Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH3:21])[C:17]([F:20])=[C:18]([CH:19]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCCl.CCN=C=NCCCN(C)C.Cl.Cl.[F:44][C:45]([F:53])([F:52])[CH2:46][NH:47][C:48]([NH:50][NH2:51])=[O:49]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][NH:50][C:48]([NH:47][CH2:46][C:45]([F:53])([F:52])[F:44])=[O:49])=[O:5]
Reactant: NNC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution containing (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 mL) was added sequentially EDC.HCl (70.6 mg, 0.368 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl then with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography afford the title compound as a glassy oil (40 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, J=15.8 Hz, 1H), 6.42 (dd, J=16.0, 7.7 Hz, 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −68.56, −73.02; ESIMS m/z 627.9 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:25].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N+:15]([O-:43])=[CH:16][CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]=2[C:8]1=[O:25]
Reactant: O=C1c2c(-c3ccccc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2c(-c3ccccc3)cc[n+]([O-])c2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
5-[3,5-Bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 5; 729 mg) was dissolved in methylene chloride (10 mL). To the resulting solution, 3-chloroperbenzoic acid (524 mg) was added, and then the mixture was stirred at room temperature for 24 hours. The reaction mixture was purified on a silica gel column chromatography (ethyl acetate:methanol=5:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine 10-oxide (411 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[OH:21][C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:26]3[CH:27]=[C:22]([OH:21])[CH:23]=[CH:24][CH:25]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)c1
Temperature: 90 °C
Yield: 83.9 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA66) (48.7 mg, 168 □mol, 1.0 eq) and 3-Hydroxyphenylboronic acid pinacol ester (MW 220) (148 mg, 672 □mol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (4 mL) for 5 min. Dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (3.07 mg, 4.20 □mol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15.5 h. The red solution was cooled and diluted with EtOAc (6.5 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (6.5 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography gave a colorless solid (49 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 46.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-(trifluoro-methoxy)phenylsulfanyl)benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to obtain {6-chloro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.127 g, 44%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].C1(S([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:27][N:26]=2)(=O)=O)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[CH:27][N:26]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To 4.08 g of 3,4-dichlorophenol dissolved in a 25 ml THF/25 DMSO mixture was added 2.9 g of t-BuOK and then 8.99 g of 2.5-bis(phenylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature, then added to 3 to 4 volumes of water and stirred. The brown precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the purified product, 2-(3,4-dichlorophenoxy)-5-(phenylsulfonyl)pyridine (68% yield), as white shiny needles, m.p. 113°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[C:5]2[CH3:14].[Cl:15][C:16]1[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>ClC1C=CC=CC=1Cl>[CH3:14][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([N:1]3[C:22](=[O:21])[C:17]4=[C:16]([Cl:15])[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:18]4[C:19]3=[O:20])[CH:3]=2)[N:8]=[C:7]([CH3:13])[CH:6]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Cc1cc(C)c2cc(N)cc(C)c2n1
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c2cc(N3C(=O)c4c(Cl)c(Cl)c(Cl)c(Cl)c4C3=O)cc(C)c2n1
Yield: 87 %

Procedure:
350 g of o-dichlorobenzene was added to 186 g (1.0 mole) of 6-amino-4,8-dimethylquinaldine and 286 g (1.0 mole) of 3,4,5,6-tetrachlorophthalic anhydride, and the mixture was refluxed at the boiling point for 4 hours. The reaction mixture was then cooled. The crystals precipitated were collected by filtration, and dried to afford 394 g (0.87 mole) of 4,8-dimethyl-6-(3,4,5,6-tetrachlorophthalimido)-quinaldine. Then, 372 g (1.30 moles) of 3,4,5,6-tetrachlorophthalic anhydride, 2,000 g of 1,2,4-trichlorobenzene and 40 g of anhydrous zinc chloride were added, and the mixture was heated under reflux for 3 hours. Then, 500 g of dimethylformamide was added, and the mixture was stirred under reflux for 1 hour. The product was treated in the same way as in paragraph (C) of Example 1 to afford 571 g (0.79 mole) of a yellow compound. Since the compound obtained was scarcely soluble in dimethylformamide, its visible spectrum could not be measured. In its infrared spectrum (KBr), absorptions ascribable to --CO--N--CO-- were observed at 1730 cm-1 and 1790 cm-1, and absorptions ascribable to --CO--C--CO--, at 1645 cm-1 and 1695 cm-1. The elemental analysis values of this product were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].CCC[CH2-].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:4][CH:3]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC1(F)Oc2cccc(Cl)c2O1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-Chloro-2,2-difluorobenzo[d][1,3]dioxole (3 g, 15.58 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −75° C. N-Butyllithium (2.5 M in hexanes; 6.86 mL, 17.14 mmol) was added dropwise keeping the temperature below −65° C. The reaction mixture was then stirred at −75° C. for 1 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.19 g, 17.14 mmol) was then added to the reaction mixture dropwise keeping the temperature below −65° C. The reaction mixture was then allowed to warm to room temperature, added to diethyl ether (200 mL) and extracted with water (2×100 mL). The aqueous phases were combined and acidified to pH 4 with concentrated HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum to provide the title compound as an off-white solid (3.82 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 1.36 (s, 12H); EIMS m/z 318.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[O-2].[Ca+2].C1C2C(=NC3C(C=2)=CC=CC=3)C=CC=1.[P:26](Cl)(Cl)([Cl:28])=[S:27]>C1C=CC=CC=1>[Cl:28][P:26]1(=[S:27])[O:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:1]1
Reactant: S=P(Cl)(Cl)Cl
Reactant: OCc1ccccc1O
Agent: [Ca+2]
Agent: [O-2]
Agent: c1ccc2nc3ccccc3cc2c1
Solvent: c1ccccc1
Product: S=P1(Cl)OCc2ccccc2O1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Into a three-necked, 500 ml flask were placed 31 g (0.25 mole) o-hydroxybenzyl alcohol, 56 g (1.0 moles) calcium oxide, a catalytic amount (0.1 g) of acridine, and 600 ml of benzene. To this reaction mixture was added 46.5 g (0.275 mole) of thiophosphoryl trichloride, dropwise, over a period of 120 minutes with stirring. The temperature was maintained at 22° C by use of a water bath. After the addition of the thiophosphoryl trichloride the mixture was stirred overnight. The mixture was then filtered, the solids washed with four equal portions of benzene (total of 200 ml) and the washings combined with the filtrate. The filtrate was then washed with two equal portions of a 5 percent aqueous bicarbonate solution (total of 100 ml), dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure. The residue crystallized, affording 39 g (71%) pf 2-chloro-4H-1,3,2-benzodioxaphosphorin-2-sulfide, m.p.=44°-45° C. Analysis: %Cl, 16.12 (calculated); 16.42 (Found).
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>ClCCl>[CH:1]1([C:6]2[C:7]3[C:14]([I:15])=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1nc(C2CCCC2)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Ic1c[nH]c2ncnc(C3CCCC3)c12
Reaction time: 8 h
Yield: 371.2 %

Procedure:
4-Cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (48, 0.099 g, 0.53 mmol) was dissolved in 3.4 mL of dichloromethane under an atmosphere of nitrogen and N-iodosuccinimide (0.131 g, 0.582 mmol) was added. The mixture was stirred overnight, then quenched with aqueous sodium thiosulfate. The aqueous layer was separated and washed with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to provide the desired compound (49, 0.616 g), used in the next step without further purification. MS (ESI) [M+H+]+=313.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.CC[C:16](CC)=[C:17]([C:20]([O-])([O-])[O-:21])CC.CC(C)(C)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1[CH2:16][CH2:17][C:20](=[O:21])[O:13][C:8]=1[CH:7]=[CH:6]2
Reactant: CCC(CC)=C(CC)C([O-])([O-])[O-]
Reactant: COc1ccc2cc(O)ccc2c1
Agent: CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c3c(ccc2c1)OC(=O)CC3
Yield: 86.4 %

Procedure:
Starting with a solution of 6.29 g (36.1 mmol) of 6-methoxy-2-naphthalenol, 12.58 g (72.2 mmol) of triethyl orthoacrylate and 1.84 g (18.1 mmol) of trimethylacetic acid in 70 mL of toluene, the title compound (7.12 g; 86.4%) was obtained as a white solid, mp 122°-123° C., using the procedure of example 220.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH:44][C:45]3[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])[N:48]=[C:47]([NH:57][C:58]4[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=4)[N:46]=3)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1.[NH2:67][CH2:68][CH2:69][C@@H:70]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:71]([OH:73])=[O:72]>CN(C=O)C>[C:78]([O:77][C:75]([NH:74][C@H:70]([CH2:69][CH2:68][NH:67][C:62](=[O:63])[C:61]1[CH:60]=[CH:59][C:58]([NH:57][C:47]2[N:46]=[C:45]([NH:44][C:41]3([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[CH2:43][CH2:42]3)[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])[N:48]=2)=[CH:66][CH:65]=1)[C:71]([OH:73])=[O:72])=[O:76])([CH3:81])([CH3:80])[CH3:79]
Reactant: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Di-iso-propylethylamine (0.054 g) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g) were added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (0.1 g) and (R)-4-amino-2-((tert-butoxycarbonyl)amino)butanoic acid (0.045 g) in DMF (1 mL). The reaction was stirred at room temperature for 16 hours and (R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid was isolated by using preparative HPLC system.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([O:28][C:31]1[CH:30]=[CH:29][C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 76 %

Procedure:
4.6 g (1.0×10-2 mol) of MA-Gly-Phe-Leu-Gly-OH was esterified with p-nitrophenol (1.1×10-2 mol) in 55 ml of THF by means of dicyclohexylcarbodiimide (DCC) (1.1×10-2 mol). After 3 hours at 15° C. and 12 hours at 25° C., the dicyclohexylurea was filtered off and the remaining solution was evaporated under reduced pressure. The residue was solidified by adding dry ethyl ether and after recrystalisation from acetone:ether (3:1) gave MA-Gly-Phe-Leu-Gly-ONp in 76% yield which was analytically pure; m.p. 124°-8° C. Aminoacid analysis gave Gly:Leu:Phe of 2.0:1.0:0.99.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:37].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:35][CH3:36])[CH2:23][F:37])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(COS(=O)(=O)c1ccc(C)cc1)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Product: CCC(CF)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
The product of Example 3F (28 mg, 52.4 mop was dissolved in 0.5 mL acetonitrile in a 5 mL flask and to this was added a solution of potassium fluoride (4.5 mg, 78.6 μmol) and Kryptofix 222 (29.6 mg, 78.6 μmol) in 0.5 mL acetonitrile. The above solution was then immersed in a oil bath preheated to 90° C. The reaction was allowed to stir for 90 minutes after which all the volatiles were removed under reduced pressure and the crude mixture purified by preparative thin layer chromatography to obtain 13 mg (65%) of pure desired compound. 1H (CDCl3) δ (ppm): 7.72 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.23 (s, 2H), 4.57-4.59 (m, 2H), 4.4 (m, 4H), 1.74 (m, 2H), 1.6 (s, 9H), 1.0 (t, 3H). 13C (CDCl3) δ (ppm): 159, 158.7, 153.7, 129, 127.5, 125.2, 118.3, 116.4, 83.85 (d, 1JCF=172.2), 78, 71.1, 66.3, 27.8, 23.2, 9.48. 19F (CDCl3, CFCl3 as internal standard) δ (ppm): −228 (d of t, J=−19, −60 Hz)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27]Br)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>[OH-].[Na+].C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: OCC1CCCNC1
Reactant: COc1ccc(CCBr)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN2CCCC(CO)C2)cc1OC

Procedure:
A mixture of 2.30 g (0.02 mol) of 3-(hydroxymethyl)piperidine, 5.5 ml (0.04 mol) of triethylamine and 4.90 g (0.02 mol) of 2-(3,4-dimethoxy-phenyl)-ethyl bromide is refluxed for 2 hours. After cooling, the reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is washed with water, separated off, dried over magnesium sulphate, evaporated down in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 2%). Yield: 4.4 g (78.7% of theory), Melting point: 87.5°-89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O=[C:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21]>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:19]([CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH3:21])[C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[C:9]2[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1cccnc1C(=O)c1cc(F)ccc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Reaction time: 48 h

Procedure:
A solution of (2-amino-5-fluorophenyl)(3-methylpyridin-2-yl)methanone (0.29 g, 1.26 mmol), (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.366 g, 1.386 mmol), and sodium tetrachloroaurate(iii) dihydrate (0.025 g, 0.063 mmol) in 2-propanol (5.0 mL) was stirred at 80° C. for 24 h under an argon atmosphere, then at room temperature for an additional 48 h. The solution was purified by silica gel column chromatography eluting with a gradient of 10-40% EtOAc in hexane to afford tert-butyl 1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a dark solid: LC-MS (ESI) m/z 459.2 [M+H]+.