Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Fc1cccc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3-fluorobenzyl chloride gave the title compound. ES-MS m/e (%): 507.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)c2ccc(Cl)cc2)CC1

Procedure:
Example 100 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H, J=2.0 Hz), 7.34–7.28 (m, 5H), 7.21 (dd, 1H, J=2.0. 8.0 Hz), 7.09 (d, 1H, J=8.0 Hz), 6.98 (br s, 1H), 3.55 (q, 1H, J=7.2 Hz), 3.34 (m, 2H), 3.02 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.6 Hz), 2.68 (m, 1H), 2.51 (m, 1H), 2.39 (dt, 2H, J=6.8, 2.0 Hz), 2.29 (s, 3H), 2.04–1.97 (m, 2H), 1.80–1.60 (m, 6H), 1.52 (d, 3H, J=7.2 Hz), 1.24 (dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+]>Cl.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:9])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1

Procedure:
To the solution of 1,445 g of p-chloroaniline in 3,375 ml of 38% hydrochloric acid and 5,650 ml of water the solution of 793 g of sodium nitrite in 3.3 L of water is added during 1 hour at -5° to -8° while stirring under nitrogen. After 15 minutes 7,617 g of stannous chloride in 9 L of 38% hydrochloric acid are added during 30 minutes below 25°. The resulting suspension is stirred in an ice bath for one hour, filtered, the residue suspended in 30 L of water, and 5,000 g of solid sodium hydroxide are added during 1 hour at 0°-25°, while stirring under nitrogen. The mixture is extracted twice with 8 L of diethyl ether, the combined extracts washed twice with 4 L of water and once with saturated aqueous sodium chloride, dried, filtered, evaporated and the residue dried at 5 mmHg and room temperature, to yield the p-chlorophenyl-hydrazine melting at 82°-87°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>CC(O)CC.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)cnc2ccc(OC)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)O
Product: COc1ccc2ncc(=O)n(CC=O)c2c1
Reaction time: 3.75 h
Yield: 65.6 %

Procedure:
A mixture of 7-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinoxalinone (1.03 g, 4.75 mmol) and sodium periodate (4.68 g, 21.8 mmol) in 2-butanol (20 mL) and water (40 mL) was treated with osmium tetroxide (4% solution in water, 1.1 mL) and the mixture was stirred for 3.75 h. The butanol was evaporated and the residue was diluted with water and extracted with dichloromethane, then with dichloromethane/THF. The extracts were dried and evaporated, and the residue was chromatographed on silica eluted with 50-100% ethyl acetate/hexane to give the aldehyde (0.68 g, 66%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[NH3:27].O1CCOCC1>O>[NH2:27][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: C1COCCO1
Solvent: O
Product: NCC1CCn2c(nc3ccccc32)S1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
To 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, were added 5 g of 25% ammonia water and 40 ml of dioxane. The mixturewere heated in a sealed tube, at 120° C., for 75 hours. The reactionmixture was then condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.46 g (yield: 35.1%) of the intended product, m.p. 217°-222° C.; IR νmaxKBr cm-1 3300-2600, 1440; Anal. Calcd. for C11H13N3S: C, 60.25; H, 5.97; N, 19.16; S, 14.62; Found: C, 60.28; H, 5.99; N, 19.60; S, 14.13.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:14]1[CH:13]=[CH:12][C:11]2[C:10]3[C:18](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:17](=[O:19])[C:16]=2[CH:15]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2ccc(I)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 266.6 %

Procedure:
Add acetic acid (45 mL), concentrated sulfuric acid (5.4 grams, 0.055 moles), water (10 mL), 9-fluoreneone (9.01 grams, 0.05 moles), iodine (6.0 grams, 0.0237 moles), and periodic acid (2.85 grams, 0.0125 moles) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the reaction mixture to 45° C. and stir 1 hour, then warm to 50° C. and stir an additional 2.5 hrs. Warm the mixture to 60° C. and add additional acetic acid (45 mL). Stir the reaction mixture for an additional 10 hours, cool to room temperature and stir the reaction mixture at room temperature for about 8 hours. Collect the precipitate by filtration. Transfer the filter cake and acetic acid (40 mL) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the mixture to 70° C. and add additional acetic acid with continued warming until a clear solution is observed. Reduce the reaction mixture to 50° C. and stir at 50° C. for 2 hours. Slowly cool the reaction mixture to 25° C. and stir 1 hour. Recover the precipitate by vacuum filtration. Air-dried the resulting filter cake to provide the title compound (10.2 g, 66.6% yield). 1H NMR (CDCl3, 500.0 MHz): δ 7.95 (d, 1H, J=1.5); 7.81 (dd, 1H, J=2, 8); 7.64 (d, 1H, J=7.5); 7.50 (m, 2H); 7.33-7.24 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]O>C(O)=O>[OH:20][CH2:13][CH:12]1[O:9][C:8](=[O:10])[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: OO
Reactant: C=CCC(C(=O)O)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C1OC(CO)CC1(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
2,2-Diphenyl-4-pentenoic acid (5.0 g, 20 mmol.), 20 mL of formic acid and 2.4 mL (22 mmol.) of 30% hydrogen peroxide were stirred at 70° C. for 25 hours at ambient temperature. The solvents were evaporated at reduced pressure, the residue taken up in 20 mL of methanol and a solution of 750 mg solid NaOH in 10 mL of water was added. The mixture was warmed at 70° C. to solution, about 1 hour before cooling and acidifying with 6N hydrochloric acid. The product was extracted with ether, the organics dried (MgSO4) and evaporated at reduced pressure to give an oil in quantitative yield, the H NMR indicated a clean reaction product which was carried on without further purification. Analytical TLC (silica, 9:1, methylene chloride: EtAc) R.function. 0.35; IR (neat) 3419, 3060, 2936, 1763, 1177, 786, 763, 699 cm-1 ; 1H NMR (CDCl3)δ 2.5-2.65 (bs, 1H), 2.84-3.02 (m, 2H), 3.64-3.72 (m, 1H), 3.92-4.00 (m, 1H), 4.41-4.51 (m, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: [OH-].[Na+].CC1OC(C2C=CC=CC=2)=NC=1COC1C=CC(CO/N=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=CC=1.CO.Cl>O1CCCC1>[C:34]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 233.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added to a solution of ethyl E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-pheny]-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (451 mg, yield 90%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidine (1.2 equiv) to give 161 (17.9 mg, M+1 381.2)
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[SH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O-:17])=[O:16].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:15]([CH2:14][S:12][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[N:10][N:9]=1)([OH:17])=[O:16]
Reactant: O=C([O-])CCl
Reactant: Sc1nncn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nncn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Into 500 ml of ethanol were suspended 53 g (0.3 mol) of 4-phenyl-3-mercapto-1,2,4-triazole and 44.1 g (0.36 mol) of sodium chloroacetate. Thereto was added an aqueous solution prepared by dissolving 15.5 g (0.36 mol) of sodium hydroxide (purity, 93%) into 60 ml of water. This mixture was kept at 50° C. for 3 hours to-react the reactants. The reaction mixture was allowed to cool to room temperature, neutralized by dropwise adding 31 ml (0.36 mol) of concentrated hydrochloric acid, and then cooled to 10° C. or lower with ice. The resulting precipitate was taken out by filtration. To the precipitate was added 1.5 l of ethanol. This mixture was heated, and the insoluble matter was taken out by filtration. Thereafter recrystallization was conducted with cooling to obtain 32.3 g (0.14 mol) of the desired mercaptoacetic acid derivative. Yield, 45.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=1[C:16]1[C:15]([O:14][CH3:13])=[CH:20][CH:19]=[CH:18][C:17]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccc(I)c(Br)c1
Reactant: COc1cccc(OC)c1B(O)O
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2c(OC)cccc2OC)c(Br)c1
Temperature: 85 °C
Yield: 55.9 %

Procedure:
Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate (J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of 2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2M aqueous solution of caesium carbonate for 15 minutes under argon, then add 984 mg (0.85 mmol) of Pd(PPh3)4 and heat for 2.5 h at 85° C. After concentration under reduced pressure, distribute the residue obtained in 600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL of water, dry over MgSO4 and concentrate at reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 2.79 g of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of 4-bromobenzylalcohol (2 g, 10.7 mmol) in DCM (30 mL) at 0° C. was added Et3N (2.2 mL, 16.0 mmol) followed by methanesulfonyl chloride (910 μL, 11.8 mmol). The reaction was allowed to warm to room temperature, stirred for 2 hours and then quenched with water. Saturated aqueous NaHCO3 was added, the product was extracted with DCM, the combined organic extracts were filtered through a phase separator cartridge and concentrated to give methanesulfonic acid 4-bromo-benzyl ester (2.67 g, 10 mmol, 94%). A solution of the crude product (2.67 g, 10 mmol) in DMSO (40 mL) was stirred at room temperature for 16 hours with potassium thioacetate (1.26 g, 11 mmol). The reaction was treated with water and extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give thioacetic acid S-(4-bromo-benzyl) ester (1.81 g, 7.39 mmol, 69%). 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2 H), 7.16 (d, 2 H), 4.05 (s, 2 H), 2.35 (s, 3 H).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C>[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:41][N:40]=2)=[O:43])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: Fc1ccc(F)c(OC2CCNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)C1)c1cc(-c2ccccc2)on1
Reaction time: 0.03 h
Yield: 35.4 %

Procedure:
DIPEA (153.5 mg, 1.2 mmol) followed by HOBt (44.1 mg, 0.32 mmol) and EDCI (113.8 mg, 0.59 mmol) were added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (73.4 mg, 0.29 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (70 mg, 0.29 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 50% EtOAc in hexane) afforded 45 mg (35.4% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 428, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ 8.8-8.68 (m, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 3H), 7.4 (s, 1H), 7.34-7.2 (m, 2H), 6.9-6.75 (m, 1H), 5.3-5.0 (m, 2H), 4.2-4.0 (m, 2H), 3.9 (m, 1H), 3.8-3.7 (m, 1H), 3.7-3.5 (m, 2H), 2.3-2.2 (m, 1H), 2.1 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]=[O:13].[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]1[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:13]1
Reactant: CC(C)(CO)CO
Reactant: Cc1cc(C)c(/C=C/C=O)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(Br)c1
Yield: 96.9 %

Procedure:
A mixture of 1.00 g (4.19 mmol) of (E)-3-(2-bromo-4,6-dimethylphenyl)-2-propenal, 1.32 g (12.6 mmol) of 2,2-dimethyl-1,3-propanediol and a catalytic amount (65 mg) of p-toluenesulfonic acid monohydrate in 100 mL of dry benzene was heated at reflux in a Dean-Stark apparatus for 2 hours. The solution was washed with 1N sodium hydroxide, water (3 times), and the solvent removed under reduced pressure to give 1.32 g (97%) of (E)-2-[2-(2-bromo-4,6-dimethylphenyl)ethenyl]-5,5-dimethyl-1,3-dioxane as a white crystalline material. Purification by HPLC (70% CH2Cl2 -Hexane) gave an analytically pure sample: mp 54°-56° C.; IR (KBr) 2960, 2860, 1670 and 1610 cm-1 ; NMR (CDCl3) δ 0.77 (3H, s), 1.25 (3H, s), 2.28 (3H, s), 2.37 (3H, s), 3.58 (2 H, d, J=12 Hz), 3.74 (2H, d, J=12 Hz), 5.09 (1H, d, J=6 Hz), 5.90 (1H, dd, J=6, 15 Hz), 6.78 (1H, d, J=15 Hz), 6.96 (1H, s), 7.30 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:19][C:18]([F:21])([F:20])[CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:14][CH3:15])([CH3:12])[CH3:13]
Reactant: COc1cc(F)ccc1C(C)(C)CC=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 1.89 g (8.99 mmol) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde was added 25 mL (12.5 mmol) of a 0.5 M solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran and 2 mL (2 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added over a 2 minute period. The mixture stirred for 30 minutes and then an additional 8 mL (8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The mixture was then diluted with water and extracted with three 25 mL portions of EtOAc. The combined organic layers were washed with three 20 mL portions of 1 N aqueous HCl, three 20 mL portions of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 2.78 g of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol as an oil. The oil was dried under high vacuum to a constant weight of 2.36 g (93%) and was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2>>[F:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2)=[C:24]([O:23][CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:11]3[C:6]4[O:5][CH2:4][C:3](=[O:19])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:14][CH2:15]2)[CH:33]=1
Reactant: Cc1ccc2c(OCCBr)cc(F)cc2n1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cc(F)cc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Fluoro-5-cyanobenzoic acid (1.0 g, 6 mmol) was treated with a solution of oxalyl chloride (12 mL of 2.5 M in dichloromethane, 30 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-fluoro-5-cyanbenzoyl chloride.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:18]([Cl:26])=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23].[I:27]I>C1COCC1>[Br:16][C:17]1[C:18]([Cl:26])=[N:19][CH:20]=[C:21]([C:25]=1[I:27])[C:22]([OH:24])=[O:23]
Reactant: II
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Br)c1I
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
n-Butyllithium (1.6M in hexanes, 172 mL, 276 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (48.5 mL, 285 mmol) in anhydrous THF (200 mL) at −50° C. After 20 min, solid 5-bromo-6-chloronicotinic acid (21.6 g, 92 mmol) was added portionwise and the resultant slurry was allowed to warm to −20° C. over 1 h and stirred at that temperature for 1 h. After this time, the reaction mixture was cooled to −60° C. and transferred via cannula to a solution of iodine (70 g, 276 mmol) in anhydrous THF (100 mL) at −60° C. at such a rate that the internal temperature of the solution remained below −40° C. On complete addition, the reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was concentrated in vacuo and the resultant dark red slurry was dissolved in water (500 mL) and washed with diethyl ether (3×200 mL). The pH of aqueous layer was adjusted to 2 by the addition of 1M aqueous hydrochloric acid and the resulting beige precipitate was collected by filtration and dried under vacuum to afford the title compound (17.7 g, 53%). 1H NMR (DMSO-D6, 400 MHz): 8.30 (s, 1H).