Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25]([OH:27])=O)(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:25](=[O:27])[C:24]2[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:20])=[O:21])[CH:23]=2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccc(F)cc1OC
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by preparative HPLC using a gradient of methanol:water (10:90 to 95:5). Colorless foam (44%). MS (ESI): m/z=483.099 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>>[CH3:32][CH:31]([CH3:33])[C:30]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
2-Methyl-1-((R)-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-propan-1-one was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and isobutyryl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6](OC)[N:5]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]=[C:24](SC)[S:25][CH3:26])(=[O:22])=[O:21])[CH:15]=1.C[N:30](C)C=O>>[CH3:11][O:10][C:8]1[N:30]=[C:6]([CH3:7])[N:5]=[C:4]([NH:3][C:24]([S:25][CH3:26])=[N:23][S:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[N:9]=1
Reactant: CN(C)C=O
Reactant: CSC(=NS(=O)(=O)c1cccnc1)SC
Reactant: COc1cc(OC)nc(N)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(C)nc(NC(=NS(=O)(=O)c2cccnc2)SC)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.9 g of sodium hydride (50% oil dispersion) in 25 ml of dry N,N-dimethylformamide was added 2.3 g of 2-amino-4,6-dimethoxypyrimidine. The resulting yellow suspension was stirred at room temperature for 3 hrs., then added to 3.95 g of 3-pyridinylsulfonylcarbonimidodithioic acid, dimethyl ester. The reddish slurry was stirred at room temperature for 2 hours, poured into 250 g of icewater and filtered to remove 1.6 g of unreacted, carbonimidodithioic acid, dimethyl ester. The filtrate was adjusted to pH 4 by adding 10% hydrochloric acid and the precipitate was filtered off, rinsed with water until neutral and then dried invacuo to give 2.6 g of the desired compound, m.p. 146°-149° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[S:8]([O-:11])([O-:10])=[O:9].[Na+].[Na+].[OH2:14]>>[S:8]([O:6][C:1](=[O:7])[C:2]([S:8]([OH:11])(=[O:10])=[O:9])([S:8]([OH:11])(=[O:10])=[O:9])[C:3]([S:8]([OH:11])(=[O:10])=[O:9])([S:8]([OH:11])(=[O:10])=[O:9])[C:4]([OH:14])=[O:5])([OH:11])(=[O:10])=[O:9]
Reactant: O
Reactant: O=C1C=CC(=O)O1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(C(C(=O)OS(=O)(=O)O)(S(=O)(=O)O)S(=O)(=O)O)(S(=O)(=O)O)S(=O)(=O)O

Procedure:
75 parts of castor oil-β-naphthol oxethylation product (b) are reacted with 13.1 parts of maleic anhydride, 16.8 parts of anhydrous sodium sulfite and 146.0 parts of water.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=O)C(F)(F)F)[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12].CI.O>CN(C=O)C>[CH3:16][NH:15][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]([F:12])([F:13])[F:14])=[C:4]([Br:3])[CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Br)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CNc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 870 mg, 21.7 mmol) was added to a stirred, cooled (0° C.) solution of N-[3-Bromo-4-(trifluoromethoxy)phenyl]trifluoroacetamide (Description 50, 6.3 g, 18.0 mmol) in DMF (50 ml). The mixture was stirred at 0° C. for 20 min. and methyl iodide (1.35 ml, 21.7 mmol) was added over 5 min. The mixture was stirred at 0° C. for 45 min. and at room temperature for 4 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with water (3×100 ml) and brine (100 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (3:1 increasing to 1:1) to give the title compound as a tan oil (1.20 g, 25%). 1H NMR (250 MHz, CDCl3) δ7.11 (1H, dq, J 8.9, 1.2 Hz), 6.86 (1H, d, J 2.8 Hz), 6.56 (1H, dd, J 8.9, 2.8 Hz), and 2.83 (3H, s).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH2:6][N:7]([CH3:14])[C:8](=[O:13])[C:9]([O:11]C)=[O:10])[CH3:4].[OH-].[Na+]>O>[ClH:1].[CH3:4][N:3]([CH2:5][CH2:6][N:7]([CH3:14])[C:8](=[O:13])[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: COC(=O)C(=O)N(C)CCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN(C)C(=O)C(=O)O
Yield: 84.3 %

Procedure:
Methyl N-dimethylaminoethyl-N-methyloxamate hydrochloride (500 mg) was dissolved in water (20 ml) and the resulting solution was cooled on an ice bath under stirring. To this cooled solution was added dropwise a solution of sodium hydroxide (356 mg) in water (10 ml). After the completion of the addition, the ice bath was removed and the reaction solution was stirred at room temperature for further 1 hour and then adjusted the pH thereof to 4 with the addition of 1N aqueous HCl. The solvent was distilled off under a reduced pressure and the residue was dissolved in a small amount of water and subjected to chromatographic separation and purification on a resin,"Diaion IRA-400" ion-exchange resin using water 1N aqueous NCl as eluent. The eluates are distilled under a reduced pressure to remove the solvent, yielding N-dimethylaminoethyl-N-methyloxamic acid hydrochloride (395 mg) as a white power.
Reaction SMILES: [C:1]([C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])(=O)[CH3:2].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(OC(C1C=CC=CC=1)CN1CCCCC1)(=O)CC(C)=O.[NH2:64][C:65]1[CH:69]=[CH:68][NH:67][N:66]=1>C(O)C>[CH3:2][C:1]1[NH:64][C:65]2[N:66]([N:67]=[CH:68][CH:69]=2)[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:4]=1[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6]
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(CN1CCCCC1)c1ccccc1
Agent: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC1=C(C(=O)OC(CN2CCCCC2)c2ccccc2)C(c2cccc([N+](=O)[O-])c2)n2nccc2N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1-phenyl-2-piperidinoethyl α-acetyl-3-nitrocinnamate prepared from 7.5 g of 3-nitrobenzaldehyde and 14.5 g of 1-phenyl-2-piperidinoethyl acetoacetate is added a solution of 4.2 g of 3-aminopyrazole in ethanol, and then stirred at 50° C. for 3 hours. The mixture is concentrated at reduced pressure, and the residue is purified by column chromatography on silica gel with chloroform-ethyl acetate-ethanol eluents to give two forms of diastereromers. The initally eluated solution is concentrated and the residue is recrystallized from ethanol to give one form (α-form) of diastereomer of 1-phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate, melting at 92°-93° C. Then, the subsequently eluated solution is concentrated and the residue is recrystallized from ethanol to give the other form (β-form) of diastereomer of 1-phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate, melting at 191°-192° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[N:25]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]1=[O:38]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[N:25]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:24]2=[O:38])[CH2:13][CH2:12]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)n(-c2ccc(F)cc2)c1=O
Product: Cc1cn(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c(=O)n(-c2ccc(F)cc2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-(3-chloropropyl)-3-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-3-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 220°-222° C.; Anal.: Calcd. for C26H28F4N4O3.(HCl)2.(H2O)0.1 : C, 52.46; H, 5.11; N, 9.41%; Found: C, 52.21; H, 4.91; N, 9.26%;
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and p-methoxybenzaldehyde (0.019 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 25%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.72 (br s, 4H, piperazine N(CH2)2), 3.83 (s, 3H, OCH3), 7.10 (d, J=8.79 Hz, 2H, 3,5-ArH or 2,6-ArH), 7.24 (d, J=3.51 Hz, 1H) and 7.50 (d, J=3.55 Hz, 1H) (thiazole 4-H, 5-H), 8.09 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, 2H, J=8.76 Hz, 3,5-ArH or 2,6-ArH); 11.95 (s, 1H, CONH), 13.72 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OC(=O)C)(=O)[CH3:27].Cl>N1C=CC=CC=1.O>[CH3:26][C:27]1[O:1][N:2]=[C:3]([C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][CH:12]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:11]3)=[N:7][CH:6]=2)[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 100 °C

Procedure:
To N′-hydroxy-2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (190 mg, 0.51 mmol) in pyridine (1.5 mL) at rt was added acetic anhydride (48 μL, 0.51 mmol) and heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water, acidified with 1 N HCl (20 mL) and extracted with EtOAc. The EtOAc layer was washed with diluted brine, dried (Na2SO4) and concentrated. Combi-Flash chromatography (10 g, 50-100% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a white solid which was triturated with Et2O to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 7.81 (s, 1 H), 7.71-7.65 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.52 (s, 1 H), 3.98 (m, 1 H), 3.84-3.67 (m, 3 H), 2.61 (s, 3 H), 2.60-2.43 (m, 2 H). MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1.O>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[C:5]([N:2]([CH3:1])[NH2:3])=[N:6][C:7]([S:16][CH3:17])=[N:8][CH:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CNN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1N(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of methyl hydrazine (4.0 g, 0.087 mol, 2 eq) in ethanol (50 mL) was slowly added to a solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (10 g, 0.043 mol) in ethanol (50 mL) while keeping the reaction temperature below 15° C. After the addition was completed, the reaction mixture was stirred for 2 hours at the room temperature. Water (100 mL) was then added and the formed product was isolated by filtration. After drying, the product was recrystalized from a 1:1 toluene-hexane mixture to give 7.3 g (69%) of the desired 4-(N-methyl-hydrazino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester; LC/MS (m/e)=243.1 (MH+), Rt=1.15 min.
Reaction SMILES: P(O[CH2:14][C@H:15]1O[C@@H:18](N2C3N=CN=C(N)C=3N=C2)[C@H:17](O)[C@@H:16]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.N[C@@H:33]([CH2:37][CH2:38][C:39](N[C@H](C(NCC(O)=O)=O)CS)=[O:40])[C:34]([OH:36])=[O:35].[Cl-].[Ca+2].[Cl-]>P([O-])([O-])([O-])=O>[OH:40][C:39]([CH:14]=[CH:15][CH:16]=[CH:17][CH2:18][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:38][CH:37]=[CH:33][C:34]([OH:36])=[O:35]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: CCCCCCCCCCCC=CC=CC(O)=CC=CC(=O)O

Procedure:
5-Lipoxygenase activity was determined according to the method described by Ochi et al., J. Biol. Chem.,258, p. 5754, 1983 using a crude enzyme fraction prepared from peritoneal exudated cells of guinea pigs which were induced by intraperitoneal injection of 2% case in solution. A solution of a test drug was mixed with a reaction solution (2mM ATP, 1 mM glutathione, and the enzyme fraction in 50 mM phosphate buffer, PH 7.4) and the mixture was pre-incubated at 37° C. for 5 minutes. Calcium chloride (1 mM) and 20 μM14C-arachidonic acid were added to the mixture, and then the mixture was subjected to a reaction at 37° C. for 10 minutes. After the completion of the reaction, the product was immediately extracted, dissolved in chloroform/methanol (2:1), and developed by thin-layer chromatography. Radioactivity of the 5-hydroxyeicosatetraenoic acid (5-HETE) fraction was measured using a liquid scintillation counter. Inhibitory rate of each drug-treated group against 5-HETE generation was obtained in comparison with the solvent-treated control, and IC50 was calculated according to the probit method. The results obtained are shown in Table 2 below.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O

Procedure:
239 mg (1.16 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 0.14 ml (1.28 mmol) of 2,4-pentanedione, 0.085 ml (1.45 mmol) of acetic acid and 0.01 ml (0.12 mmol) of piperidine are heated under reflux in 25 ml of anhydrous dichloromethane for 3 h. After addition of 80 mg of pyridinium para-toluenesulfonate and heating under reflux for a further 12 h, the reaction solution is washed with water and with brine and concentrated. 308.4 mg (91% of theory) of a red oil are obtained and are directly reacted further.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.C([BH3-])#N.[Na+]>O.C(O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.9 %

Procedure:
To a stirred solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (1.65 g) and dimethylamine hydrochloride (16.3 g) in water (3.74 ml) and ethanol (6.2 ml) was added 2 N hydrochloric acid (3.74 ml). After 15 min. at room temperature, a solution of dimethylamine in water (40%) (0.85 ml) was added followed by a solution of sodium cyanoborohydride (0.156 g) in water (1 ml). After 1h, the solution was evaporated in vacuo and to the oily residue was added acetic acid (0.5 ml). After 10 min., tetrahydrofuran (100 ml) and an excess of anhydrous sodium carbonate were added, the mixture heated to boiling and allowed to cool to room temperature. After standing for 3 h, the mixture was filtered and the combined filtrate and washings evaporated to low bulk in vacuo. Decolourising charcoal was added to the hot solution and after 1h, the mixture was filtered. The filtrate was evaporated to give an oil (1.7 g) which was chromatographed on silica using methanol:0.88 ammonia (79:1) to give an oil which was dissolved in ethanol. The solution was filtered and evaporated to give an oil (0.75 g) which was crystallised from methyl isobutyl ketone to yield the title compound (0.27 g), m.p. 68°-69.5° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No. 1,565,966.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.O=[CH:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:2][CH2:3]1)#[N:8]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: N#CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of piperidine-4-carbonitrile (1.10 g, 10 mmol), tert-butyl 2-oxoethylcarbamate (1.59 g, 10 mmol) and sodium triacetoxy borohydride (2.5 g, 12 mmol) in 25 ml of CH2Cl2 was stirred at room temperature overnight. Solvent was evaporated and ethyl acetate was added and washed with water. The solvent was removed in vacuo to provide oil. The crude oil was purified by column chromatography (100% ethyl acetate) to yield colorless oil (2.3 g, 91%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]([O:27][C:28]([NH:30][C@@H:31]([C:40]([OH:42])=O)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:29])([CH3:26])[CH3:25].Cl.Cl.[Br:45][C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[CH:51][N:50]=[C:49]2[N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:24]([O:27][C:28](=[O:29])[NH:30][CH:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:40]([N:59]1[CH2:60][CH2:61][N:56]([C:49]2[C:48]3[C:53](=[CH:54][CH:55]=[C:46]([Br:45])[CH:47]=3)[N:52]=[CH:51][N:50]=2)[CH2:57][CH2:58]1)=[O:42])([CH3:23])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Brc1ccc2ncnc(N3CCNCC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDCI.HCl (230 mg, 1.2 mmol), HOBt (160 mg, 1.2 mmol) and Boc-D-4-chlorophenylalanine (240 mg, 1.2 mmol) were added to a stirred solution of 6-bromo-4-piperazin-1-yl-quinazoline bis-hydrochloride (360 mg, 0.98 mmol) and triethylamine (0.30 mL, 1.2 mmol) in DMF (8 mL) at room temperature under nitrogen. Stirred at room temperature overnight. Diluted with EtOAc (100 mL) and washed with water (3×50 mL.) Dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (100% EtOAc) to give [2-[4-(6-bromoquinazolin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester as a yellow solid (320 mg, 57%.) MS (APCI+) [M+H]+ 575.9. 1H NMR (CDCl3, 400 MHz) δ 8.75 (1H, s), 7.95 (1H, s), 7.85-7.79 (2H, m), 7.30-7.27 (2H, m), 7.17 (2H, d, J7.1 Hz), 5.39 (1H, app. d, J8.2 Hz), 4.86 (1H, app. d, J 7.3 Hz), 3.83-3.60 (6H, m), 3.36-3.26 (2H, m), 3.04-2.96 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16]
Reactant: COc1cccc(C=CC=O)c1
Reactant: NNC(N)=S
Product: COc1cccc(C=CC=NNC(N)=S)c1
Yield: 52 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-methoxycinnamaldehyde (2.47 mmol) and from thiosemicarbazide (2.47 mmol). Yield 52%.