Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[CH2:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[CH:5][CH:4]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(CN)n1C
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C)n1C
Yield: 33 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1,5-dimethyl-1H-pyrrol-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 33% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J=8.1 Hz, 1H), 8.53 (t, J=5.4 Hz, 1H), 7.44-7.33 (m, 5H), 6.37 (dd, J=8.1, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.91 (d, J=3.3 Hz, 1H), 5.64-5.63 (m, 1H), 5.15 (s, 2H), 4.32 (d, J=5.4 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 2.10 (s, 3H); MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16](Cl)=[O:17])[CH:8]=1)[CH3:4]>C1COCC1>[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([NH:2][CH3:1])=[O:17])[CH:8]=1)[CH3:4]
Reactant: CN
Reactant: CCOC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)NC)cc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a 2M solution of methylamine in THF (256 ml) at −20° C. was added a pre-cooled solution of 3-chlorocarbonyl-5-nitro-benzoic acid ethyl ester (60 g) in THF (500 ml) dropwise. This was stirred for 20 min and then filtered. The filtrate was concentrated in vacuum and the solid recrystallised from diethyl ether to give the title compound (22.5 g) as a solid. An oxalyl chloride solution in DCM (63 ml, 2M), was added with DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). Rt=1.53 min (method D).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[C:13]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: O=C1OCCC1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1OCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.43 g, 10.8 mmol) is added portionwise to a solution of α-hydroxy-γ-butyrolactone (1 g, 9.8 mmol) in DMF (15 ml) at 0° C. under a nitrogen atmosphere. 2-Bromomethylbiphenyl (2.42 g, 9.8 mmol) is then rapidly added. The reaction medium is stirred for 2 hours at room temperature and is then treated by adding 1N hydrochloric acid solution (10 ml). The aqueous phase is extracted with ethyl acetate (2×20 ml) and the combined organic phases are washed with water (4×15 ml), dried over sodium sulphate, filtered and concentrated. After purification by flash chromatography (2/1 heptane/EtOAc), the expected compound is obtained in the form of a colourless oil (1.32 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][CH3:16])[C:13](=[O:17])[C:12]([CH3:19])([CH3:18])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:11](=[O:20])[C:12]([CH3:19])([CH3:18])[C@:13]([OH:17])([CH3:21])[C@H:14]2[CH2:15][CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC[C@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C(C)(C)[C@@]1(C)O

Procedure:
Using 2-chloro-4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (48 mg) and methylmagnesium bromide-THF solution (1.65 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 27 mg, 53%).
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([Cl:21])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)O)cc1SC1CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1SC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentylthio-4-methoxybenzoic acid (9 g; that is prepared as described in Reference Example 46) in dry dichloromethane (90 mL) under nitrogen is treated with oxalyl chloride (6.2 mL). After stirring at room temperature for 2 hours, the mixture is evaporated and dried under high vacuum, to give 3-cyclopentylthio-4-methoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12](/[CH:14]=[C:15](/[NH2:17])\[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>CO.CCOC(C)=O.Cl.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C/C(N)=C\c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(N)Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 7 h
Yield: 58 %

Procedure:
To a solution of (E)-1-(5-(3,4-dichlorophenyl)furan-2-yl)prop-1-en-2-amine (2.72 g, 9.12 mmol) in MeOH (135 ml), EtOAc (100 ml) and 6.5% HCl (g) in MeOH (32 ml) was added 10% Pd/C (1.09 g). The mixture was hydrogenated under pressure (3.3 bar, Parr hydrogenating apparatus) for 7 h. The reaction mixture was filtered through Celite, evaporated and purified by chromatography (CombiFlash, silica column, eluent: 5-20% MeOH/DCM) to yield 0.811 g (29%) of the title compound as an HCl salt. 1H-NMR (400 MHz; d6-DMSO): δ 1.21 (d, 3H), 2.90 (dd, 1H), 3.04 (dd, 1H), 3.55 (q, 1H), 6.44 (d, 1H), 7.09 (d, 1H), 7.68 (m, 2H), 7.93 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
A solution of (2S)-N-(tert-butoxycarbonyl)-2-formylpyrrolidine (4.0 g, 20 mmole), carbon tetrabromide (6.67 g, 20.1 mmole) and triphenylphosphine (5.26 g, 20.1 mmole) in methylene chloride (100 mL) was stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The mixture was concentrated, then purified by chromatography, using (1:1) ethyl acetate:hexane as eluant to provide the desired product as an oil. The product was dissolved in dry tetrahydrofuran (50 mL) and cooled to −78° C. A solution of n-butyllithium (50.25 mL, 20.1 mmole, 2.5 M solution in hexanes) was added and the mixture was stirred at −78° C. for 1 h. The material was quenched with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (K2CO3), concentrated and purified by chromatography, using (1:1) ethyl acetate:hexane as eluant to provide (3.10 g, 91%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[O:52]=[C:53]1[C:62]2[CH2:61][CH2:60][NH:59][CH2:58][C:57]=2[NH:56][C:55]2[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]1=2>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:59]1[CH2:58][C:57]2[NH:56][C:55]3[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]=3[C:53](=[O:52])[C:62]=2[CH2:61][CH2:60]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
To a solution of 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (385 mg, 1.62 mmol) in DMF (8.0 mL) were added HATU (1.1 g, 2.94 mmol), DIPEA (0.75 g, 5.87 mmol), and methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate hydrobromide (410 mg, 1.6 mmol). The mixture was then stirred at room temperature for 24 h. Then the reaction was quenched by water (20 mL). The mixture was extracted with THF/EtOAc (10 ml/60 ml) three times. The organic layers were combined, dried, concentrated, and chromatographed on silica gel using gradient eluant of 0-50% methanol in dichloromethane to give the desired compound as pale solid (114 mg, 14%). MS (ESI) m/e [M+1]+478.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([O:18]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-].[H][H].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.[Pd]>[C:28]([OH:31])(=[O:30])[CH3:29].[NH2:1][CH2:4][C@H:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([OH:18])=[CH:9][CH:8]=1)[OH:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: NC[C@@H](O)c1ccc(O)c2c1OCC(=O)N2
Reaction time: 18 h

Procedure:
A solution of 8-(2-azido-1-hydroxyethyl)-5-(benzyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one, Isomer 2 (example 13, step a) (0.72 g) in a mixture of acetic acid (10 mL) and ethanol (10 mL) was stirred vigorously with 10% palladium on carbon catalyst (0.225 g) under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was triturated with acetonitrile (30 mL) to afford the subtitled compound. Yield 0.28 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=[C:7]2[O:15][CH3:16].O=S(Cl)Cl.C[CH2:22][N:23](C(C)C)[CH:24](C)C.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([N:23]([CH3:24])[CH3:22])=[O:13])=[CH:9][CH:8]=[C:7]2[O:15][CH3:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(C(=O)O)c2c(Cl)cccc12
Agent: CNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N(C)C)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthoic acid (step-4 intermediate) (0.5 g, 2.11 mmol) in CH2Cl2 (5 mL) was added, SOCl2 (0.31 mL, 4.22 mmol, 2.0 eq.) and the mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure and the crude product was dissolved in DCM (10 mL). To this, DIPEA (0.74 mL, 4.23 mmol) was added followed by dimethylamine (1.5 eq.) and the reaction mixture was stirred at RT for 3 h and then quenched with ice. The aqueous layer was extracted with dichloromethane and the combined organic layer was washed with sat. NaHCO3 solution, water, brine, dried over Na2SO4 and filtered. The solvent was evaporated to provide the desired amide derivative (528 mg, 95%) this was used in the next step without any further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[CH2:17])[C:12]([O:14]CC)=[O:13].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>S1(CCCC1)(=O)=O>[F:23][C:19]1([F:24])[CH2:17][C:11]1([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:14])=[O:13]
Reactant: C=C(C(=O)OCC)c1ccc2ccccc2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: O=C(O)C1(c2ccc3ccccc3c2)CC1(F)F
Temperature: 160 °C
Yield: 83.5 %

Procedure:
Ethyl 2-(2-naphthyl)-acrylate (4.28 g) was dissolved in sulfolane 20 ml. Sodium chlorodifluoroacetate (9.1 g) was added in portions to the solution, heated to 160° C., over 35 minutes. The reaction mixture was cooled, quenched into ice water, then extracted with ether. The ether layer was washed several times with water and after separation dried over anhydrous sodium sulphate. After evaporation of the ether, the residual dark oil was chromatographed on silica gel using petroleum ether (b.p. 40°-60°)/methylene chloride mixture as eluent. The major fraction (4.05 g) was distilled under vacuum to yield the product as a yellow oil (3.92 g; 71%). The ester was identified from i.r. and p.m.r. spectra and hydrolysed by refluxing in 1 N sodium hydroxide/ethanol solution. On acidification and extraction the solid acid was recrystallised from petroleum ether/methylene chloride to yield the acid as a white solid, m.p. 190°-2°.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[CH3:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][N:17]=[C:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-amino-5-methylphenyl phenyl ketone (2.0 g, 9.5 mmol) in HCl (45 mL of a 6M solution) at 0° C. was added sodium nitrite (NaNO2) (719 mg, 10.4 mmol) in water (2 mL). The reaction was stirred for 30 min when the homogeneous solution was added dropwise to a solution of SnCl2 (5.88, 26 mmol) in concentrated HCl (15 mL) at room temperature. The reaction was stirred for 30 min when it was filtered. The solid was then taken up in ethyl acetate (80 mL) and saturated sodium bicarbonate (80 mL). The suspension was then filtered and the ethyl acetate layer dried (Na2SO4) and concentrated to give the product (1.59 g, 80% yield). (1H NMR (DMSO-d6) δ 7.96 (d, 2H), 7.85 (br s, 1H), 7.54–7.46 (m, 3H), 7.39 (t, 1H), 7.24 (d, 1H), 2.45 (s, 3H); ES-MS (m/z) 209 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[C:3]=1[C:4]#[N:5].[C:42](Cl)(=[O:44])[CH3:43].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:42](=[O:44])[CH3:43])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(NC(C)=O)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-4-{4-amino-3-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-[(4-methoxybenzyl)oxy]-phenyl}nicotinonitrile, acetyl chloride, pyridine and CH2Cl2 was stirred at 0° C. for 1 hr. and at room temperature for 2 hrs. The usual work-up and column chromatography gave N-{4-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-[2-(1-piperidinyl)ethoxy]-phenyl}acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=1[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:26][C:27]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=3[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.39 g (0.0028 mole) of anhydrous potassium carbonate, and 0.92 g (0.0038 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate in 20 mL of N,N-dimethylformamide was heated at 90° C. for approximately 17 hours. At the end of this period the mixture was poured over ice, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an orange oil as a residue. This oil was placed on a silica gel column and eluted first with methylene chloride and then with methylene chloride/ethyl acetate (97.5/2.5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 0.82 g of 2-[2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate was recovered as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.30 (s, 3H); 2.44 (s, 3H); 3.76 (s, 3H); 4.84 (q, 1H, JHH=8.0 Hz); 5.16 (dd, 2H, JHH=10.0 Hz); 6.56 (s, 1H); 6.78-7.32 (m, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)[CH2:2]2
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccc(Br)cc1)OC1CN2CCC1CC2
Yield: 60 %

Procedure:
3-Quinuclidinol and 4-bromophenyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (60%) as a white solid: mp 217.5-219.5° C.; FAB LRMS m /z (relative intensity, %)328(16), 327 ([MH+ with Br81 ], 100), 326(16), 325 ([MH+ with Br79 ], 100).
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(Cl)(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:4]1([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CCC1(O)CCCCC1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C#CCC1(OC2CCCCO2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 2.9 g (21 mmol) of (prop-2-ynyl)cyclohexanol in 10 ml of dry ether was stirred under argon as 0.24 ml (26 mmol) of dihydropyran was added followed by about 5 mg of toluenesulfonic acid. After one hour, tlc (CHCl3, silica gel) analysis indicated that significant starting material remained. Another 0.2 ml of dihydropyran and about 5 mg of toluenesulfonic acid were added. Twice more at one hour intervals, 0.2 ml portions of dihydropyran along with a small amount of toluenesulfonic acid were added to the reaction mixture. It was left to stir under argon at room temperature for 15 hours. Potassium carbonate was then added to the mixture and it was stirred for several minutes before it was washed with water. The wash solution was back extracted with ether and the combined extracts were then washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4.6 g of 1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane) having the following spectral characteristics: nmr (CDCl3) δ 1.0-2.5 (19H, m), 3.6 (2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl3) 980, 1030, 1050, 1070, 1120, 1150, 1270, 1450, 2120, (weak) 2760, 2930 and 3300 cm-1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.O>CS(C)=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1ccc2ccccc2c1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1ccc2ccccc2c1
Reaction time: 1.8 h
Yield: 56 %

Procedure:
A 21.5g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 44.3 g (0.25 mole) of 2-(chloromethyl)-naphthalene. The reaction mixture was heated to 105° over 0.3 hours, held at 105°-110° for 1.8 hours and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness to give 31.5 g (56%) of a light yellow solid, m.p. 102 soften, 120°-138°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].O>CN(C)C=O>[N:1]([CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[N+:2]=[N-:3]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Yield: 94.7 %

Procedure:
In 40 ml of dimethylformamide was suspended 2.84 g of sodium azide, and 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added thereto and the mixture was reacted at room temperature for 2 hours. After addition of 32 ml of water to the mixture, precipitated crystals were filtered to give 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridine. Melting point: 190° C. (decomposed). These crystals were suspended in 500 ml of methanol, and hydrogenolysis was carried out by adding 0.5 g of palladium black at room temperature for one hour. After removal of the catalyst by filtration, the filtrate was condensed and recrystallized from methanol - isopropanol, and then filtered to give 7.4 g of the title compound. Melting point: 225° to 230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[N:4][C:5]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:27])=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Reactant: CC(N)c1ccc(Br)cc1
Product: CC(NC(=O)c1cc(F)cnc1Oc1ccc(F)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 2 of Example 1) and [1-(4-bromophenyl)ethyl]amine: 1H-NMR (CDCl3) δ 8.31 (1H, ddd, J=8.2, 3.1, 0.9 Hz), 8.14 (1H, d, J=7.2 Hz), 8.03 (1H, dd, J=3.1, 1.1 Hz), 7.45 (2H, dd, J=7.0, 0.9 Hz), 7.25–7.09 (6H, m), 5.28 (1H, dq, J=7.2, 7.0 Hz), 1.57 (3H, d, J=7.0 Hz); MS (ESI) m/z 433 (M+H)+, 431 (M−H)−.