Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CBr
Reactant: c1ccsc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)Cc1cccs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of thiophene (1.12 mL, 14.26 mmol) in 35 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (6.28 mL, 2.5 M in hexanes) and the resulting solution stirred at −78° C. for 20 minutes. Isobutylbromide (1.63 mL, 15.00 mmol) was added dropwise and the resulting solution stirred while warming to room temperature over 2 h before being poured into 100 mL 1 N hydrochloric acid. Organics were extracted with hexanes (3×100 mL), washed with 0.1 N hydrochloric acid (3×50 mL), water and brine (50 mL each), dried with magnesium sulfate, filtered and concentrated to give crude 2-isobutylthiophene. Used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.Cl.[NH2:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:15][CH2:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCCCC2)c1C
Temperature: 0 °C

Procedure:
A 500 mL round bottom flask was charged with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (6.00 g, 27.1 mmol), 1-aminomethyl-1-cyclohexanol hydrochloride (4.94 g, 29.8 mmol), and N,N-dimethylformamide (200 mL). The solution was cooled to 0° C. and triethylamine (8.31 mL, 59.6 mmol) was added dropwise. The solution was heated to 35° C. for 3 d. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane (300 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and dried under vacuum to yield 1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanol that was used without further manipulation in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([OH:18])(=O)=[O:16])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([Cl:20])(=[O:18])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)O)cccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1.40 g of 5-acetylaminonaphthalene-1-sulfonic acid and 2.23 g of phosphorus pentachloride are combined and stirred for 4 hours at 60° C. Then the solution is poured onto ice water and extracted with dichloromethane. The organic extracts collected are dried with sodium sulfate and evaporated down in vacuo. Yield: 1.10 g.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][CH2:9][CH3:10].[OH:11][C:12]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[OH:11][C:12]1[C:19]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:18][C:15]([CH:16]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][CH3:10])=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCc1nccn1N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CCCc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.47 g of 1-amino-2-propylimidazole hydrochloride are dissolved in 300 ml of ethanol, and 3.5 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added. The mixture is stirred at room temperature for 3 hours and the solution obtained is evaporated. The residue is treated with 150 ml of water and 150 ml of methylene chloride, and saturated sodium bicarbonate solution is added while stirring up to a neutral reaction (pH=7). The methylene chloride phase is separated. The aqueous phase is extracted once with 50 ml of methylene chloride. The methylene chloride solutions are combined, dried and evaporated. The residue is triturated with ether, and the solid is removed by filtration and dried at 60° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-propylimidazole of m.p. 160°-161°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Sn](CCCC)(CCCC)/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(Cl)ccn1
Reactant: CCCC[Sn](/C=C/c1ccccn1)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/c2ccccn2)ccn1
Temperature: 100 °C
Yield: 83 %

Procedure:
4-Chloro-2-methoxypyridine (182 mg, 1.27 mmol) and (E)-2-(2-(tributylstannyl)vinyl)pyridine (R. A. Hacck, et al. Tet. Lett 1988, 29, 2783-2786) (500 mg, 1.27 mmol) were stirred in dry toluene (4 mL) and degassed with a nitrogen stream as the temperature was increased to 100° C. Palladium tetrakistriphenylphosphine (146 mg, 0.127 mmol) was added and the reaction mixture was maintained at 100° C. under a nitrogen atmosphere for 16 h. Upon cooling, the mixture was purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) to provide the title compound (225 mg, 83%) as a green oil: 1H NMR (500 MHz, CD3OD) δ 8.63 (d, J=4.7 Hz, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.71-7.67 (dt, J=7.5, 1.6 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.28 (d, J=16.4 Hz, 1H), 7.22-7.18 (dd, J=7.2, 4.7 Hz, 1H), 7.06 (d, J=5.4 Hz, 1H), 6.85 (s, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[C:14]([F:41])=[CH:13][N:12]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[C:14]([F:41])=[CH:13][N:12]=1)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.084 g, 0.141 mmol) was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(2-(cyanomethoxy)phenyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=13.00 (br. s., 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 7.98 (dd, J=1.7, 8.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.69-7.59 (m, 1H), 7.48-7.36 (m, 2H), 7.34-7.22 (m, 2H), 6.89 (d, J=4.4 Hz, 1H), 5.09 (s, 2H). m/z (ESI) 441.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1)[CH:17]=[CH2:18]>>[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])[N:21]=1)[CH:17]=[CH2:18]
Reactant: C=CCOc1cncc(Cl)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: C=CCOc1cncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, white cristalline solid, MS: m/e=351.2, 353.2 (M+H+), was prepared in accordance with the general method of example 1b from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-Allyloxy-6-chloro-pyrazine (CAS: [107466-49-9].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=O.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>O1CCCC1>[NH:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:23]=[C:7]1[CH:6]=[CH:5][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cccc(C=CC(=O)Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1cccc(C=Cc2nc3ccccc3[nH]2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A tetrahydrofuran solution of 3.27 g of 3-methyl-2-nitrocinnamoyl chloride was dropped into a tetrahydrofuran solution of 3.41 g of o-phenylenediamine. The obtained mixture was stirred at room temperature for one hour to complete a reaction. Thereafter, the obtained solution was concentrated and extracted with ethyl acetate. The residue was heated in acetic acid at 100° C. for 2 hours to give 3.67 g of 3-[2-(1H-benzimidazol-2-yl)vinyl]-2-nitrotoluene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[BrH:20]>CS(C)=O.O>[NH2:1][C:2]1[C:7]([Br:20])=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Reactant: Br
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(=O)c2ccccc2)c(N)c(Br)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To a solution of 900 mg (3.5 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in 60 ml of DMSO, add dropwise at 0° C. 15 g of HBr 40% by weight in water. Heat at 60° C. for 24 hours. Add 400 ml of H2O and extract four times with 200 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 1/hexane 4). Yield: 65%. 1H-NMR (CDCl3, 300 MHz): d 3.67 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.59 (s, 2H, NH2), 7.06 (s, 1H Ar), 7.47–7.65 (m, 5H Ar). Mass: (M+H)+=335.98+337.98.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:13])[NH:6][C:5]2=O.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:13])[N:6]=[C:5]2[Cl:23]
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CSc1nc(Cl)c2cc(Br)ccc2n1
Temperature: 110 °C
Yield: 75 %

Procedure:
To a suspension of compound 5a (0.65 g, 2.4 mmol) in 6.2 mL of POCl3 was added 10 μL of pyridine and the mixture was heated at 110° C. for 18 hours. The reaction mixture was cooled to rt. and concentrated under reduced pressure. A saturated solution of 50 mL of aqueous NaHCO3 was added to the crude solid and the mixture was extracted with 50 mL of EtOAc. The organic layer was dried over MgSO4, concentrated under reduced pressure and purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (4:1) as eluent afforded 11a as a white solid (0.52 g, 75%). mp: 124° C.,
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH2:29])=[CH:26][CH:25]=[CH:24][CH:23]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C.C(=O)(O)[O-].[Na+]>[NH2:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH:18][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1
Reactant: Nc1cnc2ccccc2c1N
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Nc1c(NC(=O)c2cccc(C(F)(F)F)c2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 500 mg of 3-trifluoromethylbenzoic acid in 6 ml of anhydrous hexamethylphosphoramide (HMPA) and 0.6 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 380 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water, and dried to give 780 mg of 4-amino-3-(3-trifluoromethylbenzoylamino)quinoline B1 as a crude product. It is suspended in 15 g of polyphosphoric acid and heated at 120° C. for 4 hours with stirring. The mixture is poured into ice-water and neutralized with 1N sodium hydroxide. The resulting solid is filtered, washed with water and dried. It is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent, yielding 350 mg (47%) of C1 as colorless crystals.
Reaction SMILES: [NH2:1][C:2](=[S:25])[C@@H:3]([O:17][Si](C(C)(C)C)(C)C)[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].Cl[CH2:27][C:28](=O)[CH3:29]>CCO>[OH:17][C@H:3]([C:2]1[S:25][CH:27]=[C:28]([CH3:29])[N:1]=1)[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:5]
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)C(N)=S
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of benzyl ((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamate (96.8 mg, 0.253 mmol) and chloroacetone (117 mg, 101 μL, 1.27 mmol) in dry EtOH (5 mL) was heated at reflux under N2 for 20 h, then stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) to afford benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate. Rf=0.44 (50% EtOAc in hexanes). LCMS calc.=307.1; found=307.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.31 (m, 5H), 6.80 (s, 1H), 5.49 (br s, 1H), 5.06 (m, 3H), 4.26-4.18 (m, 1H), 2.38 (s, 3H), 1.09 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]>O>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: CN(C)c1cccc(CO)c1
Solvent: O
Product: CN(C)c1cccc(C=O)c1
Reaction time: 0 h
Yield: 72 %

Procedure:
The same installation as in Example 1 is used. Using a similar method to Example 1, a mixture of 320 parts of m-dimethylaminobenzyl alcohol and 50 parts of water with 300 parts of air is passed per hour over the catalyst at 530° C. and 1.2 bar. The residence time is 0.035 second and the throughput 0.45 tonne/m2.h. 228 parts of m-dimethylaminobenzaldehyde (in the form of an 88 percent strength by weight organic phase) are obtained per hour, corresponding to a yield of 72% of theory. The conversion is 94 percent and the space-time yield is 11 grams of m-dimethylaminobenzaldehyde per cm3 of catalyst volume per hour.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:12][N:11]=1)=[O:9])C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][C:13]1[CH:12]=[N:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[N:15][CH:14]=1)[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(Nc1cnc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
(+/−)-3-({5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (14.6 mg, 28.0 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M NaOH (1 mL, 1 mmol) was added. This was stirred at room temperature for 10 min. The reaction brought to pH 3 with 1 N HCl. The methanol was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give crude product. Purification by reversed-phase HPLC gave (+/−)-3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid (13.8 mg). Analytical LCMS: retention time 3.40 minutes (Waters Atlantic dC18 4.6×50 mm, 5 μm column; 5% acetonitrile/water (0.05% trifluoroacetic acid modifier) linear gradient to 95% acetonitrile/water over 4.0 minutes, hold at 95% acetonitrile/water for 1.0 minute; flow rate 2.0 mL/minute); MS (M+1): 501.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:20]4[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 1,1-dimethylethyl 1-piperazine carboxylate were reacted as described in example 9 to give the product (88%, mp: 121°-122° C.). Calc'd for C22H32N2O4 : C, 68.01%; H, 8.31%; N, 7.22%. Found: C, 67.61%; H, 8.24%; N, 7.07%.
Reaction SMILES: [C:1]1([C:7]2[O:15][C:14]3[CH:13]=[C:12]([C:16]([OH:18])=[O:17])[NH:11][CH2:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1([S:27]SC(=O)C)C=CC=CC=1.Cl>CN(C=O)C.O>[SH:27][C:13]1[C:14]2[O:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[CH2:10][NH:11][C:12]=1[C:16]([OH:18])=[O:17]
Reactant: CC(=O)SSc1ccccc1
Reactant: O=C(O)C1=Cc2oc(-c3ccccc3)cc2CN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1=C(S)c2oc(-c3ccccc3)cc2CN1
Temperature: 50 °C

Procedure:
As depicted in Scheme 35 below, 2-phenyl-4,5-dihydro-furo[3,2-c]pyridine-6-carboxylic acid (0.015 mol) is added in portions to a mixture of sodium hydride (60% dispersion in mineral oil, 0.045 mol) in anhydrous DMF (35 ml) under a nitrogen stream at 0° C. After 15 minutes phenylacetyl disulfide (0.02 mol) is added portion-wise, and the reaction is then heated to 50° C. and kept at that temperature overnight. The reaction mixture is then cooled to room temperature and poured onto crushed ice, turned acidic with 2N HCl, and extracted with ethyl acetate. The organic phase is separated, washed with brine, and dried over Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue is triturated with hexane and filtered. The obtained crude residue is then refluxed in the presence of HCl 6N and water to give 7-mercapto-2-phenyl-4,5-dihydro-furo[3,2-c]pyridine-6-carboxylic acid.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[O:14]1[CH2:19][CH2:18]C(=O)[CH2:16][CH2:15]1.[OH-].[Na+]>O1CCCC1.CO>[C:6]([CH:4]=[C:5]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)([OH:8])=[O:7]
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: O=C1CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=C1CCOCC1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
Methanol (204 ml) was slowly added to a suspension of sodium hydride (5.48 g, 228.2 mmol) in tetrahydrofuran (204 ml) at 0° C. When addition was complete, trimethylphosphonoacetate (34.22 ml, 211.4 mmol) was added to the mixture at such a rate as to maintain the temperature below 12° C. Stirring was continued for a further 10 minutes. To this reaction mixture was added a solution of 2,3,5,6-tetrahydropyran-4-one (16.28 g, 163.0 mmol) in tetrahydrofuran (20 ml), keeping the temperature below 30° C. After the addition was complete, stirring was continued for 30 minutes at room temperature, then methanol (100 ml) and 2M sodium hydroxide (326 ml) was added, and the mixture stirred overnight at room temperature. The resulting solution was concentrated to one half of the original volume, and acidified to pH 1.2 with 6M hydrochloric acid (108 ml). The reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts dried over magnesium sulfate, and solvent removed under reduced pressure to give 4-(carboxymethylene)-2,3,5,6-tetrahydropyran (22.62 g), which was used with no further purification.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)=[O:8])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.[Cu]I.[Cu]>[CH3:15][C:11]1([CH3:16])[CH2:12][CH2:13][CH2:14][N:9]([C:7]([C:4]2[CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:6][CH:5]=2)=[O:8])[CH2:10]1
Reactant: CC1(C)CCCN(C(=O)c2csc(Br)c2)C1
Reactant: C1COCCN1
Agent: [Cu]
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CC1(C)CCCN(C(=O)c2csc(N3CCOCC3)c2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(5-Bromo-thiophen-3-yl)-(3,3-dimethyl-piperidin-1-yl)-Methanone (0.1 g) was dissolved in N,N-dimethylethanol (0.5 mL). Copper (I) iodide (0.003 g), copper powder (0.001 g), morpholine (0.045 mL) and potassium phosphate tribasic (0.001 g) were added. The mixture was heated to 70° C. and stirred overnight then diluted with water (2 mL) and the solvent evaporated. The residue was purified by flash chromatography on silica, eluting with 0-60% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a gum (0.008 g). LCMS m/z 309.15 [M+H]+ RT=9.77 min (Analytical Method 1). 1H NMR δ (ppm)(CHCl3-d): 6.7 (s, 1H), 6.2 (s, 1H), 4.8 (m, 4H), 3.6-3.5 (m, 2H), 3.3 (m, 2H), 3.1 (m, 4H), 1.6 (m, 2H), 1.5 (m, 2H), 0.9 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1.C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:8](=[O:15])[C:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:19][C:18]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=2[Cl:16])[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC1(C(=O)C(=Cc2ccc(Cl)cc2Cl)n2cncn2)COCOC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 83.3 %

Procedure:
A mixture of 12.7 g (0.06 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one, 10.8 g (0.06 mole) of 2,4-dichlorobenzaldehyde, 1 g of piperidine, 0.5 g of acetic acid and 150 ml of toluene is stirred for 10 hours under reflux, with elimination of water. The mixture is then cooled, washed with three times 80 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The residue is dissolved in 250 ml of acetonitrile and the solution is decolorized with 1 g of animal charcoal at 40° C., concentrated to 40 ml and cooled to 0° C. The colorless precipitate is filtered off, washed with 40 ml of ether and dried. 18.4 g (83.3%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(2,4-dichlorophenyl)-propen-1-one, of melting point 133°-135° C., are obtained.