Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCN(CCO)CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN(CCO)CCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To a solution of triethanolamine (1.044 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.179 g, 41%). Mass (m/z): 429.2 (M++1), 427.2 (M+−1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:20][CH2:21]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(N3CCNCC3)nc3ccc(F)cc3n12
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N#Cc1ccc(N2CCN(c3nc4ccc(F)cc4n4c(=O)[nH]nc34)CC2)nc1
Temperature: 25 °C

Procedure:
A solution of 40 mg of 8-fluoro-4-piperazin-1-yl-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 36.8 mg of 2-chloro-5-cyanopyridine, and 47 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to room temperature, filtered through a plug of diatomaceous earth, and evaporated to dryness. The residue was separated by silica gel chromatography to provide a white solid. MS (M−H)−=389.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[C:2]([NH:22][NH2:23])[N:3]=[N:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: Fc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1nncc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of 3-chloro-5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazine (586 mg, 2.05 mmol) in pyridine (3 mL) at RT was added hydrazine monohydrate (0.6 mL). After addition, the reaction was heated to 100° C. for 3 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The resulting mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturted Nacl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 1-(5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazin-3-yl)hydrazine (450 mg, 78%) as an off-white solid. LC/MS (method A): RT=1.10 min, (M+H)+=282.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:35])[CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[Cl:35][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(Cl)C(C)C)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.523 mL, 4.77 mmol) and 1-chloro-2-methylpropyl chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used without further purification in the following example. 1H—NMR (CDCl3, 400 MHz): δ 0.86 (2d, 6H), 1.02 (2d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2H), 2.34 (m, 2H), 3.10 (m, 1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([OH:20])=O)[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:28].[Cl-]>>[NH2:28][C:18]([CH:17]1[N:12]2[N:11]=[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:13]2[C:14](=[O:22])[N:15]([CH3:21])[CH2:16]1)=[O:20]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Agent: [Cl-]
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(N)=O
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-benzyloxy-2-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that NH4Cl was used in place of 4-fluorobenzylamine, and the reaction time totaled 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3, and the aqueous layer was extracted twice more into EtOAc. The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and azeotroped with toluene to afford the title product as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.50-7.49 (m, 2H), 7.29-7.32 (m, 3H), 5.19 (dd, J=10.8, 24.4 Hz, 2H), 4.28-4.24 (m, 3H), 4.16 (dd, J=5.2, 13.6 Hz, 1H), 3.86-3.83 (m, 1H), 2.99 (s, 3H), 1.27 (t, J=6.8 Hz, 3H); ES MS (M+H)=373.
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C1CCOC1
Reactant: C[C@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (10.6 g, 65.6 mmol) were sequentially added to a solution of 2-chloro-N4-[(1S)-1-phenylethyl]quinoline-3,4-diamine (13.0 g, 43.7 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. for one hour. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added as heating at 90° C. was continued overnight. The reaction was still incomplete, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added in portions as heating at 90° C. was continued for a second night. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred for two hours. A precipitate was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 9.98 g of 4-chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18]O)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=C(C3C=CC(NC(NC4C=C(C(F)(F)[F:77])C=CN=4)=O)=CC=3)C(C=O)=C(CN3CCOCC3)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18][F:77])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Product: Nc1ncnn2c(CN3CCOCC3)c(CF)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Yield: 23 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 87, using N-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoro-methyl)-pyridin-2-yl]urea (which can be prepared using the procedure used for the preparation of Example 62 substituting Intermediate AJ for Intermediate Y) in place of Example 85 (N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea), 45 mg (23%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 10.16-10.10 (m, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.39-7.19 (m, 3H), 5.35 (d, J=49.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.52 (m, 4H), 2.48-2.43 (m, 4H); MS [M+H]+=562.7; LCMS RT=2.50.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[C:17]([F:18])=[C:16]([N:19](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[C:17]([F:18])=[C:16]([NH2:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(Cc2ccccc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN(C)C(=O)c1cc(N)c(F)c(C(=O)OCC)c1

Procedure:
Dissolve 5-dibenzylamino-6-fluoro-N-methyl-N-propyl-isophthalamic acid ethyl ester (275 mg, 0.595 mmol) in ethanol (6 mL). Add 10% Pd/C to the solution (50 mg). Stir the black slurry under a balloon containing hydrogen gas for 2.5 days. Filter the slurry through a pad of filtering agent and wash with ethanol. Concentrate the filtrate to give the title compound as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[N:26][OH:27])[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccccc2)c2ccccc2)=NO)cc(C)n1

Procedure:
In analogy to example 1, step 2, from 1-(2,6-dimethyl-pyridin-4-yl)-3,3-diphenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=331.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][NH:6][C:7]([C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10])=O.B.O1CCCC1.CO>O1CCCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][C:9]([CH3:11])([CH3:10])[CH2:7][NH:6][CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NCc1ccc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude crystals (1.0 g) of tert-butyl [1-(3,4-dichlorobenzylcarbamoyl)-1-methylethyl]carbamate obtained in the previous step was dissolved in tetrahydrofuran (5 ml) and cooled to 0° C. under an argon atmosphere. A borane-tetrahydrofuran complex (1.0 M/tetrahydrofuran solution) (15 ml) was added dropwise at the same temperature, removed from an ice-bath and stirred at room temperature for 2 hr. A borane-tetrahydrofuran complex (1.0 M/tetrahydrofuran solution) (5 ml) was added every 30 minutes twice in total. To the obtained reaction mixture was added methanol (10 ml) under ice-cooling, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide solution (4 ml) and the mixture was stirred at 90° C. for 1 hr. The obtained reaction mixture was extracted twice with toluene, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica-gel column chromatography (hexane:ethyl acetate=l:l) to give tert-butyl[2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate (290 mg).
Reaction SMILES: C([CH:3]([N:7]([CH:21](CC)[C:22]([O-:24])=O)[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O-])=[O:5])C.O.[NH2:28][NH2:29]>CO>[C:9]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]2[CH2:21][C:22](=[O:24])[NH:29][NH:28][C:4](=[O:5])[CH2:3]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CCC(C(=O)[O-])N(C(CC)C(=O)[O-])C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: O=C1CN(C(c2ccccc2)c2ccccc2)CC(=O)NN1

Procedure:
Reacting diethyl-N-benzhydryliminodiacetate with hydrazine hydrate in the presence of methanol at reflux temperature and a reaction time of 20 hours to afford 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[I-:11].[K+].II.Cl>[OH-].[NH4+].O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1)=[O:3]
Reactant: [I-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: II
Agent: [K+]
Solvent: O
Product: CC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.1 %

Procedure:
To a solution of 4-hydroxyacetophenone (4.0 g, 30 mmol) in 50% (v/v) of ammonium hydroxide (250 mL) at room temperature was quickly added a solution of potassium iodide (24.2 g, 146 mmol) and iodine (7.66 g, 30 mmol) in water (300 mL). The resulting mixture was stirred at room temperature for 14 hours and then passed through a celite pad. The filtrate was cooled to 10° C. and acidified slowly with HCl (12 N) to pH=1. The yellow precipitate was collected by filtration, washed with water to get 4-hydroxy-3-iodoacetophenone (6.3 g, 80%). A solution of 4-hydroxy-3-iodoacetophenone (3 g, 11.5 mmol) and 2-thiophenylboronic acid (1.46 g, 11.5 mmol) in DMF (50 mL) was mixed with potassium carbonate (3.16 g, 22.9 mmol) and Pd(dppf)2 (0.25 g, 0.344 mmol). The mixture was stirred at 90° C. for 14 hours, cooled to room temperature and passed through a celite pad. The filtrate was diluted with water and extracted with EtOAc (3×100 mL). The residue after concentration was purified by column (SiO2, Hexanes/EtOAc=4:1) to provide 4-hydroxy-3-(2-thiophenyl)acetophenone (1.1 g, 44%) as a light yellow solid. To a solution of 4-hydroxy-3-(2-thiophenyl)acetophenone (0.5 g, 2.29 mmol) in THF (50 mL) at −78° C. was added LDA in heptane-THF (2.6 mL, 4.7 mmol) and the solution was stirred for 1 hours. 2-Chloronicotinyl chloride (0.202 g, 1.15 mmol) was added and the resulting mixture was stirred at −78° C. for 1 h and 1 h at room temperature. The reaction was quenched with aqueous HCl (0.5 N) and extracted with CH2Cl2 (×3×100 mL). The residue after concentration was purified by column (SiO2, Hexanes/EtOAc=2:1) to provide the corresponding diketone (0.31 g, 76%). The above diketone (0.28 g, 0.78 mmol) was dissolved in HOAc (50 mL) and stirred at, 10° C. for 2 hours. It was poured into icy water. The solid was collected by filtration, washed with CH2Cl2 to afford 2-(4-hydroxy-3-(thiophen-2-yl)phenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.146 g, 58%) as a grey solid; MS (ES) m/z: 322.93 (M+1), 321.93 (M); MP 273.5-275° C.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[OH:33][CH2:29][CH2:30][C:31]#[C:32][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: C#CCCO
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The title compound was prepared from 5-iodo-3-methyl-1(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 3butyn-1-ol in a manner analogous to the method of Example 13 above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH3:21])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([Br:22])=[N:19][N:18]=[C:17]2[CH3:21])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 75.5 %

Procedure:
To a suspension of 4.5 g of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone in 450 ml of carbon tetrachloride was added 3.1 g of N-bromosuccinimide and the mixture was heated under reflux for 3 hours. Then, the reaction mixture was filtered and the filtrate was cooled. The resulting crystals were filtered, washed with carbon tetrachloride and dried to obtain 4.3 g of brown 5-chloro-2-(3-methyl-5-bromo-4H-1,2,4-triazol-4-yl)benzophenone. A part of the product thus obtained was recrystallized from ethyl acetate to give colorless needles, m.p. 198° - 199° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:12]C(=O)C)[C:2]=12.C([O-])([O-])=O.[K+].[K+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:2]=12
Reactant: CC(=O)OC1CCCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC1CCCCc2cccnc21
Yield: 98.6 %

Procedure:
To a solution of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester (53.26 g, 0.259 mol) in methanol (350 mL) was added K2CO3 (72.98 g, mol) and the resultant mixture was stirred at room temperature overnight. The mixture was poured into water (350 mL) and extracted with CHCl3(3×300 mL). The combined organic extracts were dried (Na2SO4), and concentrated to provide 41.70 g of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=[C:4]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][C:2]1[C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=[C:4]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)Nc1cc(N)c2[nH]c(-c3ccc(Br)cc3)nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)Nc1cc(NC(C)=O)c2[nH]c(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of 7-amino-5-(methoxycarbonyl)amino-2-(4-bromophenyl)-1H-benzo[d]-imidazole (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added acetic anhydride (18 mg, 0.17 mmol) and the solution was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using hexane/EtOAc (4/1) as the eluant to afford the desired product (55 mg, 80%) as a pale yellow powder: 1H-NMR (300 MHz, CD3OD) δ 2.24 (s, 3H), 3.74 (s, 3H), 7.65 (m, 3H), 7.67 (bs, 1H), 7.90 (m, 2H); ESI MS m/z 403.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]1[C:13]23[CH2:15][C:12]12[CH2:14]3>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]12[CH2:15][CH:13]([CH2:14]1)[CH2:11]2
Reactant: C1C23CC12C3
Reactant: COc1ccccc1[Mg]Br
Product: COc1ccccc1C12CC(C1)C2

Procedure:
Reaction of 2-methoxyphenylmagnesium bromide with [1.1.1]propellane (see A. B. Shtarev et al., J. Am. Chem. Soc. 2001, 123, 3484-3492) afforded 1-(2-methoxyphenyl)bicyclo[1.1.1]pentane, which was treated with boron tribromide to provide the requisite phenol.
Reaction SMILES: N[C:2]1N=C(O)C(NC(=O)CCOC2C=CC(F)=CC=2)=C(O)N=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[NH2:37][C:38]1[N:39]=[C:40]([SH:57])[C:41]2[N:46]=[C:45]([CH2:47][CH2:48][O:49][C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)[S:44][C:42]=2[N:43]=1.C(N(CC)CC)C.IC>N1C=CC=CC=1.CS(C)=O.O>[F:56][C:53]1[CH:54]=[CH:55][C:50]([O:49][CH2:48][CH2:47][C:45]2[S:44][C:42]3[N:43]=[C:38]([NH2:37])[N:39]=[C:40]([S:57][CH3:2])[C:41]=3[N:46]=2)=[CH:51][CH:52]=1
Reactant: Nc1nc(O)c(NC(=O)CCOc2ccc(F)cc2)c(O)n1
Reactant: Nc1nc(S)c2nc(CCOc3ccc(F)cc3)sc2n1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1nc(N)nc2sc(CCOc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.6 %

Procedure:
A solution of N-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-(4-fluorophenoxy)propanamide (2.5 g, 8.11 mmol) and phosphorus pentasulfide (3.60 g, 16.2 mmol) in dry pyridine (40 ml) was refluxed for 6 hours. After cooling down to room temperature, the precipitate was filtered off, washed with ethylacetate and dried. The crude 5-amino-2-(2-(4-fluorophenoxy)ethyl)-thiazolo[5,4-d]pyrimidine-7-thiol (2.0 g, 6.20 mmol) was redissolved in DMSO (30 ml). Triethylamine (0.85 ml, 6.12 mmol) and iodomethane (0.31 ml, 4.90 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature under a nitrogen atmosphere. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 100:1), yielding the title compound as a light yellow solid (0.45 g, 15% over 2 steps).