Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:12])[NH:8][C:9]=1[CH2:10]C)(=[O:3])[CH3:2].[CH3:13]C(=O)CC(=O)CC.[OH-].[NH4+]>C(O)C>[CH3:10][C:9]1[NH:8][C:7](=[O:12])[CH:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH3:13]
Reactant: CCc1[nH]c(=O)ccc1C(C)=O
Reactant: CCC(=O)CC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-6. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone (and 5-Acetyl-6-ethyl-2(1H)-pyridinone)--A mixture containing 50 g of 2,4-hexanedione, 100 ml of ethanol and 50 ml of concentrated aqueous ammonium hydroxide was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at 50°-60° C. to a constant weight of 48.8 g, a pale yellow oil that solidified on standing at room temperature. The nmr spectrum of this solid in CDCl3 indicated it to be a mixture of 5-amino-4-hexen-3-one and 4-amino-3-hexen-2-one in a weight ratio of 65:35. The mixture of amino-hexen-ones was dissolved in 100 ml of dimethylformamide and treated with methyl 2-propynoate and the resulting mixture was first gently heated with stirring on a steam bath for 2 hours and then refluxed for 24 hours. The reaction mixture was allowed to cool to room temperature and allowed to stand at room temperature overnight. The crystalline material that separated was collected, washed with isopropyl alcohol and dried in vacuo at 90°-95° C. to yield 11.9 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. The mother liquor was concentrated on a rotary evaporator and the residue was crystallized from isopropyl alcohol, washed with ether and dried to yield another 10.4 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. (The filtrate was concentrated in vacuo to yield 57.8 g of an oily residue which was chromatographed on silica gel (700 g) using ether as eluant. Evaporation of the ether fractions yielded 22.4 g of the least polar component, an oily material, a middle fraction of 16.4 g, a viscuous gummy oil, and as the most polar component, 7.8 g, a solid which was recrystallized from isopropyl alcohol to yield a white amorphous powder, m.p. 140°-145° C., whose nmr spectrum showed it to consist of 90% 5-acetyl-6-ethyl-2(1H)-pyridinone. Six further recrystallizations of this product resulted in 1.5 g of pure 5-acetyl-6-ethyl-2(1H)-pyridinone, m.p. 162°-164° C., as shown by its nmr spectrum.)
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH2:9][S:10][CH3:11])[C:4]([O:6]CC)=[O:5])#[N:2].[K+].[Br-]>CO>[C:1]([C:3]([CH3:12])([CH2:9][S:10][CH3:11])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C)(C#N)CSC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CSCC(C)(C#N)C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-cyano-2-methyl-3-methylsulfanyl-propanoate (2.3 g, 12.3 mmol) was added to ice-cold sodium hydroxide (5 mL, 2N) under stirring. Methanol (10 mL) was added and the ice bath removed after an hour. After 45 minutes at room temperature, volatiles were removed under reduced pressure and the residue diluted with water (20 mL). Impurities were removed by ether extraction (2×30 mL). The aqueous layer was cooled in ice, acidified to pH 3 with dilute HCl and extracted with ethyl acetate (3×30 mL). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to leave a brown gum. Yield 1.32 g (68%): IR (KBr thin film) 1735 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.19 (br, 1H), 3.10 (d, J=14.2 Hz, 1H), 2.94 (d, J=13.9 Hz, 1H), 2.33 (s, 3H), 1.73 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 173.33, 118.82, 45.86, 41.66, 23.05, 17.62.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)[CH:6]=[O:7]
Reactant: c1cn[nH]c1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1cccn1
Temperature: 120 °C
Yield: 57.9 %

Procedure:
A mixture of 4-fluoro-3-methoxybenzaldehyde (2.00 g, 12.98 mmol), pyrazole (1.32 g, 19.39 mmol), and powdered K2CO3 (2.68 g, 19.39 mmol) in DMF (20 mL) was heated to 120° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.52 g (58%) of the title compound as a yellow oil. MS 203 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:33][C:32](=[O:34])[NH:31][S:30]1(=[O:36])=[O:35])[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:33][C:32](=[O:34])[NH:31][S:30]1(=[O:36])=[O:35])[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25]
Reactant: O=C1CN(c2ccc(CC3NC(=O)c4ccccc4NC3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(CC3NC(=O)c4ccccc4NC3=O)cc2O)S(=O)(=O)N1
Reaction time: 0.13 h

Procedure:
A solution of 3-[3-benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione (452 mg, 0.89 mmol) in ethanol-acetic acid (2:1, 12 mL) is hydrogenated over 10% palladium on charcoal catalyst (106 mg) at 50 psi for 24 h. The catalyst is filtered and the filtrate is evaporated to dryness. The residue is purified by LC-MS, on a Gilson-Micromass instrument using a Phenominex Luna, 5μ, 60×21.2 mm, C-8 column, a gradient of 5% to 100% over 8 min with solvent A (water, 0.1% trifluoroacetic acid) and B (MeCN, 0.1% trifluoroacetic acid) with flow rate 20 mL/min, UV detector at 215 nm and cone voltage setting at 30 V. The purification is conducted with several runs with 50 mg of crude material being used in each run (approximately 16 runs). Pure fractions are pooled and evaporated to dryness, the residue is dissolved in water-MeCN and the solution is filtered and the filtrate is concentrated to give 3-[3-hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione as an amorphous solid: mp=180° C.; [M+1]+=417.
Reaction SMILES: Br[C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][CH2:11][CH2:12][OH:13])[N:4]([CH3:14])[N:3]=1.S(=O)(=O)(O)O>O>[NH2:7][C:6]1[CH:2]=[N:3][N:4]([CH3:14])[C:5]=1[NH:10][CH2:11][CH2:12][OH:13]
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1NCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1ncc(N)c1NCCO
Yield: 122.3 %

Procedure:
1 g (3.77 mmoles) of 3-bromo-5-(2'-hydroxyethyl)amino-1-methyl-4-nitropyrazole are hydrogenated in a solution of 380 mg (3.77 mmoles) sulfuric acid in 50 ml water for 2 hours according to method (2). 720 mg (75 percent of theory) of 4-amino-5-(2'-hydroxyethyl)amino-1-methylpyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 94° to 97° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].[C:28](=[O:31])([O-])[O-].[Cs+].[Cs+]>N1CCOCC1>[CH3:18][O:17][C:14]1[C:15]2[N:16]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:7]4[CH2:8][CH2:28][O:31][CH2:4][CH2:5]4)[CH:3]=3)[S:9][C:10]=2[C:11]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:12][CH:13]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCN1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide with cesium carbonate in morpholine. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NCCCn1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NCCCn1ccnc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A 2.50 g. portion of 1H-imidazole-1-propanamine was added to 20 ml. of toluene. A solution of 3.7 g. of m-trifluoromethylphenyl isocyanate in 20 ml. of toluene was added and the mixture was stirred overnight, then evaporated to a syrup. This syrup was triturated twice with ether giving 4.95 g. of crystals. These crystals were dissolved in methylene chloride, hot ethyl acetate or a mixture of the two and passed through a silica gel column, developing with 200 ml. of ethyl acetate and discarding the 200 ml. fraction. The column was then eluted with 10% methanol in ethyl acetate, collecting three 200 ml. fractions. These fractions were combined and evaporated in vacuo, giving 4.33 g. of the desired product as colorless waxy crystals, mp 105°-108° C.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[C:18]([CH3:19])=[C:17]([CH3:20])[CH:16]=[C:15]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CO>[C:7]([C:6]1[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:22][NH:26][CH:23]([CH3:25])[CH3:24])(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(C)c(C(=O)c2ccccc2)c(OCC2CO2)c1C
Reactant: CC(C)N
Solvent: CO
Product: Cc1cc(C)c(C(=O)c2ccccc2)c(OCC(O)CNC(C)C)c1C

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-3,4,6-trimethylbenzophenone (10.0 g.), isopropylamine (10 ml.) and anhydrous methanol (100 ml.) was heated at reflux for 17 hours. The solution was evaporated in vacuo and the residue was dissolved in water (100 ml.) containing concentrated hydrochloric acid (6 ml.). The solution was filtered through charcoal and kieselguhr, adjusted to pH 11 by means of 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed 3 times with water, dried over anhydrous sodium sulphate and evaporated. The residue was recystallized from cyclohexane to give DL-1-(2-benzoyl-3,5,6-trimethylphenoxy)-2-hydroxy-3-isopropylaminopropane (6.6 g.), m.p. 121°-123° C.
Reaction SMILES: Cl[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[C:12]([Mg]Br)#[CH:13]>O1CCCC1>[CH2:4]([O:3][Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[C:12]#[CH:13])[CH3:5]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#C[Si](OCC)(OCC)OCC
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Chlorotriethoxysilane (2.0 mL, 10 mmol, 1.0 equiv) was added to a stirred solution of 0.5M ethynylmagnesium bromide (20 mL, 10 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) at −78° C. The resulting heterogeneous light brown mixture was immediately warmed to 23° C. and stirred for 1 h. The resulting homogeneous light brown solution was heated to 50° C. and stirred for 4 h. The cooled reaction mixture was concentrated under vacuum. The resulting tan powder was slurried in hexane (50 mL), vacuum filtered, and rinsed with additional hexane (3×25 mL). The filtrates were dried over magnesium sulfate, gravity filtered, and concentrated under vacuum to provide the title compound as a pale yellow oil (1.5 g, 80% yield): IR (thin film) 3252 (w), 2976 (s), 2929 (m), 2913 (w), 2890 (m), 2046 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 3.90 (q, J=7 Hz, 6H), 2.35 (s, 1H), 1.23 (t, J=7 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][C:42](Cl)=[CH:41][C:37]=2[CH:38]=[N:39][CH:40]=1)=[O:34])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][CH:42]=[CH:41][C:37]=2[C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1)=[O:34])[CH3:31]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1cncc2cc(Cl)sc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c2ccsc12
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To the solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL N,N-dimethylformamide, 27 mg (0.61 mmol) sodium hydride was added. After 15 min. 148 mg (0.61 mmol) chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was added and stirring was continued for another 2 h at room temperature. The reaction was poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate. The phases were separated, the aqueous layers extracted with 20 mL ethyl acetate and the combined organic layers washed with 20 mL water and 20 mL brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 75:25) to give the desired compound as a white solid (71%). MS (Turbo Spray): m/z=596.3 [M+H].
Reaction SMILES: C([O:3][CH2:4][CH2:5][C:6]1([CH2:20][CH2:21][O:22]C=C)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=C.Cl>O>[OH:22][CH2:21][CH2:20][C:6]1([CH2:5][CH2:4][OH:3])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[O:13][C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: C=COCCC1(CCOC=C)c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: O
Product: OCCC1(CCO)c2ccccc2Oc2ccccc21
Reaction time: 5 h

Procedure:
A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as in Example 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.) is heated on the steambath with vigorous stirring for 5 hours. The cooled mixture is extracted three times with ether and the combined extracts are dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from chloroform-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C. Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at 5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in dry pyridine (5 ml.) with stirring. The mixture is allowed to stand at room temperature for 20 hours and is then poured into a mixture of 3 N hydrochloric acid (20 ml.) and ice (10 g.), and the resulting mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with 3 N hydrochloric acid and water, dried over MgSO4, and evaporated to dryness. The solid residue is recrystallised from acetone-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37]C(=O)C3C=CC=CC=3)[C@@H:24]([O:25]C(=O)C3C=CC=CC=3)[C@H:14]2[O:15]C(=O)C2C=CC=CC=2)[C:9](=[O:46])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:47]>>[NH2:47][C:2]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:1][C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:24]([OH:25])[C@H:14]2[OH:15])[C:9](=[O:46])[N:8]=1
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Reactant: N
Product: CCCCC(N)=Cc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1

Procedure:
A solution of 14a (1.2 g, 1.9 mmol) in methanolic ammonia (saturated at −20° C.) was stirred in a pressure bottle for 18 hr. Evaporation of the solvents and flash chromatography of the residue using ethyl acetate/methanol (4:1) gave 17a as a light yellow solid, 0.47 g (77%). 1H-NMR (DMSO-d6): δ10.2 and 7.7 (2 bs, 2H, NH2); 7.83 (d, 1H, H-6, J6,5=6.9 Hz); 5.78 (s, 1H, H-1′); 4.72 (s, 1H, vinylic); 2.17, 1.50, 1.30 and 0.90 (4 m, 9H, n-butyl).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][CH2:14][CH2:13][NH:12][C:4]1[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: OCCNc1nc(Cl)nc2c1SCCC2
Product: OCCNc1nc(N2CCNCC2)nc2c1SCCC2

Procedure:
In the same manner as described in Example 17, 2-chloro-4-(2-hydroxyethyl)amino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was reacted with anhydrous piperazine to obtain 4-(2-hydroxyethyl)amino-2-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine which was then recrystallized from ethanol. Colorless needles. Melting point: 116°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH2:11]3)([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH2:11]3
Reactant: O=C1CC2CCc3ccc([N+](=O)[O-])cc3C2=NN1c1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C1=NN(c3ccccc3)C(=O)CC1CC2
Temperature: 25 °C

Procedure:
To a mixture of 9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in ethanol and water is added iron powder with stirring at room temperature. The mixture is heated up to 50° C. on a water bath with stirring and concentrated hydrochloric acid is added dropwise carefully. The resulting mixture is further stirred with heating at 80° C. and the filtrate is concentrated. To the residue is added an aqueous sodium hydroxide solution, and the alkaline solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off to give 9-amino-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)=[C:4]([NH2:17])[N:3]=1.[O-:18][CH2:19][CH3:20].[Na+].Cl>C(O)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([O:18][CH2:19][CH3:20])=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: CC[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2C1C=CCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 2-chloro-9-(2-cyclohexenyl)-9H-adenine (310 mg., 1.24 mmole) and a solution of sodium ethoxide in ethanol (0.25-1 N, ~10 ml.) was refluxed overnight under an atmosphere of nitrogen. The reaction mixture was poured into ice-water, neutralized with 1 N HCl and extracted with ethyl acetate (20 ml.). The extracts were washed with water, dried over Na2SO4 and filtered. The filtrate was evaporated and the residue then subjected to silica gel chromatography (silica gel 7 g., eluted with 1% CH3OH--CHCl3) to give the title product in 92% yield; m.p. 67°-72° C. IR(KBr): 3320, 2940, 1640, 1595, 1465, 1410, 1385, 1340 cm-1. UV: λmaxEtOH 254 nm(ε8400), 269 nm(ε12600). NMR(CDCl3): 1.44 (3H, t, J=7 Hz), 2.00(6H, m), 4.45(2H, q, J=7 Hz), 5.20(1H, m), 5.95(2H, m), 6.16(2H, s), 7.62(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 93 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were rented by the same way with the example 106 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.78 (s, 4H), 4.14 (s, 3H), 6.94-7.11 (m, 4H), 7.35-7.45 (m, 2H), 7.74-7.77 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:21])=[C:14]([CH2:19][CH3:20])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]([OH:21])=[CH:12][C:11]=3[OH:10])=[N:23][NH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCc1cc2c(=O)c(-c3ccc(Br)cc3)coc2cc1O
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2n[nH]cc2-c2ccc(Br)cc2)c(O)cc1O
Yield: 71 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-ethyl-7-hydroxy-chromen-4-one (0.13 g, 0.38 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was columned to give 4-[4-(4-bromo-phenyl)-1H-pyrazol-3-yl]-6-ethyl-benzene-1,3-diol as a white solid (0.0969 g, 71%); Rf 0.44 Cf SM 0.79 ethyl acetate/hexane (75/25).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:4]([Cl:9])[N:5]=1
Reactant: Clc1cc(Br)cc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(-c2ccccc2)cc(Cl)n1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
A round-bottomed flask was charged with 4-bromo-2,6-dichloropyridine (Combi-Blocks Inc., 553 mg, 2.437 mmol), phenylboronic acid (446 mg, 3.66 mmol) and trans-dichlorobis(triphenylphosphine)palladium (ii) (27.8 mg, 0.04 mmol). The vial was placed under nitrogen atmosphere using two evacuation/backfill cycles. 1,4-dioxane (12 ml) and sodium carbonate (775 mg, 7.31 mmol) in water (4.1 ml) were added. The reaction mixture was sealed under nitrogen and heated at 80° C. for 1.5 h. The reaction mixture combined with that on pp14 was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude material was dissolved in DCM, and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol, 26.7% yield) as light-yellow oil. MS m/z=224.0 [M]
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCC1CC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 49.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (170 mg, yield: 49.4%).