80 Hz, 1H), 4.53 (s, 2H), 2.43 (s, 3H), 2.35 (s, 3H). HRMS calcd. for C19H16N4 (M+H)+ 301.1448. found 301.1459.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:6]=1)(=[O:4])=[O:3].C1([O:26][C:27](=O)[NH:28][C:29]2[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[N:30]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([O:37][CH3:38])[N:30]=[C:29]([NH:28][C:27]([NH:1][S:2]([C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:6]=2)(=[O:3])=[O:4])=[O:26])[N:34]=1
Reactant: COC(=O)c1cn(-c2ccccn2)nc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cn(-c2ccccn2)nc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
280 mg of Methyl 3-(aminosulfonyl)-1-(2-pyridin-yl)-1H-pyrazole-4-carboxylate and phenyl(4,6-dimethoxy-2-pyrimidinyl)carbamate were dissolved in 10 mL of acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene, 0.15 mL, was added, and the reaction was stirred one hour. The solution was diluted with 30 mL of ice-water and made acidic with concentrated hydrochloric acid. The solid that separated was collected to afford 260 mg of the title compound melting 183°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:25]2[CH:26]=[N:27][O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.73 g), 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (0.49 g), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAT) (0.40 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) (0.45 g) and N,N-dimethylformamide (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide (0.67 g, yield 70%) as a colorless prism. melting point: 134–135° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C1(C)C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([Cl:3])=[O:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
Thionyl chloride (4.0 ml, 55.0 mmol) was added dropwise to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidine-4-carboxylic acid (1.25 g, 3.98 mmol) in toluene (12 ml) and the mixture was heated at 80° C. for 2 hours. After this time, the reaction mixture was concentrated under vacuum to afford the title compound as a white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10]([NH:22][CH3:23])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[C:10]([NH:22][CH3:23])[N:9]=[C:8]2[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: CNc1nc(-c2cncc(Br)c2)c2cc(OC)c(OC)cc2n1
Reactant: CSc1ccc(OB(O)O)cc1
Product: CNc1nc(-c2cncc(-c3ccc(SC)cc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 105.2 %

Procedure:
Starting from 375 mg of 4-(5-bromo-3pyridyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 76 and 225 mg of 4-methylthiophenylboric acid, 440 mg of the title compound was obtained as pale yellow crystals in the same manner as in Example 48. m.p.; 170-172° C. MASS 419 (MH+)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:3][CH2:2]1.Br[C:24]1C=CC(OCC2CCC2)=C(C=1)C#N>>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:21])([CH3:22])[O:15]3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:2][CH2:24][CH2:3]1
Reactant: N#Cc1cc(Br)ccc1OCC1CCC1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)c(C#N)c2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCC3CCC3)c(C#N)c2)OC1(C)C

Procedure:
The preparation succeeds in a similar manner as described above for 2-cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with 5-bromo-2-cyclobutylmethoxybenzonitrile (5.0 g, 0.018 mol), giving 3.5 g of the desired product as colourless oil;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:28])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:26][C:24]1[S:25][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH:15]([OH:28])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:27][C:22]=2[N:23]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester (2.9 g, 7.1 mmol), a compound of formula (5), was dissolved in a 4N solution of HCl in dioxane (20 ml) and allowed to stir at room temperature for 4 hours. The solvent was evaporated under reduced pressure to yield a white solid. The white solid was dried under high vacuum, and then dissolved in methanol (250 ml). AG 1-X8 resin was added and the mixture shaken. Additional resin was added until a neutral pH was obtained. The resin beads were removed by filtration, and methanol removed from the filtrate under reduced pressure, and the residue placed under high vacuum overnight, to yield 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as an oil (1.9 g. 6.2 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.Cl>CN(C)C=O>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Agent: Cl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCN3CCN(c4ccccc4)CC3)c(=O)c12
Temperature: 110 °C
Reaction time: 120 h

Procedure:
2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.500 g, 1.35 mM) was stirred in dimethylformamide (10 mL), and N-phenylpiperazine (10 mL, 10.6 g, 65.5 mM) was added. The resulting yellow suspension was heated to ˜110° C. to form a clear yellow solution. The solution was heated for 6 hours during which time a precipitate formed. The suspension was cooled to room temperature and stirred for five days. The resulting yellow suspension was dissolved into aqueous methanol (500 mL, 50%). The pH of this solution was carefully adjusted to pH=6 with 1N hydrochloric acid (˜20 mL) which gave a yellow precipitate. This suspension was stirred for 1 hour and filtered to give the title compound contaminated with N-phenylpiperazine (0.753 g). This material was recrystallized from hot ethanol (200 mL) to give the title compound (0.428 g, 70%) as a yellow powder, mp 361-364° C.; MS(CI): 452 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25]O)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1>[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:17])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: OCc1ccc(C(F)F)o1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)nc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To the solution of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.35 g, 1.37 mmol) and (5-(difluoromethyl)furan-2-yl)methanol (0.20 g, 1.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise tributylphosphine (0.51 mL, 2.06 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and followed by the addition of 1,1′-azobis(N,N-dimethylformamide) (0.35 g, 2.06 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (4×20 mL). The organic solutions were combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/4) to afford the title compound as a white solid in 53% yield (0.25 g): 1H NMR (300 MHz, CDCl3) δ 6.60-6.50 (m, 1H), 6.52 (t, JH-F=54.2 Hz, 1H), 6.37-6.29 (m, 1H), 4.45 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.09-3.98 (m, 2H), 3.60-3.49 (m, 2H), 2.54 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].C[CH2:8][O:9][C:10]([CH2:12]P(OCC)(OCC)=O)=[O:11].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=O)[CH2:22]1>CN(C=O)C.O=O>[CH3:8][O:9][C:10](=[O:11])[CH2:12][C:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:21][CH:22]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1COc2ccccc21
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KOtBu (0.673 g, 6 mmol) was dissolved in dry DMF (10 ml) with exclusion of oxygen. Phosphonoacetic acid triethyl ester (0.87 ml, 6 mmol) was then added to the mixture. After 20 min a solution of benzofuran-3(2H)-one (0.536 g, 4 mmol) in dry DMF (10 ml, argon atmosphere) was added to this mixture. The reaction mixture was stirred at room temperature for 1 h and thereafter poured on to ice (50 ml) for working up. The mixture obtained was extracted with diethyl ether (4×20 ml). The organic phase was washed with water (4×20 ml), dried with Na2SO4 and then concentrated. The product formed was purified by column chromatography [silica gel 60 (50 g); cyclohexane, ethyl acetate (4:1)] and obtained in a yield of 0.372 g (48%) as a yellowish oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2].Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][C:27]4[CH2:28][CH2:29][CH2:30][CH:25]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=5)[C:26]=4[N:17]=3)=[CH:12][CH:13]=2)=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1ncc(-c2ccc(NC(N)=S)cc2)o1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: CCc1ncc(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Yield: 84.7 %

Procedure:
A solution of [4-(2-ethyl-oxazol-5-yl)-phenyl]-thiourea (124 mg, 0.50 mmol) and 2-bromo-6-phenyl-cyclohexanone (139 mg, 0.55 mmol) in ethanol (5 ml) was heated to reflux over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as eluent to yield the title compound (170 mg, 85%) as a brown solid. MS ISP (m/e): 402.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.18 (br s, 1H, NH), 7.49 (s, 4H), 7.26-7.30 (m, 3H), 7.19 (t, 1H), 7.12 (d, 1H), 4.05 (m, 1H), 2.77 (q, 2H), 2.75 (m, 2H), 2.12 (m, 1H), 1.70-1.88 (m, 3H), 1.25 (t, 3H).