Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]#[N:7])[C:4]#[N:5].[CH3:8][C:9]1[S:10][C:11](S(C)(=O)=O)=[N:12][N:13]=1>C1COCC1>[CH3:8][C:9]1[S:10][C:11]([CH:3]([C:6]#[N:7])[C:4]#[N:5])=[N:12][N:13]=1
Reactant: Cc1nnc(S(C)(=O)=O)s1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc(C(C#N)C#N)s1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Under argon, 400 mg (10.0 mmol) of sodium hydride (60% suspension in oil) are suspended at room temperature in 40 ml of THF. A solution of 661 mg (10.0 mmol) of malonodinitrile in 10 ml of THF is added dropwise, and the reaction mixture is stirred for 15 min. A solution of 891 mg (5.0 mmol) of 2-methyl-5-methylsulphonyl-1,3,4-thiadiazole in 10 ml of THF is added dropwise. The reaction mixture is heated to 50° C. and stirred overnight, cooled and concentrated using a rotary evaporator. The residue is dissolved in water and adjusted to pH=3 using HCl. A brown solid precipitates out, and this solid is filtered off and dried under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:34][C:13]([F:12])([F:33])[C:14]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:10]2/[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:19][CH2:18]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCCCO)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-1,3-thiazol-2(5H)-one (900 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.75 g) in 2-propanol (20 mL) was added piperidinium acetate (750 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. After evaporation of the solvent, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.17 g).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=O>P(Cl)(Cl)(Cl)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[O:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: NNC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(Cc2ccccc2Cl)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Semicarbazide (9.0 g, 120 mmol) was slowly added to a solution of (2-chlorophenyl)acetic acid (10. g, 60 mmol) in phosphorus oxychloride (50 mL). The mixture was stirred at room temperature for 16 hours and then poured into crushed ice (500 g). A viscous solid was decanted from the aqueous layer and then the aqueous layer was adjusted to pH 4 to 5 with sodium hydroxide (50% aqueous solution). The resulting precipitate was filtered and then washed with sodium carbonate (10% aqueous solution, 100 mL) to give the product as a white solid. (5.9 g, 28 mmol, 47%). ESI-MS m/z calc. 209.0. found; 210.1 (M+1)+ 1H NMR (DMSO) δ 7.44-7.30 (m, 4H), 6.88 (s, 2H), 4.13 (s, 2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CC(C)([O-])C.[K+].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][C:19]3[C:24]([C:25]=2[C:26]=1[F:27])=[C:23]([F:28])[C:22]([O:29][CH3:30])=[CH:21][CH:20]=3.BrCCC.Cl>O1CCCC1.COC(C)(C)C.O>[F:12][C:13]1[C:14]([CH2:1][CH2:2][CH3:3])=[CH:15][C:16]2[CH:17]=[CH:18][C:19]3[C:24]([C:25]=2[C:26]=1[F:27])=[C:23]([F:28])[C:22]([O:29][CH3:30])=[CH:21][CH:20]=3
Reactant: [Li]CCCC
Reactant: COc1ccc2ccc3ccc(F)c(F)c3c2c1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCCc1cc2ccc3ccc(OC)c(F)c3c2c(F)c1F
Reaction time: 0.38 h
Yield: 33.9 %

Procedure:
A solution of 11 mmol of n-butyllithium (1.6 M solution in hexane) in 20 ml of dry tetrahydrofuran was cooled to ≦−70° C. and admixed dropwise under a protective gas atmosphere with a solution of 11 mmol of potassium tert-butoxide in 12 ml of the same solvent. After stirring for 15-30 min, a solution of 2.8 g of 3,4,5-trifluoro-6-methoxyphenanthrene in 20 ml of tetrahydrofuran was added dropwise in such a way that the internal temperature was always below −70° C. Subsequently, stirring was continued at this temperature for 2 h. 2.5 g of 1-bromopropane were then added slowly and the mixture was subsequently brought slowly to −10° C. It was admixed at −10° C. with 6 ml of water and acidified to pH 1 with concentrated hydrochloric acid. 100 ml of tert-butyl methyl ether were added, the phases were separated, and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvents were removed under reduced pressure, and the residue was chromatographed using silica gel with 9:1 (v/v) heptane/ethyl acetate. The product-containing fractions were combined, the solvent was distilled off under reduced pressure and the residue was recrystallized from acetonitrile. 1.1 g of 3,4,5-trifluoro-6-methoxy-2-propylphenanthrene were obtained.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>ClCCCl>[N:11]1([C:6](=[O:7])[CH2:5][C:4]([N:1]=[N+:2]=[N-:3])([CH3:10])[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCCNCC1
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(CC(=O)N1CCCCCC1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (8.00 g, 49.5 mmol) in anhydrous DCE (160 mL) was added azepane (12.6 mL, 3 equiv, 0.11 mol) in one portion. The reaction was stirred and left at 0° C. for 15 min and room temperature for 45 min. Aqueous 1 M HCl (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (100 mL) and saturated NaHCO3 (150 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.24 g, quant). This material was used without further purification. LRMS (ESI+) for C11H20N4O (224.1); Found: 225 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH-].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:28]([C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)CSc1c[nH]c2ccc(OC)cc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)CSc1cn(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccc(OC)cc12
Reaction time: 0.08 h

Procedure:
To a dry round bottom flask, (5-Methoxy-1H-indol-3-ylsulfanyl)-acetic acid methyl ester (25, 7.0 mg, 0.027 mmol) was dissolved with CH2Cl2 (3.0 mL). Tetrabutylammonium hydrogen sulfate (2.0 mg) and 50% KOH solution (3.0 mL) were added next. After about 5 minutes of stirring, 3,4-dichloro-benzenesulfonyl chloride (20 mg, 0.081 mmol) was added. This reaction was allowed to stir at ambient temperature overnight. The reaction was extracted with dichloromethane (2×14 mL), washed with water (5 mL), brine (5 mL) and dried over anhydrous magnesium sulfate. The reactant was filtered and rotoevaporated to give the desired product 26 as off white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[OH:10]O.O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:10])=[O:5])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCCCC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-ethyl hexanol (8.7 mmol) in CH2Cl2 (10 ml), RuCl3H2O (0.014 mmol) and tetra butyl ammonium bromide (0.2 mmol) were added. The mixture was heated at 40° C. and 30% H2O2 (v/v) (3 ml) was added dropwise. After 1 hours the reaction was complete. Water is added, the organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure to give the crude product of the title that was purified by flash chromatography (pure CH2Cl2) obtaining 0.8 g of the desired product. Yield 65%.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(O)COCCOCCO.C(OC=C)(=O)C.[CH:22]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]OC=C)=[CH2:23].C(OCCOCCOCCO)=C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH:22]=[CH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C=COCCOCCOCCOC=C
Agent: C=COCCOCCOCCO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: OCCOCCOCCO
Solvent: C=COC(C)=O
Product: C=COCCOCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and sodium acetate (1.2 mmol) in toluene (2.0 ml),triethylene glycol (1 mmol) and vinyl acetate (4 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that triethylene glycol divinyl ether, triethylene glycol monovinyl ether, and triethylene glycol monovinyl ether monoacetate were produced in yields of 63%, 3%, and 18%, respectively, with a conversion from triethylene glycol of 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([OH:16])=O.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:25]1[CH2:26][CH2:27][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)=[O:16]
Reactant: COc1ccccc1-c1oncc1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1oncc1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1479.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([C:16]([OH:18])=O)=[CH:3]1.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CN(C1C=CC=CN=1)C.ON1C2C=CC=CC=2N=N1>[CH3:20][C:19]([CH3:22])([O:23][C:24]([NH:26][NH:27][C:16]([C:4]1[NH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2](=[O:1])[CH:3]=1)=[O:18])=[O:25])[CH3:21]
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: CC(C)(C)OC(=O)NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (61.3 g, 0.25 mol) was suspended in 500 ml of dimethylformamide at room temperature, followed by the addition of 39.65 g (0.3 mol) of N-(t-butoxycarbonyl)hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxybenzotriazole, and the mixture was stirred for 30 minutes at room temperature. Then, 57.7 g (0.28 mol) of dicyclohexylcarbodiimide, dissolved in 100 ml of dimethylformamide, was added dropwise with stirring over 30 minutes, and the mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. The remaining syrup crystallized on treatment with diluted sodium bicarbonate solution. The dried crude product was recrystallized from 2 liters of ethyl acetate to yield 69.5 g of the title compound, melting point 173°-175° C. A second crop was obtained after evaporation of the mother liquor; 3.2 g, melting point 160°-165° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:33])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:4].I[CH3:35].O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:35])[C:15]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:12][CH:13]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N(C)C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Sodium hydride (51 mg) was dissolved in dimethylformamide (5 mL), and the solution was cooled to 0° C. To the solution was added the 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid ethyl ester (500 mg) obtained in Example 1e), and the mixture was stirred for one hour. After addition of iodomethane (183 mg), the mixture was stirred at room temperature for 3 hours and water was then added. The reaction solution was concentrated, diluted with ethyl acetate, and washed with water. The resulting solution was dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=4:1 to give the title compound (141 mg).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:36](=[O:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.42 g, 12.6 mmol) was added to a solution of 1-benzyl-4-piperidinamine (2.0 g, 10.5 mmol), 4-methoxyphenylacetic acid (1.83 g, 11.0 mmol), 1-hydroxybenzotriazole hydrate (1.56 g, 11.5 mmol) and triethylamine (2.70 ml, 26.2 mmol) in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×), dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a white solid, 3.44 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5](N)=[C:4]([F:11])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.[Br-:19]>Br.O.C(OCC)(=O)C>[Br:19][C:5]1[CH:7]=[C:8]([O:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[F:11]
Reactant: [Br-]
Reactant: COc1cc(N)c(F)cc1Cl
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143 mol) in 10% HBr (250 mL) was cooled to 0° C. and a solution of sodium nitrite (15.0 g, 0.218 mol) in water (20 mL) was slowly added. Methylene chloride (50 mL) and curpric bromide (30.0 g, 0.244 mol) were added slowly and then the mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was filtered through a bed of celite and extracted with methylene chloride (2×100 mL) and the combined organic phases were dried (sodium sulfate) and concentrated. Chromatography of the dark oil (5% ethyl acetate in hexanes) gave 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6 g, 0.070 mol): 1H NMR (CDCl3): δ 7.20 (m, 1H) 7.05 (dd, 1H), 4.00 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.Cl.O[N:31]=[C:32]([NH2:35])[CH2:33][CH3:34]>>[CH2:33]([C:32]1[N:35]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:4]3[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]3)=[O:9])[CH2:11]2)[O:27][N:31]=1)[CH3:34]
Reactant: O=C1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1
Reactant: CCC(N)=NO
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCNC(=O)C3)C2)n1

Procedure:
250 mg (0.626 mmol) of 1-[(3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]-piperidine-3-carboxylic acid (Example 206A) and 85.8 mg (0.689 mmol) of N′-hydroxy-propanimidamide hydrochloride were reacted according to the General Method 1. Yield: 127 mg (44% of theory).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][N:12]3C(=O)C4=CC=CC=C4C3=O)=[CH:4][C:3]=2[O:2]1.NN>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1
Reactant: CCCCC(CN1C(=O)c2ccccc2C1=O)c1ccc2c(c1)OCO2
Agent: NN
Solvent: CO
Product: CCCCC(CN)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To 10.7 g (30 mmol) of N-(2-(3,4-methylenedioxyphenyl)hexyl)-phthalimide, were added 240 ml of methanol and 3.75 ml (60 mmol) of hydrazine (mono hydrate) and the mixture was refluxed for two hours. After cooled to room temperature, the solvent was evaporated off from the reaction mixture and residue was added with 15% aqueous sodium hydroxide and extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. By evaporating off the solvent, 5.0 g of oily (+)-2-(3,4-methylenedioxyphenyl)-hexylamine was obtained (Yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:17][CH2:18][C:19]([CH3:25])([OH:24])[C:20]([F:23])([F:22])[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:19]([OH:24])([CH3:25])[CH2:18][NH:17][C:13]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=1)=[O:15]
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: CC(O)(CN)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC(O)(CNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (397 mg, 1.392 mmol), 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (250 mg, 1.392 mmol) and HATU (529 mg, 1.392 mmol) were dissolved in DMF (10 ml) and stirred at RT for 2 min. 4-Methylmorpholine (0.413 ml, 4.18 mmol) was added and stirring continued at RT for 3 h. The reaction mixture was poured onto ice/water (100 ml) and extracted with EtOAc (250 ml). The organic extract was washed with sat NH4Cl solution (˜50 ml), dried over MgSO4 and concentrated in vacuo to give a pale brown oil. The oil was dissolved in CHCl3 (˜3 ml) and loaded onto a 24 g ISCO (silica) column eluting with iso-hexane:EtOAc to afford the title product; LC-MS Rt=1.46 mins; [M+H]+410.1, Method 2minLC_v002. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, bs), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s). 19F NMR (400 MHz, DMSO-d6) δ −62.71 (CF3, s), −80.48 (C3, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]([F:20])([F:19])[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>CC(=O)CC>[F:20][C:10]([F:19])([F:9])[S:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])=[CH:16][CH:17]=1
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(SC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CC(C)(C)Oc1ccc(SC(F)(F)F)cc1
Reaction time: 20 h

Procedure:
13.8 g (0.1 mol) of dried potassium carbonate and 1.6 g (0.01 mol) of potassium iodide are suspended in a solution of 19.4 g (0.1 mol) of 4-(trifluoromethylthio)phenol in 250 ml of dry butanone and 15.4 g (0.15 mol) of 3-chloro-3-methyl-1-butyne are added dropwise. The mixture is then heated under reflux with stirring for 20 hours, 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g of potassium carbonate are added once again and the mixture is further heated under reflux for 40 hours. Inorganic constituents are filtered off, the solution is concentrated, and the residue is taken up in 200 ml of methylene chloride and extracted using 1 N NaOH solution. The organic phase is washed with water, dried and concentrated, and the residue is filtered through silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([CH2:13][CH3:14])[CH:3]=1.C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:25])[OH:21])=[CH:3][C:4]=1[CH2:13][CH3:14])[CH3:10]
Reactant: CCc1cc(Br)ccc1N(CC)CC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCc1cc(B(O)O)ccc1N(CC)CC
Yield: 34.8 %

Procedure:
In a manner similar to that of Example 1c, by reacting 3 g of (4-bromo-2-ethylphenyl)diethylamine (11.7 mmol) with 5.2 mL of a 2.5 M solution of n-butyllithium and 3.2 mL (14 mmol) of triisopropyl borate, 0.9 g of 4-diethylamino-3-ethylphenylboronic acid (yield=35%) is obtained in the form of a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][C:22](=O)[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCCC
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 80 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-4-methoxybenzamide, the title compound was synthesized according to Example 2b. Yield: 80%. Melting point: 95-96° C. (Hexane).