Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([NH2:28])[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([NH:28][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22]
Reactant: Brc1ccc2cnccc2c1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](Nc2ccc3cnccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
124 mg of 6-bromoisoquinoline (3), 488 mg of cesium carbonate and 202 mg (2S,4R)-4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester hydrochloride were dissolved in 6 ml of DMF and degassed. 46 mg Palladium acetate and 132 mg of Xanthphos were added and the mixture was stirred at 100° C. for 5 h. After cooling to rt the mixture was filtrated, evaporated and the residue was purified by chromatography on silica gel (50% ethyl acetate in heptane to 100% ethyl acetate). To obtain (2S,4R)-4-(Isoquinolin-6-ylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colourless oil.
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:6]=1[O:7][C:8]([C:11]1[N:12]([CH3:35])[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20](CC2C=CC(OC)=CC=2)[CH2:19]3)=[N:14][N:15]=1)([CH3:10])[CH3:9].[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[F:4][C:5]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:6]=1[O:7][C:8]([C:11]1[N:12]([CH3:35])[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH2:19]3)=[N:14][N:15]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CN2Cc3cc(-c4nnc(C(C)(C)Oc5ccc(F)cc5F)n4C)ccc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: Cn1c(-c2ccc3c(c2)CNC3=O)nnc1C(C)(C)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
Acetonitrile (25 ml) and water (8.3 ml) were added to 5-{5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-(4-methoxybenzyl)isoindolin-1-one (629 mg), and cerium (IV) ammonium nitrate (1.71 g) was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:20% methanol-chloroform solution=100:0 to 0:100), the solvent was evaporated under reduced pressure, and the residue was solidified with 2-propanol:diisopropylether (1:1) to obtain, as a colorless powdery solid, 5-{5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-triazol-3-yl}isoindolin-1-one (247 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](C#C)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:12](SC1C=CC(I)=CC=1)[CH2:13][CH2:14][CH2:15][CH3:16]>C(NCC)C.[Cu]I>[C:4]1([C:1]#[C:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCSc1ccc(I)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The product from step 2.4 (2.82 g) and the product from step 2.2 (6.0 g) were mixed in diethylamine (44 ml). Copper (I) iodide (0.026 g) and dichloro di(triphenylphosphine) palladium (0) (0.193 g) were then added and the mixture was then stirred at 20° C. under argon for 16 hrs. Purification by chromatography gave 4.3 g or tolane product, rapt. 43° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[NH:19][N:20]=[CH:21][CH:22]=2)[O:12]1.C(N(CC)C(C)C)(C)C.Cl.[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>C(O)(C)C>[N:20]1[NH:19][C:18]([C@@H:13]2[C@H:14]([OH:17])[C@H:15]([OH:16])[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[O:12]2)=[CH:22][CH:21]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2ccn[nH]2)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1[C@H](O)[C@H](n2cnc3c(NC4CCOCC4)ncnc32)O[C@@H]1c1ccn[nH]1
Yield: 12.4 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furan-3,4-diol (35 mg) was dissolved in isopropanol (3 ml), N,N-di-isopropylethylamine (0.12 ml) and tetrahydro-pyran-4-ylamine hydrochloride (46 mg) were added, and the resulting solution was heated under reflux under nitrogen for 17 h. The solvent was removed in vacuo, the residue dissolved in methanol (10 ml), and 8% sodium bicarbonate (3 ml) added, followed by silica gel (3 g). The solvents were removed in vacuo and the residue added to a flash column of silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4:1) afforded the title compound as a clear viscous gum (5.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[OH:41][CH:38]1[CH2:39][CH2:40][N:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:22]3[CH:21]=[C:20]([O:19][C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[S:13])=[CH:43][CH:42]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:30][CH2:31]2)[CH2:36][CH2:37]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 4 h
Yield: 19 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (214 mg) and (+)-10-camphorsulfonic acid (105 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=100:0 to 97:3) to provide the title compound (58.6 mg, 19%) as white powder.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>C1COCC1>[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (1.99 g, 50% in oil, 41.4 mmol, extracted with hexanes) was stirred in THF (50 ml) in a flame-dried flask at 0° C. under nitrogen. Indole-3-carboxaldehyde (5.00 g, 34.5 mmol) was added as a powder in small portions, and then the mixture was warmed to 40° C. for 30 min. The mixture was again cooled to 0° C., and benzyl chloroformate (4.92 ml, 34.5 mmol) was added. After warming to room temperature and stirring overnight, the mixture was poured into water (50 ml) and extracted with CH2Cl2 (50 ml). The organic layer was washed with water (50 ml), dried with MgSO4, filtered and evaporated to 9.2 g (95%) of a gold-brown oil. Crystallization from hot hexane gave 8.47 g (88%) of white crystalline product: mp 70°-71°
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:23]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)=O)[CH:12]=[C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][CH:34]([OH:36])[CH3:35]>C1(C)C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:23]3[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:33]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:34](=[O:36])[C:35]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C(C(=O)c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)=C1c1ccccc1
Temperature: 2 °C
Reaction time: 0.7 h
Yield: 85.3 %

Procedure:
3,5-bis(phenylethynyl)benzil (65.6 grams, 0.16 mole) prepared in the manner of Example 1,1,3-diphenylacetone (37.8 grams, 0.18 mole), 2-propanol (583 milliliters) and toluene (218 milliliters), were added to a 2 liter glass four neck Morton reactor containing a magnetic stirring bar. The reactor was additionally outfitted with chilled (2° C.) condenser, a thermometer with thermostatically controlled heating mantle and a subsurface tube for sparging with nitrogen. Under a nitrogen atmosphere, an addition funnel was loaded with tetrabutylammonium hydroxide (1M in methanol) (5.46 milliliters) diluted into 2-propanol (97 milliliters) which had been sparged with nitrogen. This addition funnel was then attached to the reactor under dynamic nitrogen flow. Sparging and heating of the stirred slurry commenced, and after 42 minutes, once a reflux (80° C.) was achieved, a clear light yellow colored solution had formed. At this time, the sparge tube was move up out of the solution in the reactor to provide nitrogen overhead, then dropwise solution of the catalyst commenced, inducing the formation of a dark red color. After 92 minutes at reflux, 44 milliliters of the catalyst solution had been added and HPLC analysis indicated that full conversion of the 3,5-bis[phenylethynyl)benzil reactant had been achieved, with minimum formation of coproducts. After a cumulative 101 minutes at reflux, the heating mantle was removed from the reactor, additional 2-propanol was added (413 milliliters), then an ice bath was placed under the reactor and the stirred contents were maintained therein for the next 39 minutes until a temperature of 5° C. was achieved. The product was recovered via filtration through a coarse flitted glass funnel. The product cake on the funnel was washed with two portions (50 milliliters) of 2-propanol, giving a clear filtrate with the second wash. Drying in a vacuum oven to provided 79.66 grams (85.3 percent isolated yield) of 4-(3,5-bis(phenylethynyl)-phenyl)-2,3,5-triphenylcyclopentadienone (unsymmetrically substituted 3,5-AAB monomer) as a dark red purple colored crystalline product. HPLC analysis revealed the presence of the desired product at 100 area percent.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].Br[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][CH:21]=2)[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:12]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: Brc1cccc2ccccc12
Product: CCNC(=O)c1c(Cl)cccc1-c1cccc2ccccc12
Yield: 28 %

Procedure:
The title compound was prepared from the compound of Example f and 1-bromonaphthalene (0.76 g, 3.65 mmol) according to General Method D. It was obtained as 0.28 g of a white solid, a 28% yield. m.p. 181-182° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9]OC(=O)CC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].[SH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1>O>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 60 °C
Yield: 82.3 %

Procedure:
In water (30 ml) were dissolved 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (3.14 g), sodium hydrogen carbonate (1.84 g) and 5-mercapto-1-methyl-1H-tetrazole (1.4 g) and the solution was adjusted its pH to 5.5, followed by stirring and heating at 60° C. for one hour. After cooling, the reaction solution was washed with dichloromethane (20 ml) and the aqueous layer was adjusted to pH 3.3, followed by stirring for one hour under ice-cooling. The resultant precipitates were collected by filtration and washed with water, methanol and acetone in this order, followed by drying to give 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.7 g).
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([N+:15]([O-])=O)[CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[N:11]=[CH:10]2>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([NH2:15])[CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[N:11]=[CH:10]2
Reactant: Cn1ncc2cc([N+](=O)[O-])cc(Cl)c21
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cn1ncc2cc(N)cc(Cl)c21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
Tin (II) chloride (50 mg) was added to a ethanol (2 ml) solution containing 7-chloro-1-methyl-5-nitro-1H-indazole (30 mg), followed by stirring at 100° C. for 0.5 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 0:1). 7-Chloro-1-methyl-1H-indazol-5-amine (10 mg) was thus obtained.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([CH:14]=[O:15])=[CH:13][C:7]=2[O:6]1.N#N.O>ClC(Cl)C>[Cl:2][CH2:5][O:6][C:7]1[C:8]([OH:9])=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:13]=1)[CH:14]=[O:15]
Reactant: [Cl-]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: N#N
Agent: [Al+3]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Reaction time: 1.25 h
Yield: 96.7 %

Procedure:
AlCl3 (6 g) and dry dichloroethane (15 ml) are added to a three-neck round bottom flask, which has been purged with N2, and the dispersion is cooled to -5°. A solution of 6-nitropiperonal (3 g; 0.0154 mol) (available from Aldrich Chemical Co.) in 12 ml dry dichloroethane is added to the dispersion, in one portion, while the temperature and N2 atmosphere are maintained. The reaction mixture is stirred for 1.25 hours, and 100 ml H2O (0°) is added. The emulsion is stirred for 15 minutes, then extracted with 3×100 ml ethyl acetate. The combined organics are washed with saturated NaCl, then dried over Na2SO4. After filtration, the ethyl acetate is removed at reduced pressure. Recrystallization from ethyl acetate gives 3.45 g (97%) of (10): mp 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[N+](=[CH2:26])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([CH3:26])[N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: C=[N+]=[N-]
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Solvent: CO
Solvent: ClCCl
Product: Cn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 3 h

Procedure:
A solution of 2.65 g of 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one in a mixture of 16 ml of methanol and 16 ml of methylene chloride is treated at 0° with 100 ml of ethereal diazomethane solution. After 3 hours, a further 33 ml of diazomethane solution are added and the mixture is left to stand for a further 2 hours. After evaporation of the solution, the residue is chromatographed on 80 g of silica gel while eluting with chloroform/ethanol (99:1). The crude product is recrystallized from ether/hexane. There is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-2-methyl-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 142°-143°.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C(N1C=CN=C1)([N:20]1C=CN=C1)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (6.0 g., 0.024 mol) and 1,1'-carbonyldiimidazole (4.0 g., 0.024 mol) in dimethylformamide (120 ml) is heated at 110° C. for 2.5 hours under nitrogen. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice bath temperature for 2 hours and at room temperature for one hour. The precipitate is filtered off, washed with tetrahydrofuran and dried to give the product (5.2 g.), mp 340° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:6]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 2 h
Yield: 10.4 %

Procedure:
Into around-bottom flask, was placed a solution of 2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoic acid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). EDC.HCl (67 mg, 0.35 mmol, 2.00 equiv), 4-dimethylaminopyridine (64 mg, 0.52 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 39 mg, 0.18 mmol, 1.00 equiv) were added and the solution was stiffed for 2 h at room temperature. The reaction was quenched with water (20 mL) and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organics was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep Phenyl, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (30% CH3CN up to 60% in 9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (8.0 mg, 10%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>CN(C=O)C.N1C=CC=CC=1>[NH2:24][C:25]1[C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=[CH:32][C:33]=1[NH:34][C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)c2cc(Cl)nnc2Cl)c1N
Temperature: 50 °C

Procedure:
3,6-Dichloropyridazine-4-carboxylic acid (1.15 g, 5.96 mmol) and 1,1′-carbonyldiimidazole (CDI (0.97 g) in DMF (25 ml) were stirred at room temperature for 2 h. A solution of 2,3-diaminobenzamide (1.30 g, 5.96 mmol) in pyridine (25 ml) was added and the solution heated at 50° C. for 4 h. The cooled solution was concentrated and partitioned between ethyl acetate (EtOAc) and water, the organic layer separated, dried, filtered and concentrated to give the product.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.579 g) was dissolved in chloroform (15 mL) and was cooled in an ice bath to 1° C. NBS (1.02 g) was added gradually, keeping the reaction temperature below 2° C. The reaction was stirred for 30 mins (with cooling in an ice bath) before being allowed to warm to room temperature. The reaction was then stirred for 6 h. Chloroform (50 mL) was added and the mixture was partitioned with water (50 mL) and was separated using a hydrophobic frit. The organics were evaporated under reduced pressure to give the title compound as a brown foam (1.867 g).
Reaction SMILES: [N:1]1([C:8](=[O:32])[CH:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](O)([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[O:23][CH3:24])[CH2:14][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C>[N:1]1([C:8](=[O:32])[CH:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[O:23][CH3:24])[CH2:16][CH2:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccsc1C1(O)CCN(CCC(C(=O)N2CCCCCC2)c2ccccc2)CC1
Solvent: CC(=O)O
Product: COc1ccsc1C1=CCN(CCC(C(=O)N2CCCCCC2)c2ccccc2)CC1

Procedure:
The title compound was prepared from 1-azepan-1-yl-4-[4-hydroxy-4-(3-methoxy-thiophen-2-yl)-piperidin-1-yl]-2-phenyl-butan-1-one (1.35 g, 2.9 mmole) and acetic acid (80 mL) in the manner previously described above to yield 1.1 g of product, m.p. 108°-12 ° C.