Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([CH3:29])[CH2:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH2:25][CH2:26][CH3:27])[C:16]=2[O:15]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].Cl>CCOCC.O.CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:28][C:23]1[CH:22]=[CH:21][C:17]2[C:18](=[O:20])[CH2:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)([CH3:29])[O:15][C:16]=2[C:24]=1[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CBr
Reactant: CCCc1c(O)ccc2c1OC(C)(CCCCCCOC1CCCCO1)CC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCOC1CCCCO1)CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of 0.706 g of rac.-2,3-dihydro-2-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]-7-hydroxy-2-methyl-8-propyl-4H-1-benzopyran-4-one, 16 ml of N,N-dimethylformamide, and 0.477 g of anhydrous potassium carbonate was stirred at room temperature for 2 hours. A 0.33 ml (0.53 g) portion of methyl bromoacetate was added and stirring was continued for 17.5 hours at room temperature. The mixture was poured into water and the pH was adjusted to 7 with 0.5N hydrochloric acid. The organic product was isolated by extraction with 3 portions of ether. The ether extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate filtered and concentrated in vacuo to give a yellow oil. This material was purified by high pressure liquid chromatography (HPLC) (silica gel, 2:1 hexane-ethyl acetate) yielding 0.589 g (70.8%) of rac.-[[3,4-dihydro-2-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].CCN=C=N[CH2:14][CH2:15][CH2:16][N:17](C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1(N)CC1>>[CH:16]1([NH:17][C:1](=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC/C=C/C(=O)O
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCC/C=C/C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipitate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide compound 37 as a fine white solid. 1H NMR (500 MHz, d6-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H), 5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H), 1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([NH:28][C:29]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:21][CH2:20]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)Nc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol)) in CH2Cl2 (5 mL) at 25° C. is added phenyl isocyanate (33 mg, 0.28 mmol). After being stirred at 25° C. for 2 h, the reaction mixture is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid phenylamide (49 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:15])[CH3:14])[CH:5]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:14])[CH3:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OC(=S)N(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OC(=S)N(C)C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
To a stirred solution of 3-dimethylthiocarbamyloxy-5-hydroxybenzoic acid methyl ester (2.37 g, impure) in DMF (30 mL) at room temperature was added K2CO3 (3.85 g, 27.9 mmol), followed by iodomethane (1.16 mL, 18.6 mmol). After stirring for 3.5 h at room temperature the reaction mixture was partitioned between ethyl ether (200 mL) and H2O (200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 33% EtOAc in hexanes as an eluent to furnish 3-dimethylthiocarbamyloxy-5-methoxybenzoic acid methyl ester (1.30 g, 4.83 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:30])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate (16 μL, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2 hours and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) followed by preparative HPLC (column Aqusil C18, gradient elution with 60-95% MeOH in water, 45 min) to afford the title compound 269a (13 mg, 40% yield) as an off-white solid. 1H NMR (CD3OD) δ (ppm): 8.41(s, 1H), 8.16(d. 1H, J=5.6 Hz), 8.02(dd, 1H, J1=2.3 Hz, J2=12.2 Hz), 7.62(d, 1H, J=3.3 Hz), 7.44(m, 1H), 7.37-7.33(m, 4H) 7.31-7.26(m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H, J=5.7 Hz), 3.76(s, 2H), MS (m/z): 421.1(M+H) (found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[C:18]3[C:23](=[O:24])[O:22]C(C)(C)OC3=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:28]([Mg]Br)#[C:29][CH3:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:28]#[C:29][CH3:30])[CH2:18][C:23]([OH:22])=[O:24])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc(C=C3C(=O)OC(C)(C)OC3=O)cc2)cc1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a stirring THF (120 mL) solution of compound 12.2 (13.8 g, 37.5 mmol) under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water, dried over MgSO4, filtered, and concentrated to a brown oil. A solution of this brown oil in 5:1 pyridine-water (360 mL) was heated at 100° C. for 36 h. The reaction mixture was cooled to room temperature and put in an ice-water bath. Concentrated HCl was carefully added to pH ˜2. The resulting suspension was extracted with ethyl acetate (200 mL×3), dried over MgSO4, filtered, and concentrated to an off-white solid. Recrystalization from ethanol gave 9.5 g (78%) of compound 12 as a white powder. 1H NMR(500 MHz)DMSO-d6) δ 12.2 (s, 1H); 7.37 (d, 2H, J=8.5 Hz); 7.27 (d, 2H, J=8.5 Hz); 6.95 (d, 2H, J=8.0 Hz); 6.94 (d, 2H, J=8.5 Hz); 4.99 (s, 2H); 3.95 (m, 1H); 3.76 (s, 3H); 2.60 (m, 2H); 1.78 (d, 3H, J=1.5 Hz). MS ESI (neg.) m/e: 323.0 (M−1).
Reaction SMILES: N1C=CN=C1.[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[NH:23][C:24]1[NH:25][CH2:26][CH2:27][N:28]=1>O1CCCC1>[C:6]([N:28]1[CH2:27][CH2:26][N:25]=[C:24]1[NH:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 71.6 %

Procedure:
3.40 g (50 millimoles) of imidazole are dissolved in 25 ml of absolute tetrahydrofuran, a solution of 3.54 g (25 millimoles) of nicotinoyl chloride in 25 ml of absolute tetrahydrofuran is added dropwise at room temperature, and the mixture is stirred for a further 2 hours. The imidazole hydrochloride which has precipitated is then filtered off, the filter residue is washed with a small amount of anhydrous tetrahydrofuran, the combined filtrates are added to a solution of 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 25 ml of absolute tetrahydrofuran, and the mixture is stirred overnight. The solvent is then stripped off under reduced pressure on a rotary evaporator and the residue is twice recrystallized from isopropanol. 4.8 g of pure 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 172.5°-174° C. are obtained; the material is identical with the product described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[S:19])[NH2:18])[CH2:13][C@@H:12]1[C:20](=[O:32])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38](=[O:44])[CH:39](Br)[C:40](=O)[CH3:41])([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:19][C:39]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:44])=[C:40]([CH3:41])[N:18]=2)[CH2:13][C@@H:12]1[C:20](=[O:32])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2C(=O)OCc2ccccc2)cc1
Solvent: CC#N
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2C(=O)OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
A mixture of the compound (1.51 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (1.58 g) in acetonitrile (15 ml) was stirred at 80° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2-2:3) to give the title compound (1.29 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[I:18]Cl.BrC1C=C(C(O)=O)C=C2C=1OC(C)(C)CC2(C)C>CC(O)=O>[I:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Reactant: ClI
Agent: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(I)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH was added ICl (0.07 ml, 1.4 mmol). The resulting colored solution was stirred at room temperature for overnight. Following the same procedure as for the synthesis of 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid (Compound P), the reaction gave the title compound (107 mg) as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH3:17])[C:6]=2[CH:16]=1
Reactant: CCCCNC
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Solvent: CN(C)C=O
Product: CCCCN(C)c1c(CCC)c(=O)oc2ccc(Br)cc12

Procedure:
A solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.4 g) and N-methylbutylamine (3 ml) in dimethylformamide (2 ml) was heated under reflux for 30 minutes and then allowed to cool overnight. Evaporation followed by column chromatography yielded 6-bromo-4-(butylmethylamino)-3-propyl-2H-1-benzopyran-2-one, as an oil. (compound 18).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[CH3:18][C:19]1([CH3:27])[CH2:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1.CCOC(C)=O.CCCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:8][C:6](=[C:22]1[C:23](=[O:25])[CH2:24][C:19]([CH3:27])([CH3:18])[CH2:20][C:21]1=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C([O-])CCCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OCc2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
To a stirred solution of mono-benzyl adipate (2.36 g, 10 mmol) in dry CH2Cl2 (50 ml) was added 5,5-dimethyl-1,3-cyclohexanedione (1.4 g, 10 mmol), N,N′-dicyclohexylcarbodiimide (2.1 g, 10.1 mmol) and 4-dimethylaminopyridine (1.22 g, 10 mmol). The resulting solution was allowed to stir at room temperature for 18 h. The solution was cooled and filtered to remove the precipitated N,N′-dicyclohexylurea. The filtrate was evaporated and the residue redissolved in EtOAc (50 ml) and washed with 1 M KHSO4. The organic extract was washed with brine (92×10 ml), dried (MgSO4) and evaporated to yield a white/yellow amorphous powder. Flash silica chromatography (EtOAc/hexane 1:2 v/v) afforded benzyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoate (3.00 g, 84%) as a white crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1CCBr)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17].O.[C:19](O)(=O)[CH3:20]>>[N+:1]([C:4]1[C:5]([NH:14][CH2:19][CH3:20])=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N:16]([CH3:17])[CH3:15])([O-:3])=[O:2]
Reactant: CNC
Reactant: CC(=O)O
Reactant: Nc1c(O)ccc(CCBr)c1[N+](=O)[O-]
Solvent: O
Product: CCNc1c(O)ccc(N(C)C)c1[N+](=O)[O-]

Procedure:
0.0766 mol (20 g) of 3-nitro-4-(β-bromoethyl)-aminophenol is heated for 20 minutes, at 60° C., in 60 ml of a 40% strength aqueous solution of dimethylamine. The reaction medium is poured into 300 ml of iced water and then neutralised with acetic acid. The expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 151° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
0.077 mol (10.0 g) of ethyl(R)-3-hydroxybutyrate is dissolved in 90 ml of dimethylformamide and 0.151 mol (10.3 g) of imidazole is added. The mixture is cooled to 0° C. under protective gas in an ice bath and 0.083 mol (16.05 g) of triisopropylsilyl chloride is added dropwise over 5 min. The mixture is stirred at room temperature for a further 5 hours, hydrolyzed with water, the product is extracted with tert-butyl methyl ether, and the organic phase is dried using Na2SO4 and concentrated under reduced pressure on a rotary evaporator.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:11])/[CH:7]=[C:8](\Cl)/[CH3:9])[CH:2]([CH3:4])[CH3:3].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:5][C:6](=[O:11])/[CH:7]=[C:8](\[N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)/[CH3:9])[CH:2]([CH3:4])[CH3:3]
Reactant: C/C(Cl)=C/C(=O)OCC(C)C
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/C(=C/C(=O)OCC(C)C)n1cncn1

Procedure:
0.1 Mol (17.7 g) of 3-chlorocrotonic acid isobutyl ester in 100 ml acetonitrile, 012 mol (8.3 g) of 1,2,4-triazole and 0.12 mol (16.5 g) of anhydrous potassium carbonate were refluxed for 5 hours. After removal of the solvent under reduced presure, the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. After distillation of the methylene chloride under reduced pressure, the 3-(1,2,4-triazol-1-yl)-crotonic acid isobutyl ester was obtained in the form of a weakly yellow oil.
Reaction SMILES: Cl([O-])(=O)(=O)=[O:2].[C:6]([N+:10]1[O:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:16]([NH:22][C:23]1[CH:31]=[C:30]([Cl:32])[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][C:24]=1[C:25](O)=[O:26])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O.O>[C:6]([NH:10][C:14](=[O:2])/[CH:13]=[C:12](\[O:11][C:25](=[O:26])[C:24]1[CH:28]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[C:30]([Cl:32])=[CH:31][C:23]=1[NH:22][CH2:16][C:17]1[O:21][CH:20]=[CH:19][CH:18]=1)/[CH3:15])([CH3:9])([CH3:8])[CH3:7]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: Cc1cc[n+](C(C)(C)C)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-tert-butyl-5-methylisoxazolium perchlorate (120 g.; 0.005 mole) is added to a solution of 2-furfurylamino-4-chloro-5-methylsulfonylbenzoic acid (1.65 g.; 0.005 mole) and triethylamine (0.7 ml.) in dimethylformamide (15 ml.). The resulting solution is allowed to stir at room temperature for 2 hours, and then diluted with H2O (75 ml.). The white solid which precipitates is collected and dried, yield 2.4 g. (crude), m.p. 140°-145° C. Recrystallization from butyl chloride yields N-tert-butyl-3-(2-furfurylamino-4-chloro-5-methylsulfonylbenzoyloxy)crotonamide, m.p. 148.5°-150° C. (dec. with eff.).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.[Li+].[CH3:29]C([N-]C(C)C)C.IC>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([CH3:29])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Li+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a -78° C. solution of the ester from Step 1 (35 mg, 0.08 mmol) in 3 mL THF was added LDA (1.5M in cyclohexane, 0.1 mL, 0.15 mmol), and the solution was stirred for 30 min. A solution of iodomethane (0.1 mL, 1.6 mmol) in 1 mL HMPA was then added by syringe. The solution was stirred 15 min at -78° C., then warmed to 0° C. and quenched with saturated NH4Cl. The mixture was partitioned between ether and water and the organic layer was washed with water and brine and dried over MgSO4. The residue was purified by flash chromatography (15% ethyl acetate/hexanes) to provide 24 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]1OCCOCCOCCOCCOCCO[CH2:16]1.C([O:35][C:36](=[O:39])[CH2:37]Br)C>C(O)C>[CH2:15]([N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:37][C:36]([OH:39])=[O:35])[CH3:16]
Reactant: Nc1ccc(F)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC(=O)O)c1ccc(F)cc1

Procedure:
4-Fluoroaniline (5 g), potassium carbonate (3.11 g) and a catalytic amount of 18-Crown-6 were stirred together in 50 ml of ethanol. A solution of ethylbromoacetate (7.52 g) in 25 ml of ethanol was added dropwise and the reaction was heated to reflux.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(piperidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (870 mg, 2 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(piperidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (365 mg, 44%) as a white solid: LC/MS m/e calcd for C24H29N3O3 (M+H)+: 408.52, observed: 408.2.