Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:14]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOCCCCc1cccc(N2C(=O)CNC2=O)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
3-(3-{4-[(6-Hydroxyhexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione (2.67 g) in CH2Cl2 (50 ml) and triethylamine (1.2 ml) was treated with methanesulfonyl chloride (1.22 ml) and the mixture was stirred at 20° C. for 1.5 h. The mixture was diluted with CH2Cl2 and washed with 2M HCl, NaHCO3, dried and purified by chromatography on Biotage (40 g) eluting with EtOAc-petroleum ether(1:1) and then with 2% MeOH—CH2Cl2 to give the title compound (1.186 g) ES+ve 427 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(C(Cl)=O)=O.[NH2:18][C:19]1[C:20]([F:27])=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[F:25].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=1[F:27])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1c(F)ccc(O)c1F)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzoic acid (5.1 g, 23.3 mmol, 1.0 eq) in CH2Cl2 (50 mL) were added (COCl)2 (8.8 g, 69.9 mmol, 3.0 eq) and DMF (0.07 mL). The reaction mixture was stirred at room temperature for 1.5 h then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (30 mL) and added dropwise to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (3.0 g, 20.9 mmol, 1.0 eq) and NaHCO3 (5.3 g, 62.9 mmol, 3.0 eq) in THF (3 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (5.78 g 79%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][O:18][CH3:19].[C:20]([C:24]1[CH:25]=[CH:26][C:27]2[NH:28][C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=3)([CH3:23])([CH3:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.C1COCC1.[Cu]I>[C:20]([C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:2]3[CH:7]=[C:6]([C:8]([CH3:15])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[CH:5]=[CH:4][C:3]=3[O:16][CH2:17][O:18][CH3:19])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=3)([CH3:23])([CH3:22])[CH3:21]
Reactant: COCOc1ccc(C(C)(C)CC(C)(C)C)cc1I
Reactant: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(C)CC(C)(C)C)cc1-n1c2ccc(C(C)(C)C)cc2c2cc(C(C)(C)C)ccc21

Procedure:
Heat a mixture of 4.96 g (13.18 mmol) of 2-iodo-1-(methoxymethoxy)-4-(2,4,4-trimethylpentan-2-yl)benzene (P3), Preparation 3; 3.68 g (13.18 mmol) of 3,6-di-t-butylcarbazole (P1), Preparation 1; 0.53 g (2.6 mmol) of CuI, 8.42 g (39.54 mmol) of K3PO4, and 0.63 g (4.13 mmol) of N,N′-dimethylethylenediamine in 25 mL of toluene under nitrogen atmosphere to reflux and reflux for 24 hours. Cool the reaction mixture, dilute it with 25 mL of THF, and filter to remove solid. Concentrate the filtrate to give a solid residue. Crystallize the solid residue from acetonitrile to yield 5.5 g (90%) of (P4) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Mg+2].[Cl-].[SH-].[Na+].[S:20]([O-])(O)(=O)=O.[K+]>CN(C=O)C.O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1)(=[S:20])[NH2:2]
Reactant: C=CCOC(=O)c1ccc(C#N)cc1
Reactant: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C(N)=S)cc1
Reaction time: 1 h

Procedure:
In 50 ml of DMF was dissolved 2.50 g (13.3 mmol) of allyl 4-cyanobenzoate, then, 2.8 g of magnesium chloride.6H2O and 2.20 g (27.5 mmol) of 70% sodium hydrosulfide were added to the solution at room temperature, and after stirring at the same temperature for one hour, 150 ml of water was added to the mixture. After adjusting the pH to 3 with a 20% aqueous potassium hydrogen sulfate, the precipitated solid was collected by filtration to obtain 2.92 g (13.2 mmol) of allyl 4-thiocarbamoylbenzoate as yellowish solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])([CH3:15])([CH3:14])[CH3:13]>O.O1CCCC1.CCOCC>[C:12]([O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:29])[C@H:24]([CH:26]([CH3:27])[CH3:28])[NH:25][C:8]([O:10][CH3:11])=[O:9])([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C

Procedure:
A solution of sodium carbonate (110.5 g) in water (1.5 liters) and L-Valyl-L-Proline tert-butyl ester in tetrahydrofuran (THF; 1 liter) were combined and cooled to 0° C. The mixture was diluted with ether (400 ml) and methyl chloroformate (39.4 g) was added dropwise. The reaction mixture was then allowed to warm ambient temperature over 2 hours. The layers were separated and the organic phase was washed twice with 1M hydrochloric acid, followed by saturated aqueous sodium bicarbonate solution and brine. The aqueous phase was extracted with ether. All organic phases were combined and dried (MgSO4) and the solvent removed to give N-(methoxycarbonyl)-L-valyl-L-proline tert-butyl ester (125.9 g); 1H NMR (300 MHz, DMSO/d4-trifluoroacetic acid): 4.23 (dd, 1H), 4.06 (d, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 3.55 (s, 3H), 2.16 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.42 (s, 9H), 0.94 (m, 6H); MS: m/z=329 (M+1).
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20][C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)[C:13]=3[CH3:30])[CH2:6][O:5]2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:3]1[C:4]2([O:5][CH2:6][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:39])[C:13]=3[CH3:30])[CH2:8][O:9]2)[CH2:1][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Reaction time: 0.92 h
Yield: 86.1 %

Procedure:
To a toluene (20 ml)-methanol (2 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-ylmethoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (499 mg, 1.17 mmol) obtained in the step (13d), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (280 mg, 1.05 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred in the same conditions for 55 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected with ethyl acetate, and concentrated. To the residue, diethyl ether was added and then the mixture was concentrated to obtain the title compound (445 mg, yield: 86.1%) as a colorless foam.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
Cutter, L. A. in U.S. Pat. No. 4,145,375 presents a process for copolymerizing styrene and maleic anhydride which involves a sequence of operations in which maleic anhydride is first gradually admixed with styrene in a mass stage under polymerizing conditions to rapidly form styrene-maleic anhydride polymer. The styrene-rich mixture is then suspended in water and the styrene polymerization completed as in a conventional mass/suspension polymerization system. The suspension step further modifies the polymer by opening the anhydride group to form free carboxylic acid groups on the polymer chain. Following the heating period, the polymerization mixture is cooled; the polymer beads are separated from the water by a solid-bowl centrifuge, and dried in a rotary air drier. The polymers resulted have Mw=100,000-500,000, and the content of residual styrene is between 0.02 and 0.1% by weight. A disadvantage of this process is that the final product is a blend of polystyrene and SMA copolymer, the polystyrene being a major contaminant, with multiple implications making it unfavorable for bio-applications. Similar problems exist for front polymerization which uses excess of styrene. Szalay, J. et al., Macromol. Rapid Commun. 1999, 20, 315-318.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]1([C:13]2[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[C:14]=2[O:23][CH3:24])[CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:15]([F:22])[C:14]=2[O:23][CH3:24])[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1c(C2CCC2)ccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1c(C2CCC2)ccc(-c2cnc(N)cn2)c1F
Temperature: 80 °C
Yield: 97 %

Procedure:
To a 1000 mL round-bottom flask were added a stir bar, 2-amino-5-bromopyrazine (19.95 g, 115.3 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g, 112 mmol), Pd(dppf)Cl2.CH2Cl2 (5.92 g, 7.28 mmol) and K2CO3 (47.33 g, 343 mmol). The flask was flushed with nitrogen and then charged with sparged toluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). The reaction vessel was heated at 80° Celsius for 17 hours before cooling to room temperature. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was extracted with EtOAc (200 mL×3), the combined extracts dried over MgSO4, filtered and concentrated to dryness. The residue was subjected to FCC to give the title compound (29.68 g). MS (ESI): mass calcd. for C15H16FN3O, 273.13; m/z found, 273.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:10])=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Nc1nccs1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.4 mmol) in DCM (10 ml) was added triethylamine (0.23 ml, 1.68 mmol) and HOBt (0.23 g, 1.68 mmol) at 0° C. After stirring at this temperature for 5 min. added 2-aminothiazole (0.168 g, 1.68 mmol) and followed by EDCI (0.332 g, 1.68 mmol). The resulting solution was stirred for 12 h. then quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL). The organic phase was successively washed with 2% HCl (50 mL), brine (50 mL) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:10 ethyl acetate:hexanes) to give 2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide (0.325 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.58 (s, 6H), 6.76 (d, J=8.8 Hz, 2H), 7.01 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.50 (d, J=3.6 Hz, 1H), MS (EI) m/z 296.9 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CN([C:17]([O:21][N:22]1N=NC2C=CC=N[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CONC>CN(C=O)C>[CH3:17][O:21][N:22]([CH3:23])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:13]
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and O,N-dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then the solvent was evaporated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-methoxy-N-methylquinoxaline-6-carboxamide as yellow solid (5.1 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.CO>[C:19]1([C:16]2[O:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:18][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccccc3)o2)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc(-c2nnc(C3CCNCC3)o2)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (795 mg, 2.41 mmol, 1.0 eq) in CH2Cl2 was added TFA (1.5 mL, 19.5 mmol, 8 eq). The reaction was stirred for 1 h and 7 N NH3 in MeOH (2 mL) was added dropwise for the pH to reach 7. The solvent was evaporated in vacuo giving the title product as a white solid (553 mg) which was used without further purification for the next step. MS (m/z, MH+): 230.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C@@:5]12[CH2:13][C:12]1([CH3:15])[CH3:14].[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH:22]=[C:21](Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>C(#N)C.[Cu]I>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH:22]=[C:21]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C@@:5]3([CH2:13][C:12]3([CH3:15])[CH3:14])[C:6]2=[O:11])[CH:20]=1
Reactant: COC(=O)c1cc(Br)cc(N2CCOC2=O)c1
Reactant: CC1(C)C[C@]12C(=O)Nc1ccc(F)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@]3(CC3(C)C)c3cc(F)ccc32)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
A suspension of (R) and (S)-5′-fluoro-2,2-dimethylspiro[cyclopropane-1,3′-indolin]-2′-one (2 mmol) (prepared as in Example 100), methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate (682 mg, 2 mmol), CuI (76 mg, 0.4 mmol), potassium carbonate (545 mg, 4 mmol) and N,N′-dimethyl-ethane-1,2-diamine (86 uL, 0.8 mmol) in acetonitrile (15 mL) was stirred for 16 hours at 90° C. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford the title compound as white powder (480 mg, 80%) which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.[Na+].Cl[C:19]([F:24])([F:23])C([O-])=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH:19]([F:24])[F:23])[CH:3]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-fluorophenol (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2CO3 (0.9 g, 6.54 mmol) and stirred at 25° C. for 10 min. Water (0.5 mL) was added to the above mixture followed by addition of 2-Chloro-2,2,-difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100° C. for 3 h. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.2-6.9 (2H, m), 6.8-6.7 (1H, d), 6.7-6.2 (1H, m).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[C:7]([S:14][CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=1)=O.Cl.Cl.[NH2:24][NH2:25]>C(O)C>[CH3:15][S:14][C:7]1[C:8]2[C:9](=[O:11])[NH:25][N:24]=[CH:1][C:3]=2[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:6]=1
Reactant: CCOC(=O)c1c(C=O)nc(-c2ccccc2)nc1SC
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CSc1nc(-c2ccccc2)nc2cn[nH]c(=O)c12
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (600 mg, 1.98 mmol) in ethanol (15 mL) was added hydrazine dihydrochloride (0.2 g, 1.98 mmol) and the mixture refluxed for 1 hour. The precipitated solid was filtered and dried in vacuum. The desired product (520 mg) was obtained by column chromatography over silica gel using methanol/dichloromethane as eluent. 1H-NMR (400 Hz, DMSO-d6): δ 13.19 (s, 1H), 8.54 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 7.64-7.58 (m, 3H), 2.67 (s, 3H); MS m/z 271.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[C:17]1([C:2]2[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cc(OCc2ccccc2)cnc1Cl
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(OCc2ccccc2)cnc1-c1ccccc1
Yield: 84 %

Procedure:
6.8 g (28.6 mM) of 2-chloro-3-fluoro-5-(phenylmethoxy)pyridine, 110 ml of DME and 4.18 g (34 mM) of phenylboronic acid are mixed. 6.64 g (156 mM) of lithium chloride and 1.65 g (1.4 mM) of tetrakis(triphenylphosphine)palladium are added. Finally, 38 ml (76 mM) of 2 M potassium carbonate solution are added and the mixture is refluxed for 18 hours. After hydrolysis in 250 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water and then with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (95/5, then 90/10; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 84%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.Cl.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:18](=[O:20])[CH3:19])=[N:3]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2c(Cl)ccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(Cl)ccnc2n1
Temperature: 80 °C
Yield: 33.6 %

Procedure:
A stirred solution of 2,5-dichloro-[1,8]naphthyridine (Barlin, G. B.; Tan, W.-L. Aust. J. Chem. 1984, 37, 1065) (0.1001 g, 0.503 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through for 15 min. Tetrakis-(triphenylphosphine)palladium(0) (30.0 mg, 0.0259 mmol) and tributyl(1-ethoxyvinyl)tin (0.170 mL, 0.503 mmol) was added and the mixture was heated at 80° C. for 17 h under nitrogen. The mixture was diluted with ethyl acetate (20 mL) and shaken with 2 N aqueous HCl (15 mL) for 1 min. The mixture was adjusted to pH 6 with 4 N aqueous NaOH and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×15 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 15% EtOAc/CH2Cl2, followed by a further column on silica gel eluting with 50% EtOAc/isohexane, to afford 34.9 mg (34%) of the title compound as a white solid. δH (360 MHz, CDCl3) 2.95 (3H, s), 7.68 (1H, d, J 4.6), 8.33 (1H, d, J 8.4), 8.76 (1H, d, J 8.8), 9.12 (1H, d, J 4.9).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]([CH3:4])[CH3:3].[F:7][C:8]([F:19])([F:18])[CH2:9][CH2:10][Si:11](OC)([O:14][CH3:15])[O:12][CH3:13].[SiH4].CCCCCC>C(OCC)C.CCCCCC>[F:19][C:8]([F:7])([F:18])[CH2:9][CH2:10][Si:11]([CH2:1][CH:2]([CH3:4])[CH3:3])([O:12][CH3:13])[O:14][CH3:15]
Reactant: CC(C)C[Mg]Cl
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: [SiH4]
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[Si](CCC(F)(F)F)(CC(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to room temperature and charged with 150 ml of diethyl ether and isobutylmagnesium chloride (0.06 mol, 30.24 ml). This was stirred and heated slightly to 30° C. A second Schlenk flask (100 ml) was purged with nitrogen to room temperature and charged with 75 ml hexane and 3,3,3-trifluoropropyltrimethoxy silane (0.0504 mol, 10 ml) and stirred. The silane/hexane solution was added dropwise via cannula to the Grignard/diethyl ether mixture producing a white precipitate midway through the addition. After addition (1.25 hrs.), the reaction mixture was stirred at room temperature for one hour. The flask was fitted with a reflux condenser and the reaction mixture was refluxed for two hours, then allowed to cool to room temperature. The reaction mixture was filtered through a medium porosity frit, using Celite diatomaceous earth and glass wool as a filtering aid. The solids collected weighed 7.55 g (theoretical=4.56 grams of magnesium salts). The slightly cloudy filtrate was kept under nitrogen overnight.