Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH3:25]>CCOCC.CCCCC.C1COCC1>[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)([OH:39])[C:35]([F:36])([F:37])[F:38])[CH3:25]
Reactant: CCOCCn1cccc1C(=O)C(F)(F)F
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 75 mg (0.23 mmol) of N-(4-bromophenyl)-N-methyl-benzenesulfonamide in 4 mL of Et2O at −78° C. was added dropwise 285 μL (0.49 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 10 min. To this mixture was then added a solution of 81 mg (0.34 mmol) of N-ethoxyethyl-2-trifluoroacetylpyrrole in 3 mL THF and the mixture was allowed to gradually warm to room temperature over an 18 h period. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:30])[CH2:13][CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[O:28][CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12](=[O:30])[CH2:13][CH:14]([C:20]1[CH:25]=[C:24]([C:5](=[O:7])[CH3:6])[CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[O:28][CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:10]
Reactant: CCCCCC(CC(=O)OCC)c1cccc(OC)c1OC
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(CC(=O)OCC)c1cc(C(C)=O)cc(OC)c1OC
Temperature: 0 °C
Yield: 85.6 %

Procedure:
To a solution of 800 mg (6.00 mmol) of anhydrous aluminum chloride in 5 ml of methylene chloride were added 0.43 g (6.05 mmol) of acetyl chloride with stirring and ice cooling and then dropwise a solution of 925 mg (3.00 mmol) of 3-(2, 3-dimethoxyphenyl)octanoic acid ethyl ester in 3 ml of methylene chloride. The resultant mixture was allowed to react under ice cooling for 20 minutes and added portionwise into ice water. The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with water and aqueous saturated sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) to give 900 mg of 3-(5-acetyl-2, 3-dimethoxyphenyl)octanoic acid ethyl ester as a colorless oil. Yield, 86%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:3]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1cc(Br)ccn1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccn2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
1-(4-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.2 g, 6.6 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (1.8 g, 6.6 mmol), and piperidine (1.3 mL, 13.2 mmol) were added to ethanol (66.1 mL). The reaction mixture was stirred at 90° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 2.1 g of the titled compound as a yellow liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C19H17IN4O4S, 524.0; m/z found, 523 [M−H]−. HPLC (reverse phase): RT=8.32 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.06 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 9.01 (br s, 1H), 8.51 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.90 (dd, J=8.4, 7.4 Hz, 1H), 7.38 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 3.70-3.40 (br m, 6H), 3.30-3.05 (br m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol), 2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxide monohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heat the resulting mixture to 55° C. for 40 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Chromatograph the solid using flash chromatography and elute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5% dichloromethane to obtain 2.267 g of the title compound (8.36 mmol, 45% yield) as an orange amorphous solid: Mass Spectrum (m/e): 272(M+1).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH:9]1([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:7]1[O:6][CH2:5][CH2:4][CH:3]([CH2:2][NH:16][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:8]1
Reactant: NCC1CCCCC1
Reactant: ClCC1CCOCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1CCC(CNCC2CCOCO2)CC1

Procedure:
7.7 Grams of 1-chloro-2,4-methylenedioxybutane and 6.4 g of cyclohexylmethylamine are dissolved in 80 ml of dimethylformamide (DMF). Thereto are added 9.4 g of potassium carbonate and 17.0 g of sodiumiodide. The mixture is refluxed for 3 hours with heating. DMF is removed by evaporation under reduced pressure. The residue is extracted with diethyl ether. The extract is washed with water and dried with anhdyrous magnesium sulfate. The solvent is removed by evaporation. The residue is purified by a silica gel column chromatography (chloroform: methanol=20:1) and then subjected to distillation by glass tube oven to obtain 4.5 of N-(2,4-methylenedioxy-1-butyl)-N-cyclohexylmethylamine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: NCCN
Product: NCCNC(=O)c1ccc(F)cc1

Procedure:
7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylene diamine are heated to 130° (bath temperature) for 2 hours. The mixture is poured on to ice/hydrochloric acid and extracted with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloroform extracts, the residue (7.6 g) is recrystallized from ethyl acetate/hexane, the being obtained N-(2-aminoethyl)-4-fluorobenzamide, m.p. 57°-60°. The hydrochloride melts at 214°-216°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10](I)[C:3]=12.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([NH:44][C:45]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:54])=[C:29]([O:28][CH3:27])[CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 29.8 %

Procedure:
A mixture of tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.27 g, 0.00057 mol), benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.26 g, 0.00068 mol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.000034 mol) and sodium carbonate (0.15 g, 0.0014 mol) in ethylene glycol dimethyl ether (7 mL) and water (3 mL) was heated at 85° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under the reduced pressure. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with water and brine, and dried over magnesium sulfate. The organic layer was filtered through silica gel twice to remove the catalyst, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.00017 mol).
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[O:5][C:4]=1[CH3:15].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31]C)=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[O:5][C:4]=2[CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 3-[chloro(cyclohexyl)methyl]-5-(4-fluorophenyl)-2-methylfuran (1.3 g), methy 5-aminopyridine-2-carboxylate (0.7 g), sodium carbonate (0.5 g) and sodium iodide (1.4 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (5 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg) were added ethyl β-alaninate hydrochloride (261 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg), triethylamine (237 μl) and N,N-dimethylformamide (10 mL), and the obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (521 mg, 60%) as an amorphous compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:17][CH:16]=1)(=O)=O>CN(C=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]#[C:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:17]=3)=[N:24][CH:25]=2)=[CH:30][CH:31]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCCC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
99 μL (1.0 mmol) piperidine are added to a solution of 85.6 mg (0.2 mmol) of 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl methanesulphonate in 2 mL DMF and the reaction mixture is stirred for 18 h at RT. The solvent is distilled off i.vac., the residue is stirred with 5 mL water and 40 mL DCM, the organic phase is separated off and dried with Na2SO4. After the desiccant and solvent have been eliminated the residue is triturated with 20 mL diethyl ether and suction filtered.
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[NH2:7][C:4]1[C:3]2=[CH:8][CH:9]=[C:10]([C:15](=[O:17])[CH3:16])[N:2]2[N:1]=[CH:6][N:5]=1
Reactant: Nc1ncnn2cccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(N)ncnn12
Temperature: 60 °C
Yield: 34.1 %

Procedure:
To a suspension of pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 7.46 mmol) in nitrobenzene (40 mL) was added AlCl3 (2.98 g, 22.36 mmol), followed by acetyl chloride (2.34 g, 29.82 mmol). The resulting solution was heated (60° C.) for 5 h and cooled to rt. The reaction mixture was poured onto ice-water and solid sodium bicarbonate was added with stirring until the solution was basic. This mixture was extracted with ethyl acetate (3×100 mL) and then the combined organic layers were concentrated under reduced pressure. The residue was stirred with MeOH (100 mL) and potassium carbonate (5 g) overnight. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using a gradient of 5-30% MeCN in water to afforded 448.0 mg (34%) of the title compound. 1H-NMR (DMSO-d6) δ 9.63 (bs, 1H), 8.47 (bs, 1H), 8.03 (s, 1H), 7.76 (d, J=3.2 Hz, 1H), 7.40 (d, J=2.9 Hz, 1H), 2.57 (s, 3H); MS [M+H]+=177.1; LCMS RT=1.37 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:15][C:16]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2cnc(OC)cn2)sc(Br)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)OCc2ccccc2)csc1-c1cnc(OC)cn1
Reaction time: 4 h

Procedure:
10% Pd/C is added to methyl 4-(benzyloxycarbonylamino)-5-bromo-2-(5-methoxypyrazin-2-yl)thiophene-3-carboxylate (157) in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 4 h. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 158.
Reaction SMILES: [OH-].[K+].[C:3]([OH:20])(=[O:19])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:3]([OH:20])(=[O:19])/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC/C=C/C=C/C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC=C/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.9 %

Procedure:
To the trans-2-tetradecenal (2.3 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene) triphenylphosphorane (4.4 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). Potassium hydroxide (2.8 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-hexadecadienoic acid (2.0 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.1 g) and N,N'-dicyclohexylcarbodiimide (1.6 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-hexadecadienoic acid (0.8 g). To the active ester (340 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK283 in the yield of 270 mg.
Reaction SMILES: O1CCCC1.C(O)C.[Cl:9][C:10]1[C:11]([NH:35]C(C2CC2)=O)=[N:12][CH:13]=[N:14][C:15]=1[NH:16][C:17]1[C:22](=[O:23])[N:21]2[C:24]3([NH:31][C:32](=[O:33])[C:20]2=[C:19]([CH3:34])[CH:18]=1)[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3.[OH-].[Na+]>O>[NH2:35][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]2[C:22](=[O:23])[N:21]3[C:24]4([NH:31][C:32](=[O:33])[C:20]3=[C:19]([CH3:34])[CH:18]=2)[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[C:10]=1[Cl:9]
Reactant: Cc1cc(Nc2ncnc(NC(=O)C3CC3)c2Cl)c(=O)n2c1C(=O)NC21CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Nc2ncnc(N)c2Cl)c(=O)n2c1C(=O)NC21CCN(C)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A flask containing tetrahydrofuran, ethanol and water (1:1:1, 5 mL each) was charged with 6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione (3, 0.17 g, 0.371 mmol) and sodium hydroxide (75 mg, 1.85 mmol). The reaction was stirred at 50° C. for 16 h. After completion, the reaction mass was extracted with 10% methanol in dichloromethane. Combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate concentrated under vacuum obtained solid was washed with ether and dried under vacuum to afford 6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione as light yellow solid. Yield: 88 mg, 31%; MS (ESI) m/z 390.14 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.10 (brs, 2H), 3.30-3.20 (m, 2H), 2.90-2.82 (brs, 2H), 2.49-2.40 (m, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 1.46-1.40 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.C([C:14]1[CH:15]=[CH:16][C:17]([NH2:24])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)#N.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:17]1[CH:16]=[CH:15][C:14]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:19][C:18]=1[S:20]([NH2:23])(=[O:21])=[O:22]
Reactant: Cn1ccnc1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccnc1-c1ccc(N)c(S(N)(=O)=O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
To a solution of 1-methylimidazole (4.8 ml, 60 mmol) in dry THF (120 ml) at −78° C. was added n-BuLi (2.5 M in hexane, 26 ml, 65 mmol) and the yellow mixture was stirred for 45 min at −78° C. A solution of ZnCl2 (2M in THF, 75 ml, 150 mmol) was added slowly and the cooling bath was removed. The colorless solution was stirred for another 10 min at 0° C. 5-Iodo-2-aminobenzenesulfonamide (see compound 37) (2.1 g, 7 mmol) and Pd(PPh3)4 (0.5 g, 5 mol %) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and made slightly basic (pH=8-9) with 1 M NaOH followed by extraction with EtOAc (3×150 ml), drying (Na2SO4) and evaporation of the solvent gave a dark oil. Flash-chromatography with 5% MeOH in CH2Cl2 as eluent gave 1.33 g (75%) of 2-amino-5-(1-methyl-1H-2-imidazolyl)-1-benzenesulfonamide as colorless crystals. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. >250° C. (decomp).