Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 12.3 g of (3R, 4S)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 150 ml of DMF is added a solution of 1.6 g of potassium cyanide in 24 ml of water under ice-cooling and the mixture is stirred at room temperature (approx. 25° C.) for 30 minutes. To the reaction mixture are added ice water and ethyl acetate, and the ethyl acetate layer is taken, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column [eluant: ethyl acetate-n-hexane (1:1)] to give 6.7 g of (3S, 4RS)-4-cyano-3-tritylamino-2-azetidinone (4R:4S=1:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH2:14][CH3:15].CCN=C=NCCCN(C)C.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: Cc1cc(O)c(C(=O)O)c(=O)o1
Reactant: CCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOC(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
In 30 ml of toluene, 0.85 g of 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylic acid, 0.9 g of 1-propanol and 0.12 g of 4-dimethylaminopyridine were dissolved, and 0.96 g of WSC was added to the mixture, and the mixture was stirred at room temperature for 16 hours. Subsequently, water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated a saturated solution of sodium chrolide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.37 g of propyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 2).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[OH-].[Na+].C1(C)C=CC=C(O[C:21](=[NH:25])[NH:22][C:23]#[N:24])C=1.C1C(O)=CC=CC=1C>C(O)(C)C>[C:21]([NH:22][C:23]([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[NH:24])#[N:25]
Reactant: NCCCc1c[nH]cn1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CC(C)O
Product: N#CNC(=N)NCCCc1c[nH]cn1
Temperature: 25 °C

Procedure:
6.2 g. (0.031 mole) of 4-(3-aminopropyl)imidazole dihydrochloride is converted to the free base using NaOH. The free base is combined with 5.4 g. (0.031 mole) of O-m-tolyl-N-cyanoisourea in 100 ml. isopropanol. This mixture is refluxed for 3 hours. The mixture is then cooled to room temperature, filtered to remove insoluble material and the solvent is evaporated to obtain a cloudy oil of the product mixed with m-cresol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2cc[nH]c2c1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
Indole-6-carboxaldehyde (90 mg, 0.62 mmol) was dissolved in anhydrous methanol (3 mL). Methylamine (0.95 mL of 2M solution in methanol, 1.86 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (3 mL). Sodium borohydride (24 mg, 0.62 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (2 mL, 1N) was added and the indole was extracted with ethyl acetate (3×10 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (98 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.12 (d, J=3.1 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.81 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].C(O)[C@@H](O)C(O)[C@@H](O)[CH2:15][OH:16]>>[OH:10][CH2:1][C@@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:15][OH:16])[OH:9])[OH:7])[OH:5])[OH:3]
Reactant: OC[C@@H](O)C(O)[C@@H](O)CO
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Xylitol (for example, “Xylitol P” manufactured by Nikkne Chemical and Synthetic Industry Co., Ltd., “Xylisorb” manufactured by Roquette, and “Xylit P” manufactured by Towa Chemical Industries Co, Ltd.; etc.
Reaction SMILES: [C:1](=[O:21])([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=CC=C(Br)[CH:5]=1.BrC1C=C(CO)C=CC=1.[CH3:31][C:32]1[C:63]([CH3:64])=[CH:62][CH:61]=[CH:60][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]1[C:49]2[C:44](=[C:45]([C:50]3[CH:51]=[N:52][N:53](C(C)(C)CO)[CH:54]=3)[CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39]>>[C:1](=[O:21])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:2][CH2:3][C:4]([N:52]1[CH:51]=[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:44]=2[CH2:43][CH2:42][CH2:41][N:40]3[C:38](=[O:39])[CH2:37][CH2:36][CH2:35][O:34][C:33]2[CH:60]=[CH:61][CH:62]=[C:63]([CH3:64])[C:32]=2[CH3:31])[CH:54]=[N:53]1)([CH3:5])[CH3:9]
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(C(C)(C)CO)c4)cccc32)c1C
Agent: OCc1cccc(Br)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(C(C)(C)COC(=O)Oc5ccc([N+](=O)[O-])cc5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with 4-(2,3-dimethylphenoxy)-1-(5-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one. LCMS, [M+H]+=627.5.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CCCCCCO
Product: CCCCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and hexan-1-ol (100 μl; 0.781 mmol), example 46 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][S:4](=O)[S:5][CH2:6][CH:7]=[CH2:8].[OH2:10].CO>O.CC(C)=O>[CH2:1]=[CH:2][CH2:3][S:4][S:5]/[CH:6]=[CH:7]/[CH2:8][S+:4]([O-:10])[CH2:3][CH:2]=[CH2:1]
Reactant: O
Reactant: C=CCSS(=O)CC=C
Solvent: CC(C)=O
Solvent: CO
Product: C=CCSS/C=C/C[S+]([O-])CC=C

Procedure:
1 gram of Allicin as prepared above (in Example 4) was dissolved in 10 ml of 40% water-acetone solution and the solution was heated between 63–64 C for 4 hours. The reaction mixture was diluted with 30 ml of 50% water-methanol and washed 5 times with 10 ml of n-pentane. The pentane was kept aside for further processing. The lower water-acetone-methanolic layer was then saturated with ammonium sulphate and extracted with 20 ml dichloromethane. The dichloromethane layer was separated, dried with Magnesium Sulphate, filtered and evaporated to yield crude Ajoene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl([O-])(=O)(=O)=O.[Li+].Cl[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18].O>[N+](C)([O-])=O.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[C:17](=[O:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1ccc(C)cc1
Reactant: COC(=O)CCCCCCC(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COC(=O)CCCCCCC(=O)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
4-Methylanisole (732 mg) was dissolved in nitromethane (30 ml) to prepare a solution. Anhydrous lithium perchlorate (3.8 g), methyl 7-chlorocarbonyl-heptanoate (1.28 ml), and scandium triflate (300 mg) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give methyl 8-(2-methoxy-5-methylphenyl)-8-oxo-octanoate (992 mg, yield 57%).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1/[CH:20]=[N:21]/[S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23]>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C@@H:20]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1Br
Reactant: C=CCCCBr
Agent: II
Solvent: C1CCOC1
Product: C=CCCC[C@H](NS(=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1Br
Temperature: 40 °C
Yield: 53.8 %

Procedure:
To a 100 mL three-neck RBF equipped with stir bar and condenser was added Mg (excess), catalytic iodine, THF (20 mL), followed by 5-bromopent-1-ene (1.93 g, 12.9 mmol) added in small increments. The mixture was heated to 40° C. for 1 hour. The reaction was cooled to room temperature and the freshly made Grignard reagent was added via syringe into a 250 mL RBF with N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (2.3 g, 6.5 mmol) in THF (20 mL). Upon completion, the reaction was quenched with saturated aqueous NH4Cl and partitioned with ethyl acetate. The organic was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to yield N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}-2-methylpropane-2-sulfinamide (1.5 g, 3.5 mmol). 1H NMR (500 MHz, CDCl3) δ7.71 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.41 (d, J=6.4 Hz, 1H), 5.77 (m, 1H), 5.03 (m, 2H), 4.87 (m, 1H), 3.65 (m, 1H), 2.11 (m, 2H), 1.86 (m, 1H), 1.82 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.22 (s, 9H).
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:43])[NH:24][C:25](=[O:42])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH2:34][C@H:35]3[CH2:39][O:38]C(C)(C)[O:36]3)[CH:28]=2)=[CH:14]1>CO.O>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:43])[NH:24][C:25](=[O:42])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH2:34][C@H:35]([OH:36])[CH2:39][OH:38])[CH:28]=2)=[CH:14]1
Reactant: Cn1cc(C2=C(c3cccc(SC[C@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(SC[C@H](O)CO)c3)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Yield: 86 %

Procedure:
Toluenesulfonic acid (10 mg) was added to a solution of 3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (60 mg) in methanol (10 mL) and water (1 mL) and the reaction mixture was heated at 50° C. for 2 h. The volatiles were removed and the residue was partitioned between water and EtOAc. The organic layer was washed with NaCl (sat.) and dried over sodium sulfate. The crude product was purified on a silica gel column with 10/45/45 of MeOH/CH2Cl2/hexane and further purified by recrystallization from CH2Cl/hexane to give 3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (47 mg). MS (EI): M+ 408.
Reaction SMILES: CN1CCN([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N:13]3[N:17]=[N:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14]3)[CH:8]=2)C1=O.[I:25]C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[I:25][C:7]1[CH:8]=[C:9]([N:13]2[N:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(I)c1
Reactant: CN1CCN(c2cccc(-n3nnc(-c4ccccn4)n3)c2)C1=O
Agent: O=Cc1ccccn1
Product: Ic1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 1-methyl-3-[3-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]imidazolidin-2-one, but using 3-iodoaniline (11 g, 50 mmol) and pyridine-2-carboxaldehyde (4.7 mL, 50 mmol), 2-[2-(3-iodophenyl)-2H-tetrazol-5-yl]pyridine was obtained as a biege solid. 1H-NMR (CDCl3, 300 MH) δ NMR 8.92 (d, 1H), 8.69 (m, 1H), 8.44 (d, 1H), 8.30 (d, 1H), 8.03-8.06 (m, 1H), 7.87-7.88 (m, 1H), 7.56-7.59 (m, 1H), 7.32-7.35 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.018 g, 0.050 mmol) and pyridine (0.7 mL) in CH2Cl2 (0.7 mL) was added methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 36.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: NCCCCO
Reactant: O=C1N[C@H](C(=O)O)CS1
Product: O=C1N[C@H](C(=O)NCCCCO)CS1
Yield: 41.3 %

Procedure:
Following a procedure similar to that described in Example 16(a), but using 1.2 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.23 g of N-(4-hydroxybutyl)amine, 0.735 g of the title compound was obtained as colorless crystals, melting at 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:21]2[C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccc(Cl)cc1
Yield: 83 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-chlorobenzaldehyde as described in Example 11 to give 1-nitro-5-(p-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 217°-219° C. Yield: 83%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([Cl:23])[C:17]=1[CH:24]([O:26][C:27]1[CH:54]=[CH:53][C:30]2[N:31]=[C:32]([NH:34][C:35]([NH:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[O:36])[S:33][C:29]=2[CH:28]=1)[CH3:25].[OH-].[Na+]>ClCCl.C(OC(C)C)(C)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([Cl:23])[C:17]=1[CH:24]([O:26][C:27]1[CH:54]=[CH:53][C:30]2[N:31]=[C:32]([NH:34][C:35]([NH:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[O:36])[S:33][C:29]=2[CH:28]=1)[CH3:25]
Reactant: CC(Oc1ccc2nc(NC(=O)NCCN3CCN(C(=O)OC(C)(C)C)CC3)sc2c1)c1c(Cl)ccc(F)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(Oc1ccc2nc(NC(=O)NCCN3CCNCC3)sc2c1)c1c(Cl)ccc(F)c1Cl
Reaction time: 4 h

Procedure:
add 0.376 cm3 of trifluoroacetic acid to a solution of 0.250 g of 1,1-dimethylethyl 4-{2-[({6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}carbamoyl)amino]ethyl}piperazine-1-carboxylate trifluoroacetate in 5 cm3 of dichloromethane. Continue stirring for 4 hours at a temperature close to 20° C. The reaction mixture is then evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 10 cm3 of water. The mixture obtained is adjusted to pH 9 with a 1N solution of sodium hydroxide and then extracted three times with 20 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, then filtered and evaporated to dryness under reduced pressure (2 kPa). The white solid obtained is solidified in 5 cm3 of diisopropyl oxide, filtered and then dried under reduced pressure. We obtain 0.117 g of 1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-piperazin-1-ylethyl)urea trifluoroacetate in the form of a white powder, which has the following characteristics:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[H][H]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: O=C(CCCBr)c1ccccc1
Product: BrCCCCc1ccccc1

Procedure:
Subsequently, the 4-bromobutyrophenone (3) as obtained above is reacted with hydrogen in the presence of a metal catalyst to give 1-bromo-4-phenylbutane.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Temperature: 80 °C

Procedure:
To a suspension of 15 g (0.0794 mol) of 2,6-dichloropurine in 250 mL of absolute ethanol was added 12.7 mL (0.0873 mol) of triethylamine and 10.62 mL (0.0873 mol) of 4-chlorobenzylamine. The mixture was refluxed at 80° C. for 16 h (the formation of creamy white precipitate was observed). The reaction mixture was cooled and the precipitated product was removed by filtration. The precipitate was washed with ethanol (350 mL) and dried in high vacuum for 24 h. Product was characterized by 1H-NMR.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:19]=3[CH:20]=2)=[O:13])=[CH:9][N:8]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[C:31]1([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([NH:11][C:12]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:21][C:19]=4[CH:20]=3)=[O:13])=[CH:9][N:8]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1nc(-c2ccccc2)ncc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cnc(-c2ccccc2)nc1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 2-phenyl-5-(5-phenyl-benzofuran-2-ylmethoxy-carbonylamino)-pyrimidine-4-carboxylic acid methyl ester (0.956. g, 1.99 mmol) in THF (20 mL), was added lithium hydroxide monohydrate (0.167 g, 3.99 mmol) in 4 ml of water. The mixture was stirred at 5° C. for 2 h, and 1N HCl was added to adjust the pH to 2. The solvents were removed in vacuo and the resulting suspension was filtered. Recrystallisation of the white crude solid gave 0.82 g of 2-phenyl-5-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-pyrimidine-4-carboxylic acid, mp: 184-185° C.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27](=[O:28])[CH:26]=[C:25]3[C:20]([C:21]4[CH:31]=[CH:30][S:29][C:22]=4[CH2:23][CH2:24]3)=[N:19]2)=[CH:14][CH:13]=1>O(Cl)Cl>[OH:10][CH2:9][C:30]1[S:29][C:22]2[CH2:23][CH2:24][C:25]3[C:20]([C:21]=2[CH:31]=1)=[N:19][N:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)[C:27](=[O:28])[CH:26]=3
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCc2sccc2-3)cc1
Reactant: CN(C=O)c1ccccc1
Agent: ClOCl
Product: Cc1ccc(-n2nc3c(cc2=O)CCc2sc(CO)cc2-3)cc1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A mixture of 1.9 g of N-methylformanilide in 1.3 ml of phosphrus oxychloride was stirred at room temperature for an hour and 2.0 g of 2-(4-methylphenyl)-5,6-dihydrothieno-[2,3-h]cinnolin-3(2H)-one was added thereto. After stirring at room temperature for 10 hours, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol and 1.0 g of sodium borohydride was added thereto under ice-cooling. After stirring for an hour, the mixture was poured into diluted hydrochloric acid and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1) as an eluent. The solid was recrystallized from a mixed solvent of isopropyl alcohol and isopropyl ether to give 0.2 g of 8-hydroxymethyl-2-(4-methylphenyl)-5,6-dihydrothieno-[2,3-h]cinnolin3(2H)-one as a brown powder, melting at 166°-169° C.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][N:35]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:12][CH2:13][CH2:14]1)=[O:22])([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CCOC(=O)c1ccc(N)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 90 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (3.3 g, ˜80% purity, 5.79 mmol), ethyl 6-aminopyridazine-3-carboxylate (CAS-Nr. 98548-01-7, 1 g, 5.57 mmol), N,N-diisopropylethylamine (0.97 mL, 5.57 mmol) and activated 3 Å molecular sieves in isopropanol (30.4 mL) was heated for 20 hours under reflux. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo, taken up in DCM and washed with dilute aqueous hydrochloric acid (1N) and brine, dried and concentrated in vacuo to give the crude title compound. Purification was achieved by chromatography on silica (gradient elution: Hexane:EtOAc 9:1 to Hexane:EtOAc 1:1) to give the title compound (2.80 g, 92% purity, 90% yield).