Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O>C(Cl)(Cl)Cl>[F:23][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][S:15]([C:16]1[CH2:20][C:19]([CH3:21])([CH3:22])[O:18][N:17]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CS(=O)C2=NOC(C)(C)C2)c1OC(F)F
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 6.2 g (17.3 mmol) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline in 40 ml of chloroform was added 3.4 g (purity: 70%, 13.8 mmol) of m-chloroperbenzoic acid under ice-cooling, followed by 1 hour of stirring. Thereafter, the whole was further stirred at room temperature for 3 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogen sulfite solution, an aqueous sodium hydrogen carbonate, water, and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting solid was washed with n-hexane to obtain 4.1 g (yield: 63.2%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethanesulfinyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 112 to 114° C.).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[Br:13])=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:29](OC)[CH2:30][NH2:31]>ClCCl.O>[CH2:1]([N:4]1[CH:29]=[CH:30][N:31]=[C:5]1[C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[Br:13])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1sc(Br)nc1Br
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1ccnc1-c1sc(Br)nc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a solution of N-allyl-2,4-dibromo-1,3-thiazole-5-carboxamide (13.0 g, 39.9 mmol) in dichloromethane (260 mL) was added phosphorus pentachloride (9.93 g, 47.7 mmol) and 4M hydrochloric acid in dioxane (1.52 mL, 6.06 mmol). The reaction was heated to 60° C. for 90 minutes under an atmosphere on nitrogen. The reaction was allowed to cool to room temperature and then aminoacetaldehyde dimethyl acetal (47.8 mL, 439 mmol) was added slowly through the condenser. The mixture was heated to 60° C. for 2 hours under an atmosphere of nitrogen then cooled to room temperature, and water was added (200 mL). The layers were separated and the organic phase was washed with water again (2×200 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and washed with dichloromethane (200 mL). To this dichloromethane solution of the intermediate was added 4M hydrochloric acid in dioxane (120 mL, 480 mmol) and the solution was stirred at 60° C. for 16 hours. The solution was decanted (leaving behind an oily black residue on the flask) then the solvent was evaporated and the residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted three more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (8.04 g, 58%). LCMS: (FA) ES+, 306 (parent minus allyl group). 1H NMR (300 MHz, d4-methanol) δ: 7.37-7.31 (m, 1H), 7.20-7.16 (m, 1H), 6.02-5.86 (m, 1H), 5.26-5.18 (m, 1H), 5.07-4.96 (m, 1H), 4.68-4.59 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4](OC)=[O:5].[NH3:15]>[OH-].[NH4+]>[NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4]([NH2:15])=[O:5]
Reactant: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: C[C@H](C(N)=O)[C@@H](N)c1ccccc1
Reaction time: 96 h

Procedure:
A solution of methyl (2S,3R)-3-amino-2-methyl-3-phenylpropionate (6.3 g, 33 mmol) in 2N methanolic ammonia (20 ml ) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After 4 d, it was evaporated followed by chromatography on a short column of silica gel (dichloromethane-methanol-conc. ammonium hydroxide=93:7:0.7; 90:10:0.8) to provide the amide as a white solid. MS (m/z): 179.2 (M+H)+; C10H14N2O requir. 178.2.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.Br[C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.Cl>C1COCC1.C1COCC1.CCCCCC.CCOC(C)=O>[O:15]=[C:4]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1cnc2ccccc2c1
Temperature: -10 °C

Procedure:
(S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.5 g, 10.76 mmol) was suspended in THF (5 mL) and stirred at −10° C., isopropylmagnesium chloride 2.0M solution in THF (5.4 ml, 10.80 mmol) was added and a solution was formed. To this solution was added a solution of Lithium tri(3-quinolinyl)magnesiate in THF/Hexane, prepared from 3-bromoquinoline (1.471 ml, 10.81 mmol) according to the procedure described by Sylvain Dumouchel et-al. in Tetrahedron 59 (2003) 8629-8640. The mixture was stirred at −10° C. for 30 min and was the allowed to reach r.t. and stirred over night, 15 h. The reaction mixture, a clear red solution, was slowly poured into ice-cooled 1M HCl (aq) (100 mL). EtOAc (150 mL) was added and the mixture was stirred for a few min, the water phase was extracted once with EtOAc, the combined EtOAc solutions was further washed with saturated NaHCO3 (aq) and brine. The crude material was purified by flash-chromatography on silica using a gradient of 0% to 40% EtOAc in Heptane. The obtained material was the further purified by HPLC to afford the subtitle compound as a yellow sticky oil. Yield 1.6 g (49%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][NH:4][C:3]1=[O:11].[H-].[Na+].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH-].[Li+].Cl>CN(C)C=O.O>[CH:15]1([N:4]2[CH2:5][CH:6]([C:7]([OH:9])=[O:8])[N:2]([CH3:1])[C:3]2=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C1CNC(=O)N1C
Reactant: BrC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(C2CCCC2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.2 %

Procedure:
A stirred solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2.0 mmol) (prepared as described in step (ii) of Example 8) in N,N-dimethylformamide (5 ml) was cooled to 0° C. under argon and treated with sodium hydride (60% dispersion in oil) (80 mg, 2.0 mmol). After 10 minutes bromocyclopentane (298 mg, 2.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours and then at 60° C. for 18 hours. After cooling to room temperature additional sodium hydride (60% dispersion in oil) (80 mg, 2.0 mmol) was added followed by bromocyclopentane (298 mg, 2.0 mmol) and the reaction mixture was heated at 60° C. for 48 hours. After cooling to room temperature a solution of lithium hydroxide (0.057 g, 2.400 mmol) in water (1 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (2M) was added to adjust the pH of the mixture to pH 2 and the solvent was evaporated. Dimethylsulfoxide (3 ml) was added to the residue and the suspension was filtered. The filtrate was purified by mass-directed automated HPLC to give 1-cyclopentyl-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (39 mg, 9%). LC/MS [M+H]+=213. Mass-Directed Automated HPLC
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH3:10].[C:11]([C:15]1[O:16][C:17]2[C:23]([S:24](Cl)(=[O:26])=[O:25])=[C:22]([Cl:28])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])([CH3:13])[CH3:12].O>O1CCCC1>[CH3:8][N:9]([CH3:10])[S:24]([C:23]1[C:17]2[O:16][C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])=[N:19][C:18]=2[CH:20]=[CH:21][C:22]=1[Cl:28])(=[O:25])=[O:26]
Reactant: CNC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
12.9 ml (93 mmol; 3.0 eq) of triethylamine and 93 ml of 2 M dimethylamine in tetrahydrofuran were added dropwise to a solution of 9.55 g (31 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzoxazole-7-sulfonyl chloride in 200 ml of tetrahydrofuran cooled to 0° C. The reaction medium was stirred at 0° C. for 3 hours and was then treated with water. The reaction medium was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over magnesium sulfate, filtered and evaporated. 9.12 g of 2-tert-butyl-6-chlorobenzooxazole-7-sulfonic acid dimethylamide were obtained in the form of a beige solid. Yield=93%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[C:10](=[O:29])[C:11]4[C:16]([C:17]([CH3:19])([CH3:18])[C:8]=3[O:7][C:6]=2[CH:30]=1)=[CH:15][C:14]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)=[CH:13][CH:12]=4.[Na+].[I-:32].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I>[CH3:27][C:24]1([CH3:28])[O:23][C@@H:22]([CH2:21][O:20][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:29])[C:9]2[C:5]4[CH:4]=[CH:3][C:2]([I:32])=[CH:30][C:6]=4[O:7][C:8]=2[C:17]3([CH3:18])[CH3:19])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(Br)ccc4c2C3=O)O1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(I)ccc4c2C3=O)O1
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (15 mg, 0.032 mmol), CuI (6.2 mg, 0.032 mmol), NaI (9.6 mg, 0.064 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.01 ml) were added and the mixture was stirred for 48 hrs under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (16 mg, 97%), which was then deprotected according to the method of A-14-2 to give the title compound.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:17]
Reactant: OC1CCCCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
To a solution of cyclooctanol (640 mg, 4.9 mmol) in dichloromethane (15 mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyl diazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RT for 10 min. The reaction mixture is rotary evaporated, and the residue dissolved in Et2O, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 397 mg of the product 413. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50 (m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H); MS: m/z 215 (M++1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:115][C:116]([CH3:136])=[CH:117][CH2:118][CH2:119]/[C:120](/[CH3:135])=[CH:121]/[CH2:122][CH2:123]/[C:124](/[CH3:134])=[CH:125]/[CH2:126][S:127][CH2:128][C@H:129]([NH2:133])[C:130]([OH:132])=[O:131]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:133][C@@H:129]([CH2:128][S:127][CH2:126]/[CH:125]=[C:124](\[CH3:134])/[CH2:123][CH2:122]/[CH:121]=[C:120](\[CH3:135])/[CH2:119][CH2:118][CH:117]=[C:116]([CH3:136])[CH3:115])[C:130]([OH:132])=[O:131])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-proline (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (232 mg, 44%) to yield Compound N-8. 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H), 1.62 (bs, 6H), 1.69 (s, 3H), 1.72 (s, 3H), 1.89 (bs, 1H), 1.98 (t, J=7.5 Hz, 2H), 2.05-2.14 (m, 6H), 2.24-2.26 (m, 1H), 2.79 (dd, J=8.0, 14.0, 1H), 3.03 (bd, J=13.0 Hz, 1H), 3.15 (dd, J=7.5, 13.0 Hz, 1H), 3.27 (dd, J=8.0, 13.0 Hz, 1H), 3.40 (m, 1H), 3.66 (bs, 1H), 4.28 (bs, 1H), 4.60 (dd, J=4.9, 8.0 Hz, 1H), 5.11-5.14 (m, 2H), 5.24 (t, J=7.4 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 24.2, 24.5, 25.3, 25.9, 27.4, 27.8, 28.7, 30.1, 30.4, 30.7, 31.1, 32.5, 33.5, 40.8, 40.9, 47.9, 48.3, 53.1, 53.4, 61.4, 61.9, 81.4, 81.7, 121.5, 125.1, 125.5, 132.1, 136.3, 140.5, 156.2, 173.6, 175.8; ES-MS: mass calcd for Chemical Formula: C28H46N2O5S 522.3. Found (M+Na) m/z 545.3.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34]>C1C=CC=CC=1>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:34])[NH2:36])=[O:14])=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (14.1 mmol) of 3-(4-trifluoromethylbenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.66 g (15.4 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 5.10 g (yield: 80.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.N[C:22]1C=CC(C(N)=O)=CN=1.O.C(OCC)C>C1(C)C=CC=CC=1.CS(C)=O>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([CH3:22])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: NC(=O)c1ccc(N)nc1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cc1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 24.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.09 g, 3.06 mmol) and 6-amino-nicotinamide (2.51 g, 18 mmol) were combined in toluene (8 ml) and heated to 100° C. for 18 hours. The mixture then was diluted with dimethylsulfoxide (8 ml) and heated to 120° C. for 2 hours. The mixture then was poured into water (120 ml) with rapid stirring. Diethyl ether was added and the resulting solid was collected by filtration. This solid was washed with 1:1 warm ethyl acetate/tetrahydrofuran and dried in vacuo to provide 6-bromo-8-cyclopentyl-2-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.233 g, 18%). MS (APCI); M++1: Calc'd, 429.06. Found, 429.1. Analyses for C18H17BrN6O2:
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:25][OH:26]>F[B-](F)(F)F.[Ag+]>[CH3:25][O:26][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Yield: 35 %

Procedure:
There were mixed 4.12 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, 9.37 g of silver tetrafluoroborate and 100 ml of methanol. The mixture was refluxed for 4 hours. The reaction mixture was cooled and filtered to remove the insolubles. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 1.27 g (yield: 35%) of 2,3-dihydro-3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[N:4][C:5]([O:11][CH3:12])=[C:6]([C:9]=1[CH3:10])[C:7]#[N:8].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.C(O)C>[CH3:12][O:11][C:5]1[N:4]=[C:3]([CH3:13])[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH3:10])[C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(C)c(I)c(C)c1C#N
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(C)c(-c2ccccc2)c(C)c1C#N
Yield: 78.6 %

Procedure:
5-iodo-2-methoxy-4,6-dimethyl-nicotinonitrile (1.6 g, 5.554 mmol), Pd(PPh3)4 (642 mg, 0.555 mmol), phenyl boronic acid (1.05 g, 8.331 mmol), and anhydrous potassium carbonate (1.54 g, 11.11 mmol) were suspended in the mixed solution of 60 mL of anhydrous toluene and 3 mL of anhydrous ethanol, and then heated to reflux for about 72 hours under the nitrogen atmosphere. The mixture was filtered, added with 100 mL of a saturated solution of ammonium chloride and then extracted twice with 100 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and then concentrated. A silica gel column chromatography (5% EtOAc/Hexanes) was performed on the resulting residue and 1.04 g (78%) of 2-methoxy-4,6-dimethyl-5-phenyl-nicotinonitrile was obtained in pale yellow solid.
Reaction SMILES: N(C(C)C)C(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=1.[Li+].CC([N-]C(C)C)C.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([C:12]([O:15][CH3:16])=[CH:11][N:10]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: COc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cnc(Br)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
N-BuLi (21.3 mL, 2.5 M in hexane, 53.2 mmol) was added dropwise to a solution of i-Pr2NH (5.9 g, 58.5 mmol) in THF (80 mL) at −78° C. The solution was stirred at 0° C. for 1 h. A solution of 2-bromo-5-methoxypyridine (10 g, 53.2 mmol) in THF (30 mL) was added dropwise to the LDA solution at −78° C. The mixture was stirred at −78° C. for 2 h and poured onto an excess of dry ice and allowed to warm to RT before being treated with NaOH (5% a.q., 100 mL). The mixture was washed with DCM and acidified to pH 4 by addition of HCl (6 N, 20 mL). The solids were collected by filtration to give the product of 2-bromo-5-methoxyisonicotinic acid (10 g, yield: 83%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.34 (s, 1H), 7.70 (s, 1H), 3.92 (s, 3H). MS (M+H)+: 232/233.
Reaction SMILES: Br[C:2]1[S:6]/[C:5](=[CH:7]\[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])/[N:4]([CH2:19][CH2:20][CH2:21][CH3:22])[C:3]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:19]([N:4]1[C:3]([CH3:23])=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[S:6]/[C:5]/1=[CH:7]\[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCCN1C(C)=C(Br)S/C1=C\C(=O)c1cc(Cl)ccc1OC
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: [K+]
Solvent: C1COCCO1
Product: CCCCN1C(C)=C(c2ccc(F)cc2)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 80 °C

Procedure:
A mixture of the product from Example 13 (126 mg, 0.3 mmol), 4-fluorophenylboronic acid (45 mg, 0.3 mmol0, triphenylphosphine (79 mg, 0.3 mmol), potassium carbonate (69 mg, 0.5 mmol) and Pd(Ph3P)4 (35 mg, 0.03 mmol) in dioxane (10 mL) was refluxed at 80° C. for 48 min. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 2:1) to afford 50 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.44 (sextet, J=7 Hz, 2H), 1.74 (quintet, J=7 Hz, 2H), 2.32 (s, 3H), 3.87 (s, 3H), 4.02 (t, J=7 Hz, 2H), 6.68 (s, 1H), 7.13 (d, J=9 Hz, 1H), 7.33 (t, J=9 Hz, 2H), 7.47 (m, 3H), 7.66 (d, J=3 Hz, 1H); MS (ESI) m/z 432 (M+H)+. Anal calcd for C23H23ClFNO2S.0.25H2O: C, 63.29; H, 5.43; N, 3.21. Found: C, 63.20; H, 5.25; N, 3.04.