Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C-:12]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:15]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]1[C:29]([CH3:32])([CH3:31])[CH3:30].[CH-:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.[Fe+2:39].O>CCOCC.CCCCCC>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C-:12]1[C:13]([C:29]([CH3:30])([CH3:31])[CH3:32])=[C:14]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]([C:21]([CH3:24])([CH3:23])[CH3:22])=[C:16]1[C:17]([CH3:20])([CH3:19])[CH3:18].[CH-:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.[Fe+2:39]
Reactant: CC(C)(C)c1c(C(C)(C)C)c(C(C)(C)C)[c-](CC(=O)CCCCBr)c1C(C)(C)C
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1c(C(C)(C)C)c(C(C)(C)C)[c-](CCCCCCBr)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
First, 2.27 g (17.02 mmol) of AlCl3 was dissolved in 200 ml of dry Et2O in a Schlenk flask under controlled, positive nitrogen pressure. Second, the solution was cooled to 0 degrees centigrade and 17.0 g (17.0 mmol) of 10 M LIAlH4 was charged into the flask via syringe. The resulting suspension was warmed to room temperature and agitated for approximately 15 minutes. Next, 10.00 g (17.02 mmol) of the above prepared 6-bromo-1-(tetra-tert-butylferrocenyl)-2-hexanone was slowly added to the suspension. Once the addition of the ketonic product was complete, the solution was heated to reflux for approximately 3 hours, after which time the solution was cooled to room temperature. The reaction was then quenched by slowly adding H2O to the solution. When no further exothermic reaction was observed, 250 ml of H2O was added to dilute the solution. The solution was then transferred to a separatory funnel, whereupon the organic layer was collected and the aqueous layer was extracted with 100 ml of Et2O. The organic portions were combined and then washed with NaHCO3 and brine. Next, the solution was dried over MgSO. The solution was then decanted from the drying agent and filtered. Next, the solvent was removed via rotary evaporation yielding a yellow orange oil. The oil was dissolved in a small amount of hexane, applied to a vacuum assisted gel column, and eluted with more hexane. Upon solvent removal, 8.73 g of 6-bromo-1-(tetra-tert-butylferrocenyl)hexane was isolated as a yellow orange solid.
Reaction SMILES: Br/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[C:3](\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)/[CH2:4][CH3:5].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:19]([C:21]1[CH:26]=[CH:25][C:24](/[C:2](/[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:3](\[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)/[CH2:4][CH3:5])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC/C(=C(/Br)c1ccc(F)cc1)c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
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
Product: CC/C(=C(\c1ccc(F)cc1)c1ccc(C=O)cc1)c1ccccc1
Yield: 92.6 %

Procedure:
To a solution of the bromide 3 (2.0 g, 6.54 mmol) in DME (30 mL) was added 4-formylbenzene boronic acid (1.37 g, 9.11 mmol), tetrakis(triphenylphosphine)palladium(0) (800 mg, 0.7 mmol), and 2N aqueous sodium carbonate(4.8 mL, 9.6 mmol). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 5% EtOAc/hexanes) to give the aldehyde (4) as a white solid (2.0 g, 92%): 1 H NMR (CDCl3) δ 9.83 (m, 1 H), 7.52 (d, J=8.4 Hz, 2 H), 7.15 (m, 11 H), 2.49 (q, J=7.3 Hz, 2 H), 0.94 (t, J=7.3 Hz, 3 H); APcI m/z: 372 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:29])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[C:15]([F:29])=[CH:16][C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][C:19]=3[F:20])[C:8](=[O:12])[N:9]([CH2:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[O:34])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.96 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.21 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.2 g, 59%).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[C:18]([Cl:33])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:20][C:14]=2[N:13]=1)(=[O:8])[O:5]CC)C.C[Si](N[Si](C)(C)C)(C)C.Br[Si](C)(C)C>C(Cl)Cl>[C:24]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:19]2[C:18]([Cl:33])=[CH:17][C:15]3[NH:16][C:12]([CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[N:13][C:14]=3[CH:20]=2)=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CCCc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1)OCC
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: O=P(O)(O)CCCc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 25-1 (196 mg, 0.41 mmol) in 8 mL of CH2Cl2 was added hexamethyldisilizane (2 mL), followed by bromo trimethylsilane (0.54 mL, 4.1 mmol). The reaction was stirred for 18 h at ambient temperature. The organic solvent was removed in vacuo, followed by the addition of H2O (2 mL). The crude product was sonicated and yielded a grey powder. The product was collected by vacuum filtration and washed three times with H2O and two times with MeOH. The product was dried in vacuo to give title compound 25-2 as a grey solid.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][F:33]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][F:33])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: O=C(CF)CBr
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(CF)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromo-3-fluoropropan-2-one (example 3A) using the same procedure for 2.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:39])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:17]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:10]=1)C.Cl>C1COCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[C:17]3[C:16]([NH:15][C:11]4[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:39])=[O:5])[CH:14]=[CH:13][CH:12]=4)=[N:21][CH:20]=[N:19][C:18]=3[O:22][C:23]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)/C=C/c1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(/C=C/C(=O)O)c4)c23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Add 0.73 ml of 1N sodium hydroxide solution dropwise to a mixture of 120 mg (0.244 mmol) of (2E)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acrylic acid ethyl ester in 2 ml of THF. Stir the mixture at 50° C. overnight, then cool and acidify with 1N hydrochloric acid. Filter off the precipitated solid with suction, wash repeatedly with water and dry at 50° C. under high vacuum overnight. 106 mg (93.7% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH:29]([C:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccccc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: Nc1cncnc1
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(F)cc(Nc2cncnc2)c1
Temperature: 100 °C
Yield: 121.4 %

Procedure:
3-Bromo-5-fluorobenzonitrile (1.0 g, 5.0 mmol, 1.0 eq), 5-aminopyrimidine (571 mg, 6.00 mmol, 1.20 eq), Cs2CO3 (2.28 g, 7.00 mmol, 1.40 eq), Pd2(dba)3 (230 mg, 0.400 mmol, 0.0800 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (347 mg, 0.600 mmol, 0.120 eq) and dioxane (12.5 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 1.3 g (65%) of the title compound as an orange solid: 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.80 (s, 2H), 8.67 (s, 1H), 7.32-7.30 (m, 1H), 7.28-7.24 (m, 1H), 7.21 (dt, J=11.3, 2.2 Hz, 1H); [M+1]+: 215.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)=[O:15])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(I)c(OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(OCC)c1
Yield: 97.6 %

Procedure:
3-Ethoxy-4-iodo-benzoic acid ethyl ester (0.500 g, 1.56 mmol, CAS No. 741699-04-7) was dissolved under Ar in 12 ml of abs. DMF and treated successively with 4-(trifluoromethyl)phenyl boronic acid (0.356 g, 1.2 eq.), K3PO4 (0.564 g, 1.7 eq.), and Pd(PPh3)4 (0.054 g, 0.03 eq.). The mixture was allowed to react for 16 h at 80° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=95/5) afforded finally 0.515 g of the title compound as white solid.
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].Br[CH2:40][C:41]1[O:42][C:43](=[O:58])[C:44]2[C:49]([C:50]=1[C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[N:24]1[C:25]([NH:29][CH2:40][C:41]2[O:42][C:43](=[O:58])[C:44]3[C:49]([C:50]=2[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: O=c1oc(CBr)c(-c2cccc(F)c2)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1oc(CNc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
Tert-butyl 9-trityl-9H-purin-6-ylcarbamate (93 mg, 0.195 mmol) and 50% dispersion in mineral oil NaH (9.4 mg, 0.195 mmol) were dissolved in DMF (0.2 ml) at 0° C. A solution of 3-(bromomethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C4, 50 mg, 0.150 mmol) in DMF (0.6 mL) was then added. The reaction mixture was stirred at 0° C. for 5 min and at RT for 15 min. The reaction mixture was then diluted with EtOAc (20 mL) and washed with 0.2 M HClaqueous, sat NaClaqueous dried over Na2SO4 and concentrated under reduced pressure to give the crude yellow oil. The crude was reacted with TFA (1.5 ml) in DCM (2 ml) for 1 hrs. Then it was diluted with DCM and dried under reduced pressure to give an yellow oil. This was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (20 mg, 34.4%) as colourless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: COCCN1CC(c2ccccc2)NC1=O
Reaction time: 4 h
Yield: 91.5 %

Procedure:
The 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one (6.5 g) so obtained is next admixed with 10% palladium on carbon (0.7 g) in ethanol (50 ml). The mixture is thereafter hydrogenated at 50 psi at room temperature for four hours and the catalyst is filtered. Resultant filtrate is finally concentrated to yield racemic 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone (6.0 g), [α]D20 =-0.2(c=1 in CHCl3).
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=[O:11])[CH2:3]2.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCOC(C)=O>CN(C=O)C.CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:10]2[CH:6]3[CH2:7][CH2:8][CH2:9][CH:2]2[CH2:3][C:4](=[O:11])[CH2:5]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C1CC2CCCC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
20.9 g of 9-azabicyclo[3.3.1]nonan-3-one hydrochloride was dissolved in 600 mL of DMF. 89.0 g of Cs2CO3 followed by 29 g of 4-chlorobenzenesulfonyl chloride was added and the reaction mixture was stirred overnight at rt. After an additional day of stirring, the reaction mixture was poured into 1.4 L of vigorously stirring EtOAc. The mixture was stirred for 2 h and allowed to stand at rt overnight. The mixture was filtered to remove undissolved solids and the filtrate was washed with H2O (2 L×3) and brine (2 L). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. A granular, tan solid was produced. Trituration with methanol dissolved a tan impurity to afford 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one as a white crystalline solid (25.9 g, 69% yield).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)/[C:7](=[N:15]/C(=O)C(F)(F)F)/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14]2)[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(C)(C)C)cc(=N)n1CC1CC1
Yield: 87.3 %

Procedure:
A mixture of Example 27E (6.37 g, 21 mmol) and 6N NaOH aqueous (20 mL) in MeOH (100 mL) was stirred at 50° C. overnight, and then concentrated under reduced pressure. The residue was extracted by CH2Cl2 (30 mL×3) and the combined organic layers were washed with brine and concentrated to yield 3.8 g (87%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.44 (m, 2H), 0.47-0.54 (m, 2H), 1.07-1.20 (m, 1H), 1.29-1.36 (m, 9H), 3.78 (s, 3H), 4.10 (d, J=6.74 Hz, 2H), 5.60 (s, 1H), 7.19 (s, 1H); MS (+DCI) m/z 208 [M+H]+.
Reaction SMILES: [CH2:1]([CH:9]1[O:11][CH:10]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:23][OH:24]>>[OH:11][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]([O:24][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCCCCCCC1OC1CCCCCCCC(=O)OC
Reactant: CO
Product: CCCCCCCCC(O)C(CCCCCCCC(=O)OC)OC

Procedure:
The methyl 8-(3-octyloxiran-2-yl)octanoate (2) (4.8 g; 0.015 mol), Amberlyst 15 (0.05 g) and methanol in excess (100 mL) were placed under reflux for 12 hours. The reaction mixture was filtered and the methanol removed using a rotary evaporator. The reaction mixture was dissolved in dichloromethane (100 mL) and washed with water (3×50 mL). The dichloromethane solution was separated and evaporated to obtain the intermediate compound 3.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)#[CH:18]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(F)cc1
Product: O=c1[nH]c2nccc(C#Cc3ccc(F)cc3)c2c2ccccc12
Yield: 54.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynyl-4-fluorobenzene (0.07 mL, 0.65 mmol) to provide 250 (74 mg, 54% yield) as a tan solid. LC-MS (M+H=315 obsd.=315).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.[O:16]=[S:17]1(=[O:32])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[O:32]=[S:17]1(=[O:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[S:8][CH2:7]3)[CH2:28][CH2:27]2)=[N:18]1
Reactant: O=S1(=O)N=C(N2CCNCC2)c2ccccc21
Reactant: O=C1N(CCCCBr)CSC12CCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N(CCCCN2CCN(C3=NS(=O)(=O)c4ccccc43)CC2)CSC12CCCC2
Temperature: 85 °C
Yield: 52.2 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (3.50 g), 1-(1,1-dioxo-1,2-benzisothiazol-3-yl)piperazine (3.30 g), K2CO3 (4.98 g) and NaI (280 mg) in acetonitrile (230 ml) was heated at 85° C. for 20 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.89 g of needles, m.p. 137°-140° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[CH:22]=[CH2:21]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: C=CCBr
Product: C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Yield: 60.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and allyl bromide were reacted by the same way with the example 45-1 to obtain the titled compound (190 mg, yield: 60.8%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:54]1[C:59]([C@H:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65]2[CH:70]=[CH:69][N:68]3[N:71]=[CH:72][C:73]([C:74]([O:76][CH2:77][CH3:78])=[O:75])=[C:67]3[N:66]=2)=[CH:58][C:57]([F:79])=[CH:56][N:55]=1.[NH2:80][CH2:81][CH2:82][NH:83][C:84](=[O:90])[O:85][C:86]([CH3:89])([CH3:88])[CH3:87]>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]>[C:86]([O:85][C:84]([NH:83][CH2:82][CH2:81][NH:80][C:54]1[C:59]([C@H:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65]2[CH:70]=[CH:69][N:68]3[N:71]=[CH:72][C:73]([C:74]([O:76][CH2:77][CH3:78])=[O:75])=[C:67]3[N:66]=2)=[CH:58][C:57]([F:79])=[CH:56][N:55]=1)=[O:90])([CH3:89])([CH3:88])[CH3:87]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3NCCNC(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of Pd2 dba3 (7.05 mg, 0.00770 mmol), Cs2CO3 (125 mg, 0.385 mmol), rac-Binap (19.2 mg, 0.0308 mmol), (R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (50 mg, 0.128 mmol), and tert-butyl 2-aminoethylcarbamate (24.7 mg, 0.154 mmol) in degassed toluene (1 mL) was first purged with nitrogen, then sealed and subjected to microwave irradiation (120° C.) for 16 hours. After cooled to ambient temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (2×5 mL). The organic was dried (Na2SO4) and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system C18 12+M cartridge, 5 to 70% acetonitrile/water) to yield the desired product as white foamy solid (38 mg, 58% yield). MS (apci) m/z=514.1 (M+H).