Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Na].CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:3]1[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ncccc1Br
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1ncccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Bromo-2-methylpyridine (500 mg) and tert-butyl piperazine-1-carboxylate (650 mg) were dissolved in toluene (7.5 ml), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one_palladium (3:2) (40 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (18 mg), and 2-methylpropan-2-ol sodium (391 mg) were added thereto in this order under a nitrogen atmosphere, followed by warming to 100° C. and stirring overnight. The reaction mixture was subjected to liquid separation with CHCl3 and water, the organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CHCl3 to 5% MeOH/CHCl3) to obtain tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (790 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18].[H-].[Na+].COC1C=C(OC)C=CC=1C[N:26]([C:39]1[S:43][N:42]=[CH:41][N:40]=1)[S:27]([C:30]1[CH:35]=[C:34]([F:36])[C:33](F)=[CH:32][C:31]=1[F:38])(=[O:29])=[O:28]>CN(C)C=O.ClCCl.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][C:33]1[C:34]([F:36])=[CH:35][C:30]([S:27]([NH:26][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:28])=[O:29])=[C:31]([F:38])[CH:32]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Nc1ncnc2c1ncn2-c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-(6-amino-9H-purin-9-yl)-4-chlorophenol (0.053 g, 0.2 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.009 g, 0.2 mmol) and the mixture was stirred for 1 h at ambient temperature. N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.107 g, 0.24 mmol) was added and the mixture was stirred at ambient temperature for 16 h and partitioned between ethyl acetate (100 mL) and saturated aqueous ammonium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC to afford 4-(2-(6-amino-9H-purin-9-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 17% yield (0.018 g): 1H NMR (300 MHz, DMSO-d6) δ8.48 (br s, 1H), 8.39 (s, 1H), 8.17 (br s, 1H), 7.95-7.74 (m, 4H), 7.74-7.58 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.34-7.22 (m, 1H); MS (ES+) m/z 536.6 (M+1), 538.6 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11](O)=[O:12]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1cccc(Br)c1
Product: O=C(Cl)COc1cccc(Br)c1

Procedure:
Thionyl chloride (5 ml, 70 mmol) is added at ambient temperature to 3-bromophenoxyacetic acid (5.77 g, 25 mmol). The reaction mixture is brought to reflux for 2 hours. After returning to ambient temperature, it evaporates and the acid chloride is used. The 3-bromophenoxyacetyl chloride previously obtained is dissolved in dichloromethane (150 ml) and added to a solution of aluminum chloride (6.7 g, 50 mmol) in 50 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 30 minutes and then poured into a an equal volume water-ice mixture (400 ml). The mixture is extracted with dichloromethane, dried over MgSO4 filtered and evaporated. The raw product is purified by flash chromatography on silica (eluent petroleum ether ether=100:10). 0.96 g of 6-bromo-3-coumarone is obtained (yield=18%) of formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(NCC)C.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) in diethylamine (75 mL) was added PdCl2(PPh3)2 (280 mg, 0.4 mmol), trimethylsilylacetylene (2.36 g, 24.0 mmol) and copper(I)iodide (20 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 24 h, filtered and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (8:2) as eluent. The desired (3,5-dichloro-phenylethynyl)-trimethylsilane product was isolated in 4.85 g yield.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.Cl[C:36](Cl)([O:38][C:39](=O)[O:40]C(Cl)(Cl)Cl)Cl.N(C1C=CC(C2N=C3N(C(C)C)N=CC3=C(N3CC4OC(CC4)C3)N=2)=CC=1)=C=O>ClCCl.CO>[CH3:36][O:38][C:39](=[O:40])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C(C)C)c3n2)cc1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (0.027 g, 0.07 mmol) in dichloromethane (2 mL) was treated with triethylamine (0.028 mL), followed by a solution of triphosgene (0.011 g, 0.04 mmol) in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, methanol (excess)—was added to the 3-(6-(4-isocyanatophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After 10 minutes, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 35 minutes to provide methyl{4-[1-isopropyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate (15 mg, 48%). MS (ES+): 423.2 (M+H)+
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][C:8]1[C:9]2[O:16][CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1.CN([CH:20]=[O:21])C.[Cl-].[NH4+]>C1COCC1>[CH3:6][S:7][C:8]1[C:9]2[O:16][C:15]([CH:20]=[O:21])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CN(C)C=O
Reactant: CSc1ncnc2ccoc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncnc2cc(C=O)oc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Butyl lithium (as 1.6 M in hexanes, 7 mL) was added to a solution of 4-(methylthio)furo[3,2-d]pyrimidine (Intermediate 85) (1.21 g) in THF (25 mL) at −70° C. The reaction was stirred for 5 minutes, DMF (5 mL) added, and the reaction mixture allowed to warm to ambient temperature. 30% Saturated ammonium chloride solution (50 mL) was added and the mixture extracted into EtOAc (3×50 mL). The combined organics were washed with 50% saturated sodium carbonate solution (50 mL), water (50 mL), dried and the solvent removed to afford the title compound as a pale yellow solid (1.02 g) (the product contained 20% unreacted starting material but was used without further purification in subsequents steps);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(-c2ccc(F)cc2)cc1
Product: Fc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
A mixture of 0.9 g (4.8 mmol) of 4-(4-fluorophenyl)pyridine-1-oxide and 10 mL of phosphoryl chloride is heated at reflux overnight.
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:25]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCCCCC>O1CCOCC1>[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH:24][C:32](=[O:33])[CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(CC1CCCCC1)Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
336 mg (4.0 mmol) NaHCO3 were added to a solution of 294 mg (1.0 mmol) [2-[2-(benzenesulfonyl)-ethylsulfanyl]-pyridin-3-yl]amine (VPF-002) in dioxane (10 ml) and the mixture was stirred for 10 min at RT. Then 321 mg (2.0 mmol) 2-cyclohexylacetylchloride were added at 5° C. and the mixture was stirred for a further 16 h at RT. Then it was diluted with EE and filtered through kieselguhr. The filtrate was washed with a saturated aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:1) of the residue yielded 368 mg (0.9 mmol, 88%) N-[2-[2-(benzenesulfonyl)-ethyl-sulfanyl]-pyridin-3-yl]-2-cyclohexyl acetamide. MS: m/z 419.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4cc(S(N)(=O)=O)c(F)cc4F)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (67 mg, 26%). MS (ISN) 507.2 [(M−H)−]; mp 270° C.
Reaction SMILES: C(O[CH2:5][C@@H:6]([O:23]S(C)(=O)=O)[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[O:23]1[CH2:5][C@H:6]1[C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a suitable reactor was added 5 (2 g, 4.98 mmol), THF (20 mL), MeOH (20 mL), and K2CO3 (1.5 g, 10.96 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 15 hr. The mixture was filtered, and the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil. After being purified by flash column chromatography, 6 was obtained as a white solid in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[C:19]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CC(O)C>[CH3:23][C:21]1[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=2[F:10])[C:20]=1[C:19]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])=[O:24]
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc(Cl)c1F
Yield: 50.9 %

Procedure:
A mixture of 320 mg of 3-chloro-2-fluorobenzaldehyde, 252 mg of methyl 3-aminocrotonate and 510 mg of 2-(N-benzyl-N-methylamino)ethyl acetoacetate in 2 ml of 2-propanol was refluxed for 6 hours, and then the solvent was distilled off in vacuo. The residue was purified by the methods of a column chromatography on silica gel to yield 500 mg of the desired compound (106)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=O)[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC>C1COCC1>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[CH2:10][N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([CH2:26][OH:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cc(CO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)CN2C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The title compound was synthesized by solubilizing 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.36 mmol) in THF (20 mL), and adding borane-dimethylsulfide (2.0M, 1.8 mL, 3.6 mmol) slowly. The solution was stirred for 18 h and then heated to 50° C. for 2 hours. The reaction mixture was then washed with water (×2), brine, and the solvent evaporated. The final compound was purified by reverse phase HPLC and basified to give the free base (8.1 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.96 (m, 8 H) 2.82 (s, 3 H) 3.48 (t, J=13.39 Hz, 2 H) 3.78 (t, J=12.00 Hz, 2 H) 3.86 (s, 3 H) 4.43 (d, 2 H) 4.84 (t, J=7.83 Hz, 1 H) 5.07 (t, J=5.81 Hz, 1 H) 6.82 (d, J=8.34 Hz, 1 H) 6.95 (s, 1 H) 7.31 (s, 1 H) 7.66 (s, 1 H) 8.21 (d, J=8.08 Hz, 1 H). [M+H] calculated for C21H27F2N5O2, 420; found 420.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])[C:10]2=[N:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:30]1([NH:35][C:36]2[N:38]=[C:5]([C:7]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:15]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])[C:10]4=[N:9][C:8]=3[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:4]=[CH:3][N:37]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)C=Nc1cccn2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C=Nc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a solution of N′-[3-[(2E)-3-(dimethylamino)-2-propenoyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide (130 mg, 0.34 mmol) in N,N-dimethylformamide was added N-cyclopentylguanidine hydrochloride (168 mg, 1.02 mmol), followed by anhydrous potassium carbonate (140 mg, 1.02 mmol). The resulting solution was heated at 100° C. for 16 hours. Upon cooling to room temperature, ethyl acetate and water were added. The phases were separated and the organics were washed with brine. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to give N′-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide (80 mg, 53%) as a solid. 1H NMR (CDCl3): δ 9.09 (broad s, 1H), 8.60 (s, 1H), 8.04 (d, 1H), 7.63 (q, 2H), 7.04 (t, 2H), 6.78 (m, 2H), 6.36 (d, 1H), 5.14 (d, 1H), 4.31 (m, 1H), 3.10 (s, 3H), 3.05 (s, 3H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); MS m/z 444 (M+1).
Reaction SMILES: [C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=1)(=[O:3])[CH3:2].[CH3:35][I:36]>>[I-:36].[C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=1[CH3:35])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)N(Cc2ccccn2)C(C)=O)c1
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)c1
Product: [I-]
Yield: 98 %

Procedure:
The title compound is prepared by the procedure of Example 28, using 1.08 g of product from Example 29 and 16.36 g of methyl iodide. The residue is recrystallized from methyl alcohol to give 1.38 g of the desired product as yellow crystals with hygroscopic properties.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]2=[O:13])[CH3:2].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[C:8](=[O:13])[C:9]1=[O:12]
Reactant: CCc1cccc2c1NC(=O)C2=O
Reactant: Clc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Product: CCc1cccc2c1N(Cc1ccccc1Cl)C(=O)C2=O
Yield: 80.7 %

Procedure:
Using a method similar to Preparation 15, with 7-ethylisatin (88 mg, 0.5 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene beads(630-720 mg, 1.4-1.6 mmol, 2.2 mmol/g, Fluka) and 2-chlorobenzyl bromide (0.065 mL, 0.5 mmol) gives 121 mg (85%) of the title compound as crude material as a red-orange solid. MS (ES): m/z=300 (M+1).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(O[C:10]1[C:15]2=[CH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N+:22]=3[CH:23]=[C:14]2[CH:13]=[CH:12][CH:11]=1)(=O)C>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:15]([C:23]1[N+:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=[C:15]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12)[CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Oc1cccc2c[n+]3ccccc3cc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Yield: 115.8 %

Procedure:
The above 10-acetoxybenzo[b]quinolizinium perchlorate (3.3 g) was dissolved in 500 mL of water, the solution was boiled, and filtered. To the filtrate was added 100 mL of 30% sodium perchlorate solution and the mixture was chilled. The precipitated solid was isolated by filtration and dried in vacuo to afford 1.9 g of 10-acetoxybenzo[b]quinolizinium perchlorate (Formula II: R1 =R2 =H; R7 =10--OAc; X- =ClO4-). The filtrate was extracted with methylene chloride (3×100 mL), the organic layer was dried and concentrated to yield an additional 0.32 g of the desired acetate perchlorate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[CH3:35])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:42][CH:43]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[CH3:35])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
A mixture of hydroxylammonium chloride (1 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxy-2-methylphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.28 g, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].O=S(Cl)Cl.[CH3:21][O:22][C:23](=[O:33])[C:24]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:25]=1[NH2:32].CCCCCC>CCOC(C)=O>[CH3:21][O:22][C:23](=[O:33])[C:24]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:25]=1[NH:32][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COC(=O)c1c(N)cc(Br)cc1Br
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Br)cc(Br)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 59.3 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.22 g, 0.98 mmol), SOCl2 (0.35 mL, 0.49 mmol), and 2-amino-4,6-dibromo-benzoic acid methyl ester (0.15 g, 0.49 mmol). After normal workup, the pure objective compound (0.15 g, 59%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, DMSO-d6) δ 1.39 (d, J=6.8 Hz, 3H, CH3), 3.55 (s, 3H, OCH3), 3.88 (s, 3H, CO2CH3), 3.89 (m, 1H, CH), 7.32 (d, J=9.0 Hz, 1H, ArH), 7.63 (dd, J=8.8, 1.8 Hz, 1H, ArH), 7.80-7.84 (m, 2H, ArH), 8.13-8.15 (m, 1H, ArH).