Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([O-:24])([CH3:23])[CH3:22].[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([O:24][C:21]([CH3:23])([CH3:22])[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of 4-benzyl-8-chloro-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.0 g), tBuONa (0.70 g) and BINAP (0.068 g) in toluene (10 mL) was deaerated with an argon gas, Pd2(dba)3 (0.050 g) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-tert-butoxy-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.81 g, 72%) as an colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=1.O>C1COCC1.[S].[P]>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Agent: [K+]
Agent: [P]
Agent: [S]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 19 h
Yield: 81.7 %

Procedure:
25.8 ml (12.9 mmol) of potassium diphenylphosphide solution in THF (manufacturer: Aldrich) are added dropwise at -5° C. to a solution of 3.09 g (13.2 mmol) of diethyl 4-fluorophenylphosphonate, prepared as described in Phosphorus Sulfur 1980, 9(2), 197.202, in 20.0 ml of THF. After stirring for 19 hours at 23° C., the mixture is hydrolyzed by adding 20 ml of degassed water and stirring for 15 min. After extraction with ethyl acetate, and drying the organic phase over Na2SO4, the mixture is concentrated on a rotary evaporator. 4.20 g of diethyl 4-diphenylphosphinophenylphosphonate (82% of theory) are obtained in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:24]([N:18]1[CH2:19][C@H:5]([C:4]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=2)[C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 103.9 %

Procedure:
To a solution of the compound (20.4 g) obtained in step 1 and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (22.0 g) in toluene (180 mL) was added a solution of trifluoroacetic acid (1.31 mL) in toluene (18 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added ethyl acetate (300 mL), and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give methyl (3R*,4S*)-1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (33.4 g, 100%) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:14][C:15](=O)[CH2:16][C:17](=O)[CH3:18]>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:15]([OH:14])[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[C:9]2[N:12]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(-c3ccccc3)cc2n1

Procedure:
To a solution of 5-phenyl-2H-pyrazol-3-ylamine (9.18 g, 57.6 mmol) and 3-oxo-butyric acid methyl ester (9.33 mL, 86.5 mmol) in acetic acid (70 ml) was refluxed for 28 hrs. The reaction mixture was then allowed to cool, filtered, and the precipitated solid washed with acetic acid and dried in vacuo to afford 5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidin-7-ol as a white solid (11.86 g; 85%) MS m/z @ 242 (m+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:21]1[CH:22]=[CH:23][C:24]2[N:29](O)N=[N:27][C:25]=2[CH:26]=1.N1C=CC=CC=1CN>ClCCl>[N:27]1[CH:23]=[CH:22][CH:21]=[CH:26][C:25]=1[CH2:24][NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: NCc1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (11.6 g, 50 mmol) in dichloromethane (100 mL) is added EDC (14.4 g, 75 mmol), HOBT (7.65 g, 50 mmol), and 2-pyridylmethylamine (6.48 g, 60 mmol). The resulting solution is stirred at 25° C. for 18 h, then diluted with dichloromethane (200 mL) and washed with 2 M hydrochloric acid and 2 M sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 2-pyridylmethylamide as a white solid (16 g, 100% yield).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Br:36]N1C(=O)CCC1=O.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O.O[C@@H]([C@H]1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)=C(C3SC4=C(C(=O)CC)N=CN4C=3)[C@H](C)[C@H]12)C>[Br:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: CCC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CSc1nc(Br)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
4Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (77 mg) was dissolved in 5 ml of benzene at room temperature. N-bromosuccinimide (33 mg) and 5 mg of 2, 2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 70 mg of 4-nitrobenzyl (1S,5R,6S)-2-(5-bromo-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.Cl>CN(C=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 13.3 %

Procedure:
Sodium hydride (0.653 g, 60% in mineral oil, 16.338 mmol) was suspended in DMF (10 mL) under argon, and 4-fluorophenol (0.915 g, 8.169 mmol) added in two portions. The mixture was stirred for 20 minutes then ethyl 6-chloro-3-pyridinecarboxylate (1.515 g, 8.169 mmol) was added together with additional DMF (4 mL) added to aid solubility. The mixture was heated to 80° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature and water (30 mL) was added. The solution was acidified to pH 3 with 2M HCl and extracted with ethyl acetate (×3). The combined ethyl acetate layers were dried and concentrated to produce a brown oil. The crude product was purified by chromatography. Elution with a 0-25% Et2O/petroleum ether gradient gave the title compound as a colourless oil (0.284 g). δH (CDCl3, 400 MHz) 8.81 (1H, dd), 8.28 (1H, dd), 7.11 (4H, m), 6.95 (1H, d), 4.37 (2H, q), 1.38 (3H, t). MS (ES): MH+ 262.2.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]2[C:22]([C:27]#[N:28])=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2C1CCCCO1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH:7][C:31]3[N:39]=[CH:38][N:37]=[C:36]4[C:32]=3[N:33]=[CH:34][NH:35]4)[CH3:9])[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]=2[C:22]=1[C:27]#[N:28]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
{(S)-1-[7-Cyano-6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethyl}carbamic acid tert-butyl ester (215 mg, 0.54 mmol) was dissolved in HCl in dioxane (4N, 5 mL) and the reaction mixture stirred at RT for 1 hour. The mixture was concentrated in vacuo and the residue dissolved in IPA (5 mL). 6-Chloro-9-(tetrahydropyran-2-yl)-9H-purine (167 mg, 0.70 mmol) and DIPEA (275 μL, 1.61 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give an off white solid LCMS (Method C): RT=2.89 min, [M+H]+=502. The solid was dissolved in HCl in methanol (1.25 M, 5 mL) and the reaction mixture stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to prep. HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 346 as a white solid (66 mg, 29%). 1H NMR 300 MHz δ (d6-DMSO): 12.91 (1H, br s), 8.89-8.46 (2H, m), 8.44-7.85 (5H, m), 7.42 (1H, t, J=9.6 Hz), 5.65-5.37 (1H, m), 1.67 (3H, t, J=6.8 Hz), LCMS (Method K): RT=3.03 min, [M+H]+=418
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][C:33]([O:37][CH3:38])=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][C:33]([O:37][CH3:38])=[N:34][C:35]([O:13][C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: COc1nc(Cl)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1nc(Oc2ccc(S(C)(=O)=O)cc2)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2 mmol) is added to a solution of 4-(methylsulfonyl)phenol (1.6 mmol) in dimethylformamide (9 mL) and the mixture is stirred at room temperature for 20 min. A solution of crude 4-(4-chloro-6-methoxy-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in dimethylformamide (5 mL) is added. The reaction mixture is heated at 50° C. for 8 h. Saturated aqueous ammonium chloride solution is added and the mixture is extracted three times with ethyl acetate. The organic layer is washed with water and brine, dried (magnesium sulfate), filtered, evaporated and purified by flash chromatography on silica gel to give 4-[4-(4-methanesulfonyl-phenoxy)-6-methoxy-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]1.O.[OH-].[Cs+]>CN(C)C=O>[CH3:37][C:34]1([CH3:38])[O:33][CH:32]([CH2:31][N:2]2[C:3]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)=[CH:4][CH:5]=[N:1]2)[CH2:36][O:35]1
Reactant: CC1(C)OCC(CBr)O1
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccnn2CC2COC(C)(C)O2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.104 mmol) in N,N-dimethylformamide (0.5 mL) was added 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (20.2 mg, 0.104 mmol) and cesium hydroxide hydrate (17.4 mg, 0.104 mmol). The mixture was stirred for 16 hours at ambient temperature, filtered, washing with methanol and ethyl acetate, and concentrated under a stream of nitrogen. The resulting material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The isolated product (22.5 mg) was a 7:3 mixture of two regioisomers, N-(1-((1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-5-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and N-(1-((1-(2,3-dihydroxypropyl)-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide. This material was continued to the next step as a mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[O:16][C:17]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)=[CH:18][C:12]=2[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[OH-:27].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[O:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([OH:27])=[CH:21][CH:20]=3)=[CH:18][C:12]=2[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCN1CCc2oc(-c3ccc(Br)cc3)cc2C1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCCN1CCc2oc(-c3ccc(O)cc3)cc2C1
Temperature: 60 °C
Reaction time: 1.25 h

Procedure:
Compound 7d (Rb=H, 4.91 g, 11.68 mmol) was dissolved in toluene (100 ml) and to the solution was added potassium hydroxide (2 ml, 11.7N) and the solution was degassed. To the solution was added 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.27 g, 0.64 mmol, 0.06 eq) and tris-(dibenzylideneaceton)-dipalladium(0) (0.29 g, 0.32 mmol, 0.03 eq). The mixture was stirred at 60° C. for 1.25 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with 5% NaHCO3 solution (100 ml). The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (diethyl ether/petroleum ether, 1/1 to 1/0, v/v, Rf 0.1) to give pure compound 8d (Rb=H, 4.0 g) as a yellow solid. LC-MS (Method A): Rt 1.21, [M+H] 358.
Reaction SMILES: ON1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:11]=2)=[CH:6][C:5]([CH3:28])=[CH:4][C:3]1=[O:29].ClCC1[O:37]C(=O)C=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].ClCC1C2C(=CC=CC=2)C=CC=1.[I-].[Na+]>CN(C)C=O.CC(C)=O.C(Cl)Cl>[CH3:28][C:5]1[CH:6]=[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:11]=2)[O:37][C:3](=[O:29])[CH:4]=1
Reactant: Cc1cc(CCl)oc(=O)c1
Reactant: Cc1cc(CSc2cccc(OCc3cccc4ccccc34)c2)n(O)c(=O)c1
Agent: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(CSc2cccc(OCc3cccc4ccccc34)c2)oc(=O)c1
Temperature: 0 °C
Yield: 36 %

Procedure:
1-Hydroxy-4-methyl-6-[3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyridone 26 g of monothioresorcinol and 31.8 g of 6-chloromethyl-4-methyl-2-pyrone were dissolved in 100 ml of dimethylformamide and, while stirring and cooling in ice, 38 g of powdered potassium carbonate were added within 30 minutes, then the mixture was stirred at 0° C. for 4 hours and at room temperature for 16 hours, then 300 ml of methylene chloride were added, and the organic phase was extracted by shaking three times with water, separated off and dried, and the solvent was removed by distillation. The residue was recrystallized from methanol, and 44 g of 6-(3-hydroxyphenylthiomethyl)-4-methyl-2-pyrone, compound (C) of melting point 129 ° C., were obtained. 8.9 g of 1-chloromethylnaphthalene were added to a solution of 8 g of sodium iodide in 200 ml of acetone, the mixture was stirred at room temperature for 16 hours, and then 12.4 g of compound C were dissolved in the mixture, which was cooled to 0° C. and 6.9 g of powdered potassium carbonate were added in portions within 5 hours. After a total reaction time of 79 hours at 0° C., the solvent was removed by distillation under waterpump vacuum, the residue was taken up in methylene chloride, and the solution was washed with water, separated off, dried and concentrated, and the product as chromatographed on a column containing silica gel and using methylene chloride as mobile phase, and the main fractions were recrystallized from methanol. 9 g of pure 4-methyl-6-[3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyrone of melting point 139° C. were obtained.
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]=[CH2:27])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1>O1CCCC1.C1(C)C=CC=CC=1.[Cu].[Zn]>[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]3[CH2:1][CH2:27]3)([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1
Reactant: ICI
Reactant: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2
Agent: [Cu]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C1CC1)C2
Reaction time: 24 h

Procedure:
A mixture of the zinc-copper couple, prepared as described above, (48 gm.) and methylene iodide (37.5 gm.) in tetrahydrofuran (300 ml.) is heated under reflux in a nitrogen atmosphere for an hour. Ethyl [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (8.2 gm., 0.02 mole) is added to the cooled mixture and stirring continued at 25° C. for 24 hours. The mixture is diluted with toluene (200 ml.), filtered and the filtrate is washed successively with saturated aqueous solutions of ammonium chloride and sodium bicarbonate and then with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator at reduced pressure. The residue is purified by column chromatography using a silica-gel column to give ethyl [(5,6-dichloro-9a-cyclopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].II>CN1CCCC1=O.[Cu]>[N:23]1([C:2]2[CH:22]=[CH:21][C:5]([CH2:6][C:7]3[NH:8][C:9](=[O:20])[C:10]4[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=4[N:12]=3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(Br)cc3)nc12
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(-n4ccnc4)cc3)nc12

Procedure:
5-(4-Bromobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (390 mg, 0.00108 mol), imidazole (380 mg, 0.00558 mol), potassium carbonate (160 mg, 0.00116 mol), copper bronze (75 mg) and iodine (46 mg, 0.00018 mol) in N-methyl-2-pyrrolidinone (6 ml) were heated under a nitrogen atmosphere at 200° C. for 3 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous phase was extracted with ethyl acetate (30 ml), and the combined organic extracts washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])(C(C)(C)C)(C)C.Br.[F-].[K+].Cl>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)=[O:18])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Br
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2O)cn1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of Example 1E (1.66 g, 4.1 mmol) in DMF (25 mL) at room temperature was treated sequentially with 48% wt HBr (0.1 mL) and KF (0.48 g, 8.2 mmol). The mixture was stirred for 30 minutes, poured into 1N aqueous HCl (100 mL), and extracted with ethyl acetate (3×80 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60% ethyl acetate/hexanes to provide 0.97 g (82.2%) of the desired product. MS (ESI(−)) m/z 288 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 10.69 (br s, 1H), 10.48 (br s, 1H), 9.64 (s, 1H), 9.13 (d, J=1.3 Hz, 1H), 8.86 (d, J=1.3 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.5 and 2.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H).