Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[C:27](Cl)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:18]=[CH:17][C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccc(C(=O)N(C)C)cc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)N(C)C)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Triethylamine (1.46 ml) was added to a solution containing 3-amino-4-{[3-(dimethylamino)propyl]amino}-N,N-dimethylbenzamide (2.57 g) in chloroform (20 ml), and then stearoyl chloride (2.89 g) was added thereto while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (7.5 ml) was added to a solution containing the residue (5.53 g) in ethanol (30 ml). After being stirred for 3 hours at 90° C., the reaction mixture was neutralized with 5N sodium hydroxide aqueous solution (18 ml) and concentrated. The residue, with ethyl acetate added thereto, was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.33 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=10:1), thereby yielding the entitled compound (4.21 g) as pink wax.
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O>CO.[Pd]>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(Cc2ccccc2)CNCCNC1
Yield: 75.7 %

Procedure:
In a 500 ml flask, compound 5 (16.0 g, 38.5 mmol) was dissolved in methanol (100 mL); Pd/C (10%, 3.0 g, moistened with 0.5 ml water) was added at once followed by ammonium formate (24.0 g, 0.385 mol). The mixture was stirred and heated to reflux for 3 h. When the reaction is complete (TLC PET/AcOEt 9/1), the catalyst was removed by filtration on Celite®, and the filtrate evaporated in vacuo. The residue is redissolved in dichloromethane and washed with 5% aq. NaOH. The organic phase was then dried (Na2SO4) obtaining 6 (5.98 g, 76%) as light yellow oil. M.p.:. ESI-MS: 206 (MH+); (Calc. for C12H19N3: 205 u.m.a.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([P:9]([OH:12])(=[O:11])[OH:10])[CH:6]=[C:5]([P:13]([OH:16])(=[O:15])[OH:14])[CH:4]=1.[C:17](Cl)(Cl)=[S:18]>O>[N:2]([C:3]1[CH:8]=[C:7]([P:9]([OH:10])(=[O:12])[OH:11])[CH:6]=[C:5]([P:13]([OH:16])(=[O:14])[OH:15])[CH:4]=1)=[C:17]=[S:18]
Reactant: Nc1cc(P(=O)(O)O)cc(P(=O)(O)O)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Product: O=P(O)(O)c1cc(N=C=S)cc(P(=O)(O)O)c1
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
Aniline-3,5-diphosphonic acid hydrochloride(500 mg, 1.73 mmole) was dissolved in water(5 ml) and thiophosgene(600 mg, 5.2 mmole) was added and the mixture stirred vigorously at 20° C. for 2.5 hours. Volatiles were removed in vacuo and the residue was dissolved in water(10 ml), filtered and lyophilised. 490 mg. 96%
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.CC(O)=O.[Fe]>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-6-nitrobenzoate (715 mg, 3.59 mmol) was dissolved in EtOH/HOAc/(10 mL/10 mL), followed by addition of iron powder(602 mg, 10.8 mmol) at room temperature. The resulting mixture was refluxed under N2 for 2 hrs. After cooling down to room temperature, the brown suspension was partitioned between H2O (30 mL) and Et2O (100 mL). After separation, the aqueous solution was extracted with Et2O (50 mL). The combined organic layers were washed with 1N NaOH (3×50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, methyl 2-amino-6-fluorobenzoate, an colorless oil which became wax-type solid on standing. The crude compound was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 3.89 (s, 3H), 5.67 (s, 2H), 6.34 (ddd, J=11.58, 8.06, 1.01 Hz, 1H), 6.41 (d, J=8.31 Hz, 1H), 7.13 (td, J=8.18, 5.79 Hz, 1H); Mass spec. 170.06 (MH+), Calc. for C8H8FNO2 169.05.
Reaction SMILES: CO[C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=O.ClC1C=CC=C[N:20]=1.C1(CC#N)C=CC=CC=1>>[N:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:20]
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Reactant: Clc1ccccn1
Solvent: N#CCc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
U.S. Pat. Nos. 2,507,631 and 2,957,880 disclose synthetic procedures wherein methylphenidate, alternatively known as methyl α-piperid-2-ylphenylacetate, is prepared through a multi-step process in which 2-chloropyridine and phenylacetonitrile initially are coupled to form α-pyrid-2-ylphenylacetonitrile. The resulting α-pyrid-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which, in turn, is either: (a) catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then converted to methyl α-piperid-2-ylphenylacetate, or (b) converted to methyl α-pyrid-2-ylphenylacetate which, in turn, is hydrogenated to yield methyl α-piperid-2-ylphenylacetate.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][N:12]1C(=O)C2=CC=CC=C2C1=O.[N]=[O:24]>C(O)(=O)C>[N+:12]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([O-:11])=[O:24].[C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: [N]=O
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1C2CC3CC1CC(C2)C3
Solvent: CC(=O)O
Product: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 30 %
Yield: 17 %

Procedure:
Into a flask, 1 mmole of adamantane, 0.05 mmole of N-hydroxyphthalimide and 5 ml of acetic acid were added to mix and then the flask was equipped with a gas bag (about 1L) of nitrogen monoxide NO. The mixture was reacted for 8 hours at 100° C. with stirring. The reaction products were analyzed by gas chromatography, and, as a result, The conversion of adamantane was 95%, and nitroadamantane (yield 30%), adamantanol (yield 17%) and acetyloxyadamantane (yield 33%) were formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([CH3:25])[C:10](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:11])=[CH:5][CH:4]=1.[OH-:26].[Li+].OO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([CH3:25])[C:10]([OH:11])=[O:26])=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of (S)-3-((R)-2-(4-methoxyphenyl)propanoyl)-4-benzyloxazolidin-2-one (1.50 g, 4.42 mmol) in THF (20 ml) was added to a mixture of lithium hydroxide (750 mg, 17.6 mmol) and hydrogen peroxide (0.9 ml, 26.5 mmol, 30% in water). The reaction mixture was stirred at room temperature for 3 h. Then the solvent was evaporated, the residue was acidified with diluted HCl (10 ml) and extracted with DCM (3×50 ml). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (20%) in petroleum ether as eluent to afford 600 mg (76%) of (R)-2-(4-methoxyphenyl)propanoic acid as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[C:17]([CH3:22])=[N:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:18]3[C:17]([CH3:22])=[N:16][N:15]([CH3:14])[CH:19]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cc1nn(C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (3 g, 15.1 mmol, 1 eq) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (2.0 g, 16.6 mmol, 1.1 eq) in DCE (75 mL) add sodium triacetoxyborohydride (4.8 g, 22.6 mmol, 1.5 eq) and stir at room temperature over the weekend. Add 2 N sodium hydroxide (100 mL), separate the layers, extract the aqueous layer twice with DCM (75 mL), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM). Combine only the fractions which contain the main component and concentrate to give the title preparation as a viscous yellow oil (2.14 g, 46%). Combine all other fractions which contain main component plus impurities, concentrate then repeat the chromatography step to recover further material (1.6 g, 35%, total yield 81%). MS (ES): m/z=307.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[C:9]([CH2:8][C:4]1[C:3]([CH3:11])=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1CC#N
Solvent: c1ccncc1
Product: Cc1c(CC#N)cccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
(3-Amino-2-methyl-phenyl)-acetonitrile (11.1 g) was dissolved in 80 ml of pyridine. The solution was cooled in an ice bath and 11.3g of methanesulfonyl chloride was added. The reaction mixture was removed from the ice bath and stirred at room temperature for 30 minutes; 10 ml of water was added, and the mixture was stirred for 30 minutes, poured into ethyl acetate (EtOAc), washed with cold hydrochloric acid, washed with water, dried, and evaporated to give 16.1 g of N-(3-cyanomethyl-2-methyl-phenyl)-methanesulfonamide as a light yellow solid. ##STR105##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1cccc1
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)c1ccc2ccccc2c1
Reaction time: 38 h
Yield: 90.3 %

Procedure:
N-Methylpyrrole (19.5 g, 0.24 mole) and 2-napthalenoyl chloride (50.0 g, 0.26 mole) 300 mL of dry toluene were heated under reflux overnight with a nitrogen stream bubbling through the reaction mixture. Another 10 mL of N-methylpyrrole was added to the reaction mixture and the reflux was continued for another 38 hr. 100 mL of 20% aqueous 3-(dimethylamino)propylamine was added and stirred for 30 minutes. Et2O/THF was added and the organics were separated off, washed with 1 N HCl, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo to give 51 g (90%) of (2-naphthalenyl)(1-methyl-1H-pyrrol-2-yl)-methanone. mp 108-110° C. CIMS m/z236 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.35 (Ar, 1H); 8.0-7.9 (Ar, 4H); 7.6-7.5 (Ar, 2H); 6.95 (Ar, 1H); 6.8 (Ar, 1H); 6.2 (Ar, 1H); 4.1 (s, 3H).
Reaction SMILES: CCO[C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[O:10][C:9]2([CH2:8][CH2:7][CH:6]([CH2:4][OH:5])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml. ethylene glycol and 21 g. of p-toluenesulfonic acid in 5.5 liters of benzene were heated at reflux with stirring for 24 hours while water was separated by means of a water trap. The mixture was cooled and poured into 4 liters of ice water. The benzene layer was separated, washed with 1 liter of 5% sodium bicarbonate, 1 liter of water and 1 liter of saturated sodium chloride solution, dried and evaporated to dryness to give, after distillation, 245.6 g. of ethyl cyclohexanone-4-carboxylate ethylene ketal; b.p. 95°-99.5° C. (0.07 mm.); n25D 1.4620. A solution of 35 g. of the ketal-ester in 50 ml. of dry tetrahydrofuran was added dropwise to 5.7 g. of lithium aluminum hydride in 250 ml. of dry tetrahydrofuran, and the mixture was heated at reflux for five hours and cooled to room temperature. A saturated sodium chloride solution (11.4 ml.) was added dropwise and heating at reflux was continued for one hour. The mixture was cooled and filtered, and the filtrate was dried and evaporated to dryness to give 26.9 g. of 4-hydroxymethylcyclohexanone ethylene ketal as a clear, colorless oil which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:5]1=2.Cl[CH2:19][C:20]1[O:24][CH:23]=[N:22][C:21]=1[CH3:25].O>COCCOC>[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[N:14]([CH2:19][C:20]3[O:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:15][CH2:16][C:5]1=2
Reactant: Cc1ncoc1CCl
Reactant: Cn1c2c(c3ccccc31)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncoc1CN1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 5 h
Yield: 13.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 600 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (1.5 g) in dry DME (150 ml) and then the mixture was stirred at 60° for 5 h under nitrogen. 5-Chloromethyl-4-methyloxazole (1.2 g) was added and the mixture was stirred overnight. A further quantity of sodium hydride (60% dispersion in oil; 600 mg) was added and the mixture was stirred at 60° for 4 h, then cautiously treated with water (100 ml). The mixture was extracted with dichloromethane containing methanol (ca. 1%) (3×100 ml) and the combined extracts were evaporated. The residue was purified by FCC eluting with System A (100:8:1) to give the title compound (300 mg) as a solid, t.l.c. (System A, 100:8:1) Rf 0.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.O>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1cccnc1
Temperature: 80 °C

Procedure:
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (190 mg, 0.58 mmol), 3-pyridylboronic acid (70 mg, 0.58 mmol), Pd(Ph3P)4 (70 mg, 0.06 mmol), K2CO3 (200 mg, 1.5 mmol), DME (6 mL) and H2O (3 mL) was degassed with bubbling Ar for 15 min. The mixture was heated at 80° C. for 1 h. The reaction was poured into H2O (40 mL) and extracted with CH2Cl2 (2×30 mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3-methoxy-4-(pyridin-3-ylmethyl)phenyl]-1,3-benzoxazole as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.56 (br s, 1H), 8.45 (br d, 1H), 7.74–7.80 (m, 3H), 7.50–7.58 (m, 2H), 7.32–7.37 (m, 2H), 7.17–7.24 (m, 2H), 4.00 (s, 2H), 3.93 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (37 mg, 50%) which was obtained as a white solid. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=C[CH:10]=1.CC1C=C[C:19]([S:22](Cl)(=O)=O)=CC=1>ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[S:22]([CH3:19])[CH3:10])=[N:3][CH:4]=1
Reactant: c1ccncc1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CS(C)=Nc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
A mixture containing about 17 mmol of N-5-bromo-2-pyridinyl-S,S-dimethylsulfilimine in about 30 mL of dichloromethane solution prepared as in Example 3A omitting the recovery step was diluted with 43 mL of dichloromethane and then 10.0 g (58 mmol) of 2-amino-5-bromopyridine, 5.5 g (70 mmol) of pyridine, and 14.2 g (74 mmol) of 4-methylbenzenesulfonyl chloride were added sequentially with stirring and cooling at -10° C. The mixture was allowed to warm to 20° C. with stirring. A white precipitate formed quickly. An additional 1.6 g (20 mmol) of pyridine was added and the mixture was allowed to stand for 3 days. Dichloromethane (25 mL) was added to dissolve all the solids and the resulting solution was washed with 150 mL of 0.1N aqueous hydrochloric acid. The aqueous layer was back-extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The yellow solid residue was recrystallized from 175 mL of acetonitrile and the resulting yellow solid (a first crop of 8.3 g and a second crop of 1.5 g) was recovered to obtain the title compound (41 percent of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH:15]=[O:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+].CCOC(C)=O>CC(O)(C)C.CC(=CC)C.O>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][C:15]([OH:26])=[O:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC(=O)O
Reaction time: 0.75 h

Procedure:
To a solution of the aldehyde from Step A (1.52 g, 4.31 mmol) in 2-methyl-2-propanol (50 mL) and 2-methyl-2-butene (10 mL) at room temperature was added a solution of sodium chlorite (585 mg, 5.17 mmol) and sodium dihydrogenphosphate (595 mg, 4.31 mmol) in 10 mL of water. The reaction turned yellow, then slowly faded to light pink over 45 minutes. The solution was poured into EtOAc, and washed with sat. sodium bisulfite soln. The aqueous layer was acidified to pH 3 with 2.75M KHSO4 soln., and extracted several times with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:13][CH:12]([CH2:11][N:14]=[C:15]=[S:16])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C=CCN=C=S
Reactant: ON=Cc1ccc(Br)cc1
Product: S=C=NCC1CC(c2ccc(Br)cc2)=NO1

Procedure:
A 10 g. portion of 4-bromobenzaldoxime was chlorinated and reacted with 10 g. of allylisothiocyanate to prepare 15 g. of product, m.p. 123°-125°.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[ClH:26]>C(O)C>[ClH:26].[ClH:26].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: CC(C)CCC(Br)C(O)c1ccccc1
Reactant: NCCCN1CCCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Temperature: 110 °C
Yield: 35 %

Procedure:
A mixture of 2-bromo-5-methyl-1-phenylhexan-1-ol [prepared from 2-bromo-5-methyl-1-phenylhexan-1-one by usual NaBH4 -reduction] (1.0 g, 3.69 mmol) and 1-(3-aminopropyl)piperidine (1.05 g, 7.38 mmol) was heated at 110° C. for 4 hours in a nitrogen atmosphere. After being cooled, the reaction mixture was dissolved in lN-HCl (50 ml) and the solution was washed with ether. The aqueous layer was basified with lN-NaOH and then extracted twice with ether. The combined ethereal extract was washed three times with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC to give pale yellow oily matter. To a solution of the matter in ethanol was added in excess 18% HCl in EtOH and the resulting mixture was evaporated under reduced pressure. The residue was dissolved with heating in ethanol (15 ml) and to the mixture was then added 10 ml of acetone. The mixture was stirred at room temperature. Precipitated crystals were collected by filtration to obtain 0.52 g of the title compound (yield: 35%).
Reaction SMILES: [CH2:1]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:13].[CH2:1]([CH:7]1[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCCCCCl
Reactant: CCCCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCC1CCN(CCCCCO)CC1
Product: Cl

Procedure:
Seventeen (17) grams of 4-n-hexylpiperidine, 13 grams of 5-chloropentanol and 11 grams of triethylamine were dissolved in 100 ml. of toluene. The solution is heated in an autoclave for twelve hours at 120°-140° Centigrade. The solution is stirred with 200 ml. of 5-N NaOH. The organic phase is separated, dried, the solvent evaporated and the base distilled at 130°-135° Centigrade/0.01 mm Hg. The yield is 17.5 grams. The hydrochloride is obtained in the usual manner, according to Example 1, and melts at 142°-145° Centigrade.