Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[NH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].[CH:27](I)([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13]([O:20][CH:27]([CH3:29])[CH3:28])=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: O=c1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2[nH]1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2n1
Reaction time: 28 h
Yield: 100.4 %

Procedure:
To a suspension of 5-benzyloxy-6-bromo-4-(trifluoromethyl)-1H-quinolin-2-one (11.7 g, 29.4 mmol) and CsF (17.8 g, 117 mmol) in 150 mL DMF was added isopropyl iodide (19.9 g, 117 mmol). After 28 h, the mixture was partitioned between EtOAc (500 mL) and water (250 mL) and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (200 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford 13 g (100%) of 5-benzyloxy-6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H, J=9.0), 7.55–7.65 (m, 3H), 7.38–7.48 (m, 2H), 7.32–7.38 (m, 1H), 7.31 (s, 1H), 5.54 (sept, 1H, J=6.2), 5.06 (s, 2H), 1.42 (d, 6H, J=6.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>[Pd].CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccc(F)c2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
10% Palladium on carbon (0.095 g) was added to a solution of 3′-fluoro-3-nitrobiphenyl (L) (0.63 g, 2.88 mmol) in EtOH (20.0 mL). The flask was evacuated and replaced with a hydrogen atmosphere. The solution was stirred at room temperature for 5 h under hydrogen. The catalyst was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→15:85 EtOAc:hexanes) to afford 3′-fluorobiphenyl-3-amine (LI) (0.34 g, 1.81 mmol, 63% yield) as a light yellow oil. 1H NMR (DMSO-d6) δ ppm 7.47-7.44 (m, 1H), 7.40-7.39 (m, 1H), 7.36-7.33 (m, 1H), 7.15-7.14 (m, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.85-6.84 (m, 1H), 6.80-6.79 (m, 1H), 6.60-6.58 (m, 1H), 5.18 (s, 2H); ESIMS found for C12H10FN m/z 188 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:36])([F:35])[F:37])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 523.9.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]([S:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([CH3:8])[C:5]([OH:7])=[O:6].C(O)C>O>[CH3:8][C:4]([S:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([CH3:3])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: CC(C)(SCCc1ccc2c(c1)OCO2)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(SCCc1ccc2c(c1)OCO2)C(=O)[O-]
Yield: 92.4 %

Procedure:
A solution of 0.90 g of sodium hydroxide in 9.0 ml of water was added to 6 g of 2-methyl-2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionic acid to obtain a solution. 100 ml of ethanol was added to the solution and the solvent was distilled off. The residue was washed with ether. After filtration, the product was dried under reduced pressure to obtain 6 g of the intended compound in the form of a white powder.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].F[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:11]#[N:12]>CN(C=O)C>[CH:2]([O:4][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:15]=1)[C:11]#[N:12])([CH3:3])[CH3:1]
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 131.3 %

Procedure:
To a mixture of propan-2-ol (102.96 g 1.76 moles) in DMF (3200 mL, 8 V) at 5° C. was added NaH (122 g, 5.08 moles). The mixture was stirred for 2 hours. To this mixture 3-fluoro-5-(trifluoromethyl)benzonitrile (400, 2.1 moles) was added dropwise. The temperature of the mass was increased to 25 to 30° C. and maintained at same temperature for 1 hour. Reaction was monitored by HPLC. After completion, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and then concentrated under vacuum to give 530 g (2.31 moles; 110%) of 3-isopropoxy-5-(trifluoromethyl)benzonitrile, which was taken as such to next step with no further purification. HPLC purity—96.5% by area (a/a).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]([CH2:30][C:31]1[CH2:35][CH2:34][CH2:33][CH:32]=1)[C:24]([C@@:26]1([CH3:29])[CH2:28][O:27]1)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]1([CH2:30][C@H:23]([NH:22][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:24]([C@@:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCC2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
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: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (2.00 g, 6.78 mmol) and (S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0° C. was added HATU (3.00 g, 8.36 mmol) followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N2O6, found 473.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:17]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]3)=[O:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(Br)cc2)cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4′-bromo-[1,1′-biphenyl]-4-carboxylic acid (2 g, 7.22 mmol), (R)-pyrrolidin-3-ol (1.3 g, 14.92 mmol), and HATU (5.5 g, 14.46 mmol) were dissolved in DMF (60 mL). To this solution was added TEA (4 ml, 28.7 mmol) and the reaction mixture was stirred under N2 at room temperature for 24 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The organic layer was separated and washed with 1N HCl, saturated NaHCO3, and brine, and then dried over Na2SO4, filtered and concentrated in vacuo. Chromatography of the resulting residue over silica eluting with 3% MeOH in DCM afforded the desired product. LC-MS: calculated for C17H16BrNO2 345.04 observed m/e: 346.09 (M+H)+ (Rt: 1.62/4 min).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Br.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[C:21]([F:27])[CH:20]=1.[OH-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[O:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][C:21]=1[F:27]
Reactant: OCc1ccc(Cl)cc1F
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(Cl)cc2F)cnn1-c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 54.2 %

Procedure:
To a mixture of 2.0 g (5.0 m mol) of 4,5-dibromo-2-(3,4-dichlorophenyl)-3(2H)-pyridazinone and 0.84 g (5.2 m mol) of 4-chloro-2-fluorobenzyl alcohol was added 80 ml of N,N-dimethylformamide. The resulting mixture was cooled with ice, incorporated with 0.4 g of potassium hydroxide and then stirred for one day. Then, the procedures in Synthesis Example 2 were repeated to give a crude product. The crude product was recrystallized from benzene to give 1.3 g of the intended compound.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:14]#[C:13][CH2:12][OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Ic1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc2ccccc12
Temperature: 35 °C
Reaction time: 19 h
Yield: 48.9 %

Procedure:
To a stirred solution of de-gassed 1-iodonaphthalene (10.00 g, 39.36 mmol), propargyl alcohol (2.25 g, 40.15 mmol, 1.02 eq.), triethylamine (7.97 g, 78.72 mmol, 2 eq.) and copper iodide (0.02 g, 0.12 mmol, 0.3 mol %) in tetrahydrofuran (30 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.05 g, 0.07 mmol, 0.18 mol %). The mixture was stirred at 35° C. under an atmosphere of nitrogen for 19 h. The mixture was concentrated in vacuo to afford a black tar residue. The residue was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 30%:70%) to afford the desired compound as a yellow oil (3.51 g, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 4.64 (2H, s, CH2), 7.38-7.40 (3H, m, ArH), 7.64 (1H, m, ArH), 7.79 (1H, d, J=8.0 Hz, ArH), 7.81 (1H, d, J 8.0 Hz, ArH), 8.32 (1H, d, J 8.0 Hz, ArH).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[NH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2cc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc[nH]c12
Yield: 36 %

Procedure:
Into a 50-mL round-bottom flask was placed a solution of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (5 g, 35.52 mmol, 1.00 equiv, 96%) in trichlorophosphate (20 mL). The resulting solution was stirred at reflux for 1 h, concentrated under vacuum, dissolved in 100 mL of ethyl acetate, washed with 2×100 mL of 10% aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:8) to afford 2 g (36%) of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]=1[C:20]#[N:21].S(=O)(=O)(O)[OH:23].[OH-].[NH4+]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]=1[C:20]([NH2:21])=[O:23]
Reactant: Cc1ccc(-c2nn(-c3ccccc3)c(N)c2C#N)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3ccccc3)c(N)c2C(N)=O)cc1
Temperature: 50 °C

Procedure:
While maintaining an internal reaction temperature of 10°-15° C., 5-amino-4-cyano-3-(4'-methylphenyl)-1-phenylpyrazole (3.4 g, 12 mmol) was added in a portionwise manner to concentrated sulfuric acid (15 mL). After the addition was complete, the reaction mixture was heated at 50° C. for 4 hours. The reaction was cooled, poured over ice, neutralized with concentrated ammonium hydroxide and extracted with EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solids were recrystallized from MeOH/H2O to afford 3.0 g of the title compound; m.p. 190°-191° C.
Reaction SMILES: N#N.[Si]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([O:20][CH3:21])([CH3:19])[CH3:18])[O:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:21][O:20][C:17]([C:14]1[O:15][CH:16]=[C:12]([CH2:11][OH:10])[N:13]=1)([CH3:19])[CH3:18]
Reactant: COC(C)(C)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)(C)c1nc(CO)co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-methoxypropan-2-yl)oxazole (110 mg, 0.39 mmol) in THF (1.8 mL) was treated at 0° C. with TBAF (0.39 mL of a 1M solution in THF, 0.39 mmol) and the resulting mixture was stirred for 45 min at 0° C. The reaction mixture was diluted with EA (10 mL), washed with sat. aq. NH4Cl (5 mL) and brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a yellow oil: TLC: rf (3:7 hept-EA)=0.20. LC-MS-conditions 07: tR=0.44 min, [M+H]+=172.01.
Reaction SMILES: Br.[OH:2][CH2:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Si:24]([O:2][CH2:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 131.9 %

Procedure:
To a stirred suspension of 3-(3-hydroxymethylpyridin-2-yl)-nitrobenzene hydrobromide (0.3 g) and imidazole (106 mg) in N,N-dimethylformamide (3 ml) was added tert-butyldimethylsilyl chloride (216 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)nitrobenzene (438 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[Cu][C:26]#[N:27]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 1-bromo-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.02 g, 2.63 mmol), copper (I) cyanide (470 mg, 5.25 mmol) and anhydrous dimethylformamide (8.8 mL) was refluxed for ten minutes before it was cooled to room temperature quenched with water and ethyl acetate. The slurry was filtered. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (727 mg): MS: (+) m/z 334.83 (M+1).
Reaction SMILES: CC(C)=O.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.C(N(CC)CC)C.[Cl:24][CH:25]([CH3:29])[C:26](Cl)=[O:27]>O>[Cl:24][CH:25]([CH3:29])[C:26]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:27]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CC(Cl)C(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)Nc1nc(-c2ccccc2)cs1
Yield: 69.8 %

Procedure:
Into 50 ml of acetone, were added 12.5 g of 2-amino-4-phenylthiazole and 7.0 g of triethylamine. The mixture was cooled to -10°--20° C. To the mixture solution, 11.7 g of α-chloropropionylchloride was slowly dropped. After the completion of the dropwise addition, the resultant mixture solution was agitated at room temperature for 3 hours. Then, the reaction mixture was poured into 500 ml of water. Resulting oily substance was extracted with ethyl acetate. The extract was then successively washed with dilute hydrochloric acid and water. After drying the solution, the ethyl acetate was removed under reduced pressure. The residue was recrystallized from an ether/n-hexane mixed solvent to obtain 13.2 g of 2-(α-chloropropionylamino)-4-phenylthiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([OH:17])=[CH:9][C:8]=1[O:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:25][C:26]([OH:28])=[O:27])=[CH:9][C:8]=1[O:7]2
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccc(O)cc2oc2cccc(F)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3c(F)cccc3oc2c1
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A mixture of 1.8 g of 8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 3.2 g of potassium carbonate, 3.7 g of ethyl bromoacetate and 100 ml of DMF was stirred at 60°-70° C. for 4 hours. After cooling the mixture, 5 g of sodium hydroxide and 100 ml of water were added, and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 2.0 g of 8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 180°-183° C. This compound showed a mass spectrum having a molecular ion peak at m/e 288.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][F:5])=[CH:19][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
3-Bromo-1-fluoro propane (1.6 g, 11 mmol) was added to a mixture of (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (compound 17c) (2.0 g, 3.7 mmol) and cesium carbonate (3.6 g, 11 mmol) in DMF (60 mL). The suspension was stirred overnight at room temperature. The reaction mixture was diluted in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 1.89 g (85.1%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:21].C(=O)(O)[O-].[Na+].O>ClCCl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reaction time: 2 h

Procedure:
Compound 69B was suspended in 100 ml dichloromethane. SOCl2 was added and allowed to stir for 2 h. 20 ml Saturated sodium bicarbonate was added followed by 20 ml water and stirred for 5 minutes. The dichloromethane layer was seperated and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered through silica and eluted with dichloromethane until clear. Concentration of the filtrate gave a pink solid. MS m/z 262 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.I[CH2:17][CH2:18][CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.2 %

Procedure:
To a solution of phenol 4 (500 mg, 1.65 mmol) in acetone (25 mL) were added 1-iodopropane (0.5 mL, 4.95 mmol) and Cs2CO3 (460 mg, 4.95 mmol) at room temperature. The mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 5 (600 mg, 99%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in CH3OH (100 mL), cooled to 0° C. under Ar and treated dropwise with thionyl chloride (18.9 mL, 0.259 mol) with stirring. The bath was removed and stirring was continued at ambient temperature for 3.5 h. Water (150 mL) and solid NaHCO3 (60 g) were added, the CH3OH was removed on a rotary evaporator, and the residue extracted with CH2Cl2 (3×150 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound.