Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]Br>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: BrBr
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (9.0 mL) at −78° C. is slowly added lithium diisopropylamine (0.62 mL, 1.24 mmol, 2M in tetrahydrofuran) over 10 minutes. After 40 minutes, a solution of bromine (198 mg, 1.24 mmol) in 1.5 mL of tetrahydrofuran is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 5 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 90% dichloromethane in hexane to provide 48 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as a pink solid, 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.8 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:12]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:16]([N:12]([CH2:13][C:14]#[CH:15])[CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])=[O:25]
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a THF:MeOH:H2O (3:2:1) (3 mL) solution of 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (30 mg, 0.076 mmol), 1N aqueous solution of lithium hydroxide (0.46 mL, 0.46 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. Solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The water layer was acidified using 10% KHSO4 solution and then the organic layer was separated, dried (Na2SO4), concentrated. The residue was purified by column chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to obtain 2-[(2,4-dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid, 23 mg (81%) as a white solid. The compound contains two other minor rotamers. 1H NMR (CDCl3, 400 MHz): δ7.45-7.05 (m, 8H), 6.77 (dd, minor rotamer), 5.70 (d, minor rotamer), 4.99 (bs, minor rotamer), 4.64-4.59 (m, minor rotamer), 4.28 (d, minor rotamer), 4.29-4.18 (m, minor rotamer), 3.79-3.09 (m, 5H), 2.37 (t, minor rotamer), 2.31 (t, minor rotamer), 2.17 (t, 1H). ESI− (M−H): 375.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:5]([OH:7])=O)[NH2:4].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21].Cl>[OH-].[Na+].O1CCOCC1>[Cl:14][C:15]1[CH:16]=[C:17]([N:22]2[C:5](=[O:7])[C@@:3]([CH2:2][OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:4][C:23]2=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: N[C@@](CO)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1N[C@](CO)(c2ccccc2)C(=O)N1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
217 mg of (S)-2-hydroxymethyl-2-phenylglycine (prepared according to A. Olma, Polish J. Chem., 70, (1996), 1442-1447) are dissolved in 5 mL of 0.5 N aqueous sodium hydroxide. 300 mg of 3,4-dichlorophenyl isocyanate dissolved in 5 mL dioxan are slowly added over 10 min then the mixture is stirred for 1 h, the pH is around 7 to 7.5. 3 mL of 0.5 N aqueous sodium hydroxide are added to make the pH alkaline then 300 mg of 3,4-dichlorophenyl isocyanate dissolved in 5 mL dioxan are slowly added again. The mixture is stirred for 1 further hour at room temperature then 12N hydrochloric acid is added to acidic pH and the mixture is heated for 1 h at reflux temperature. The dioxan is removed by evaporation under vacuum, the aqueous phase is extracted with ethyl acetate. The extracts are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified over silica gel while eluting with a gradient mixture from heptane to pure ethyl acetate to provide expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])[O:4][CH2:3]1.[Na+].[CH3:21][S:22]([O-:24])=[O:23]>CN(C)C=O>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:14][CH:13]=2)=[O:11])[O:4][CH2:3]1
Reactant: CS(=O)[O-]
Reactant: CC1(C)COC(CCC(=O)c2ccc(F)cc2)OC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC(CCC(=O)c2ccc(S(C)(=O)=O)cc2)OC1
Temperature: 75 °C
Yield: 78.8 %

Procedure:
To a solution of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one (Step 4) (1.68 g, 6.3 mmol) in dimethylformamide (75 ml), methanesulfinic acid sodium salt (2.9 g, 28.4 mmol) was added. The reaction mixture was heated at 120-30° C. for 72 hours. After cooling, the solvent was removed under reduced pressure and the reaction mixture was diluted with water. The material was extracted with methylene chloride and washed with brine. After drying (MgSO4), filtration and concentration, the crude solid (2.78 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give the sulfone (1.62 g, 79%) as a white solid: mp (DSC) 104° C. Anal Calc'd. for C16H22SO5 : C, 58.88; H, 6.79; S, 9.82. Found: C, 58.76; H, 7.01; S, 10.21.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:13][CH:14]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2cccnc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.4 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500 mg) and Pd—C (100 mg) in MeOH (30 mL) was stirred at room temperature for 5.5 h. The mixture was filtered by Celite, and the filtrate was concentrated. The resulting solid was rinsed with iPr2O to give 3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
5-Chloro-2-nitrobenzoic acid (20.1 g,; 0.10 mol), is dissolved in anhydrous methanol (100 ml) and anhydrous hydrogen chloride gas is bubbled into the reaction mixture for 4 hours at room temperature. The reaction mixture is then poured into water and the aqueous mixture triturated with hexane, the hexane layer decanted, dried (anhd. MgSO4) and the solvent removed under vacuum to afford 11.7 g of methyl 5-chloro-2-nitrobenzoate, mp 50°-51° C.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([N:14]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([OH:7])=[O:5])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 1.364 g (2.97 mmol) of the product from Example 5 in 10 mL of dichloromethane was added 10 mL of trifluoroacetic acid and the mixture was stirred for 4 h at room temperature. The solvent was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with 10-100% ethyl acetate/hexane to provide 1.092 g (73%) of the desired product as a white solid. Electrospray Mass Spec 404.2 (M+H)
Reaction SMILES: [C:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH2:6]1)(=[O:3])[CH3:2].O.[C:11]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:14])[CH:12]=[O:13]>C1C=CC=CC=1>[CH2:16]([O:15][C:11]([CH:12]([OH:13])[N:8]1[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1=[O:9])=[O:14])[CH:17]=[CH2:18]
Reactant: CC(=O)SC1CC(=O)N1
Reactant: C=CCOC(=O)C=O
Solvent: O
Solvent: c1ccccc1
Product: C=CCOC(=O)C(O)N1C(=O)CC1SC(C)=O

Procedure:
4-Acetylthioazetidin-2-one (Annalen, 1974, p. 553) (1.4 g) and allyl glyoxylate hydrate (1.5 g) are refluxed for 2 hours in benzene to afford a solution of 1-(allyloxycarbonylhydroxymethyl)-4-acetylthioazetidin-2-one which is cooled and used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(OCC)(=O)C>CC(C)=O.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1

Procedure:
To a flask containing 4-nitrobenzyl bromide (21.6 g) in dry acetone (100 mL) is added potassium carbonate (34.5 g) and morpholine (10 mL). The mixture is heated to reflux overnight under a drying tube. The reaction is partioned between ethyl acetate and water and separated. The basic aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with brine, dried, and concentrated under reduced pressure to afford 21.3 g of the title compound as a solid.
Reaction SMILES: Cl.C=O.O[N:5]=[C:6](C(C)=O)C(OCC)=O.[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O.[NH3:24]>>[CH3:19][C:17]1[NH:5][CH:6]=[N:24][C:16]=1[C:15]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: N
Agent: C=O
Agent: Cl
Product: CCOC(=O)c1nc[nH]c1C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred cold (0°) suspension of concentrated hydrochloric acid (516 ml.) and paraformaldehyde (105 g.) was added ethyl 2-hydroxyiminoacetoacetate prepared from 130 g. (1 m.) of ethyl acetoacetate over two hours maintaining the reaction temperature at 5°-15°. After stirring one hour at 5°-15°, aqueous ammonia (28%) was added slowly until pH reached 5 and temperature rose to 70° over 35 minutes. The reaction mixture was held at pH 5 at 65°-70° for 30 minutes and then aqueous ammonia (28%) was added until the mixture was neutral. The mixture was cooled to 10° and the solid material was filtered off and washed with water and isopropanol and dried to give ethyl 5-methyl-4-imidazolecarboxylate, m.p. 204°-206°, yield 61-65%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][NH2:22].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COCc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Yield: 44.4 %

Procedure:
A solution of 4,6-dichloro-2-methoxymethyl-pyrimidine (250 mg, 1.3 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (196 μL, 1.3 mmol), and sodium bicarbonate (218 mg, 2.6 mmol) in EtOH (5 mL) is heated at 80° C. for three hours and poured into water (20 mL) and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 44%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(NC(C)C)(C)C.O>C1COCC1.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.[Cu]I>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 4-ethynylanisole (700 mg, 5.30 mmol), 4-iodoanisole (1.30 g, 5.55 mmol), (PPh3)2PdCl2 (74.4 mg, 0.106 mmol), and CuI (10.1 mg, 0.053 mmol) in THF (7 ml), diisopropyl amine (1.13 g, 11.1 mmol) was added dropwise under ice cooling under argon atmosphere. After stirring at room temperature for 1 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water then saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=15/1) to give bis(4-methoxyphenyl)ethyne (95%).
Reaction SMILES: FC1C=CC(S([N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][C@@H:28](O)[C:27]3=[O:32])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:68]=[C:67]2[C:62]([CH2:63][CH2:64][NH:65][CH2:66]2)=[CH:61][CH:60]=1.N1CCOCC1>C(Cl)Cl>[O:32]=[C:27]1[C@@H:28]([N:65]2[CH2:64][CH2:63][C:62]3[C:67](=[CH:68][C:59]([C:58]([F:57])([F:70])[F:69])=[CH:60][CH:61]=3)[CH2:66]2)[CH2:29][CH2:30][N:26]1[C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Product: O=C1[C@@H](N2CCc3ccc(C(F)(F)F)cc3C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of (R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (12.4 g, 24.9 mmol) in DCM (80 mL) was stirred under nitrogen at −25° C. To the reaction mixture was added DIEA (9.6 g, 13 mL, 74.6 mmol) followed by dropwise addition of triflic anhydride (10.5 g, 6.30 mL, 37.3 mmol). The reaction mixture was stirred at −25° C. for 90 minutes. A solution of 7-trifluoromethyl-tetrahydroisoquinoline (5.0 g, 24.9 mmol) in DCM (10 mL) was added to the reaction mixture and stirring was continued under nitrogen at −25° C. for 1 h. Morpholine (4.33 g, 4.3 mL, 49.7 mmol) was added and the cooling bath was removed. The reaction mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified by silica gel column chromatography (0.5-10% MeOH in DCM). The product obtained was taken up in DCM and precipitated by addition of Et2O providing a white solid (5.25 g, 40%), which was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ: 12.0 (s, 1H), 7.84 (dd, J=9.0, 22.8 Hz, 4H), 7.46 (bs, 2H), 7.32-7.30 (m, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.12 (d, J=15.3 Hz, 1H), 3.92-3.78 (m, 4H), 3.15-3.10 (m, 1H), 2.90-2.83 (m, 3H), 2.34-2.27 (m, 1H) and 2.19-2.10 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=523.3; tR=1.18 minMS (ESI) m/e (M+H+) 523.3, retention time: 1.18 min (10-99% CH3CN in H2O).
Reaction SMILES: CN(C)C=[C:4]([F:24])[C:5]([C:7]1[C:12]([NH:13][C:14](=O)[O:15][C:16](C)(C)C)=[CH:11][C:10]([F:21])=[C:9](OC)[N:8]=1)=O.P(Br)(Br)[Br:27]>FC(F)(F)C(O)=O.ClCCl.O.C(=O)([O-])[O-].[K+].[K+]>[Br:27][C:11]1[C:10]([F:21])=[CH:9][N:8]=[C:7]2[C:12]=1[N:13]=[C:14]([O:15][CH3:16])[C:4]([F:24])=[CH:5]2
Reactant: BrP(Br)Br
Reactant: COc1nc(C(=O)C(F)=CN(C)C)c(NC(=O)OC(C)(C)C)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nc2c(Br)c(F)cnc2cc1F
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of 1,1-dimethylethyl [2-[3-(dimethylamino)-2-fluoroacryloyl]-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (2.15 g, 6.02 mmol) in trifluoroacetic acid/dichloromethane (20 ml/20 ml) was stirred at room temperature for 0.5 hour under argon and evaporated. The residue was treated with ˜50 ml 2M ammonia in methanol until basic and evaporated. This residue was dried in vacuo then chromatographed eluting with 0-10% methanol in ethyl acetate affording a solid (3.64 g), 8-hydroxy-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine. 8-Hydroxy-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine (3.64 g) was dissolved in N,N-dimethylformamide (20 ml) and treated with phosphorus tribromide (0.68 ml, 7.22 mmol). After 1 hour, more phosphorus tribromide (0.68 ml, 7.22 mmol) was added. After 0.5 hour the mixture was diluted with water and basified with solid potassium carbonate. Filtration and drying in vacuo afforded the product (0.95 g, 57%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: COCCOCCBr
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Product: COCCOCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.1 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and 1-bromo-2-{[2-(methyloxy)ethyl]oxy}ethane (0.040 mL, 0.265 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0431 g, 54.6%). EI-MS m/z 405 (M+) Rt (1.85 min).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=O.CC1(C)CCCC(C)C1CC[CH2:22][C:23]([OH:25])=[O:24].CC1(C)C(C)CCC1CCCC(O)=O>>[CH3:9][C:4]1([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]1[CH2:10][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC1CCCC(C)(C)C1CCCC(=O)O
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: CC1CCC(CCCC(=O)O)C1(C)C
Product: CC1CCCC(C)(C)C1CCC(=O)O

Procedure:
3-(2,2,6-trimethylcyclohexyl)propanoic acid was synthesized in three steps starting from 2,6,6-trimethylcyclohex-1-enecarbaldehyde, analogous to the 3-step procedure described for 4-(2,2,6-trimethylcyclohexyl)butanoic acid and 4-(2,2,3-trimethylcyclopentyl)butanoic acid herein-above, as indicated below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[C:19]=S.NC(N)=S>O1CCCC1>[Cl:12][C:11]1[C:2]2[N:1]=[C:19]([NH:18][C:21]3[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1ccc(N=C=S)c(C)n1
Agent: NC(N)=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C)n(CCCO)c12
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.00 g) in tetrahydrofuran (40.0 mL) was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 14 hrs. The starting material wasn't consumed completely. To the mixture was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 36 hrs. After cooling, the solvent was removed by concentration. The residue was purified by silica gel column chromatography eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give the mixture contained thiourea and title compound. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (885.7 mg, 4.62 mmol) and triethylamine (0.71 mL, 5.08 mmol). The reaction mixture was stirred at 50° C. for 2 hrs. After cooling, the mixture was diluted with water, extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless solid, (1.50 g, 3.72 mmol, 48% (2 steps)).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[Na+]>CCOCC>[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:1][CH3:2])([OH:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried 25-mL r.b. flask containing ethylmagnesium bromide (4.0 mL of a 3.0 M solution in Et2O, 12.0 mmol, 3.0 equiv), at −10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at −10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0 M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf 0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) δ7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J=7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2-H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3, 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3], 0.89 (t, 3H, J=7.5, CH3).