Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Cl[CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])[C:15](=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27]2)[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[O:17])[CH:11]=[CH:12][CH:13]=1.[Cl-].[NH4+]>CS(C)=O>[C:1]([O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:35])[C:15](=[C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[NH:30]2)[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[O:17])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(C(C(=O)c1cccc(CCl)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(=O)OCc1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
After adding 35 mg of potassium acetate to 2 ml of DMSO solution containing 100 mg of 1-[3-(chloromethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione, the mixture was stirred at room temperature for about 2 days. The reaction liquid was mixed with an appropriate amount of saturated ammonium chloride aqueous solution, extracted several times with ethyl acetate, dried with anhydrous magnesium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 90 mg of a yellow oily substance from an ethyl acetate-hexane (1:2) eluate. By crystallizing this from a small amount of ethyl acetate-hexane (1:3) at 0° C., 68 mg (64%) of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzyl acetate (Reference Example 12-1) was obtained as yellow crystals. FA: 449
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([O-])(O)=O.[Na+]>CO>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH3:22])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 2,2-diphenylacetic acid (1 gram, 1 equiv) in dry MeOH (50 mL) was added sulfuric acid (0.4 mL) dropwise and heated to reflux. Stirring was then continued for 3 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (1.0 g, 93%) that was not further purified.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H]2CO2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CN=[N+]=[N-])C1
Yield: 103.5 %

Procedure:
A solution of (S)—(S)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (1.1 g, 4.9 mmol, 1.0 eq.), sodium azide (800 mg, 12.3 mmol, 2.5 eq.), and ammonium chloride (474 mg, 8.9 mmol) in MeOH (25 mL) was stirred at reflux overnight. The white solid residue obtained on removal of solvent was dissolved in EtOAc (25 mL) and washed with water and saturated aqueous NaCl (1×25 mL each). The organic layer was then dried over Na2SO4 and concentrated to yield (S)-3-((S)-2-azido-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.3 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[H][H]>[Pt].C(O)(=O)C>[F:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: CC(=O)Nc1c(F)ccc2nc(C)ccc12
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(=O)Nc1c(F)ccc2c1CCC(C)N2
Yield: 98.2 %

Procedure:
A mixture of 8 g of 6-fluoro-5-acetylamino-quinaldine and 0.2 g of 5% platinum on carbon was dissolved in 80 ml of acetic acid and the solution was subjected to catalytic hydrogenation according to Parr method at a hydrogen pressure of 4 kg/cm2. After a theoretical amount of hydrogen was absorbed the reaction mixture was filtered. The filtrate was then concentrated under reduced pressure to obtain 8 g of 6-fluoro-5-acetylamino-1,2,3,4-tetrahydroquinaldine as an oily product. Production of this compound was confirmed by NMR spectral analysis and mass spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:24][CH2:25][CH3:26])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Reactant: CCCI
Product: CCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 47 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.4 g) and propyl iodide (0.14 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.21 g, 47%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=3[CH:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCCCC1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Product: CC1(C)OC(=O)c2cc(OCC3CCCCC3)ccc2O1

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38.a) and (bromomethyl)cyclohexane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 291.05 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:23]([C:20]2[CH:21]=[N:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[NH2:24])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc(C#N)cn1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(N)c2ccc(OC)nc2)cn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 5-bromo-2-methoxypyridine (1.00 g, 5.32 mmol) in THF (20 mL) at −78° C. was added n-butyllithium (3.13 mL, 7.83 mmol, 2.5 M in hexane). The reaction was aged at −78° C. for about 25 min at which point the cold bath was removed. 6-methoxypyridine-3-carbonitrile (1.00 g, 7.46 mmol) in THF (10 mL) was added and the reaction aged for about 40 min warming to rt at which point the reaction was concentrated. The residue was diluted with MeOH (20 mL) and NaBH4 (0.282 g 7.46 mmol) was added. The reaction aged about 90 min at rt. The reaction was concentrated and diluted with EtOAc and aq HCl (15 mL, 2 M). The aq portion was extracted twice with EtOAc before adding aq NaOH (20 mL, 2M). The aq portion was then extracted three times with EtOAc. The combined organic portion was concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc/hexane followed by 0-20% MeOH (containing 1.5% triethylamine)/EtOAc affording the title compound. HPLC/MS: 246 (M+1); Rt=1.61 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Br:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1
Reaction time: 4 h
Yield: 88.9 %

Procedure:
3-Benzyloxybenzyl alcohol (5.00 g) was dissolved in methylene chloride (70 ml), triphenylphosphine (6.52 g) and N-bromosuccinimide (4.43 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.75 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[C:4]([F:21])[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38](=[O:40])(=[O:39])[NH2:41])=[CH:34][CH:33]=3)=[O:20])[N:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)O)c2C1
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: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)Nc3ccc(S(N)(=O)=O)cc3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The carboxylic acid intermediate 18D (400 mg) and DIEA (600 μL) were dissolved in DMF (10 mL). An aliquot of this stock solution (400 μL) was dispensed into a vial charged with 4-aminobenzene-sulfonamide (0.10 mmol). TBTU was added (0.50 mmol) to the vial and the mixture was stirred at room temperature for 2 hours. The crude mixture was purified by prep LC-MS using a gradient elution of 5% to 95% MeCN/water in 15 min. The product was taken up with DCM and diluted with hexanes. Evaporation under nitrogen flow gave the desired product, Compound 208 as a solid. LCMS (+ESI) m/z 464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)c2c(-c3ccccc3)csc2n1
Temperature: 50 °C

Procedure:
2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (2 g, 7.112 mmol), morpholine (0.9294 g, 10.67 mmol) and triethylamine (1.454 g, 2.00 mL, 14.22 mmol) were combined in ethanol (23.7 g, 30 mL, 493 mmol) and heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. The solvent volume was reduced by half and the resulting precipitate filtered off and washed with water and dried in vacuo overnight at 40° C. to afford 4-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)morpholine as a white solid.
Reaction SMILES: O[N:2]=[C:3]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]1([CH3:12])[CH3:11].[OH-].[NH4+].[H][H]>CO.[Ni]>[NH2:2][CH:3]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]1([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: COC(=O)C1CC(=NO)C1(C)C
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CC(N)C1(C)C
Yield: 82.3 %

Procedure:
To a solution of methyl 3-(hydroxyimino)-2,2-dimethylcyclobutanecarboxylate (1.0 equiv.) in MeOH (0.4 M) was added ammonium hydroxide (0.2 M) and Raney nickel (20 wt percent). The mixture was stirred at 50° C. under 50 psi hydrogen atmospheres for about 6 h. After completion of the reaction, the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the crude title compound methyl 3-amino-2,2-dimethylcyclobutanecarboxylate (82.3% yield) as green liquid. The product was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.56 (s, 3H), 2.50 (s, 0.4H), 2.14 (s, 0.24H), 1.94 (s, 0.35H), 1.71 (s, 0.73H), 1.05 (s, 2.0H), 0.76 (s, 2H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:10]([OH:12])=[O:11].[CH:13]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.ClCCl>[ClH:1].[CH3:13][O:11][C:10]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:3]1[NH2:2])=[O:12]
Reactant: N[C@H]1CCCCC[C@H]1C(=O)O
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
cis-2-Amino-cycloheptanecarboxylic acid hydrochloride (0.75 g, 3.89 mmol) was dissolved in methanol (5 mL). Benzene (7.5 mL) was added followed by the dropwise addition of a 2.0 M solution of (trimethylsilyl)diazomethane in dichloromethane (3.5 mL). The yellow solution continued to stir at 25° C. for 20 min. The solution was concentrated in vacuo to afford a yellow powder. The powder was suspended in methanol (20 mL) and concentrated in vacuo to afford the desired product, cis-2-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (0.8 g, 3.86 mmol, 99%), as a white powder. 1H NMR (400 MHz, D2O) δ: 1.33-1.86 (8H, m), 2.60-2.62 (1H, m), 2.75-2.78 (1H, m), 3.27-3.30 (1H, m), 3.39-3.44 (1H, m), 3.62 (3H, s).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][NH2:22]>ClC1C=CC=CC=1>[CH3:18][N:19]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:22]2[CH2:21][CH2:20]1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CNCCN
Solvent: Clc1ccccc1
Product: CN1CCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
22.6 Parts of o-benzoyl-benzoic acid are dissolved in 100 ml of chlorobenzene. 7.4 Parts of N-methylethylenediamine are added within 10 minutes. The temperature is then raised within 1 - 2 hours to such an extent that some chlorobenzene is continuously distilled off with the reaction water until the boiling point of the pure chlorobenzene (130°-132°) is attained. 80-90% of the theoretical amount of reaction water can be removed from the distillate. The remainder of the chlorobenzene is distilled off from the reaction mass in vacuo and the viscous oil which remains is crystallised by the addition of about 10 parts of ethyl acetate. The 1-methyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one so obtained of the formula ##STR10## is filtered off and recrystallised from a mixture of 30 parts of ethyl acetate and 30 parts of petroleum ether (B.P. 30°-60° ). M.P. 120°-122°.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[N:12]=[C:11]([Cl:16])[N:10]=[C:9](Cl)[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].CC(O)C.[OH-].[NH4+:23]>O>[NH2:23][C:9]1[C:8]2[CH2:7][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]([Cl:16])[N:10]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C1CCc2nc(Cl)nc(Cl)c2C1
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1CCc2nc(Cl)nc(N)c2C1
Temperature: 130 °C

Procedure:
A mixture of 6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (7.68 g), 2-propanol (7 mL) and 30% ammonium hydroxide (12 mL) was heated in a sealed tube at 130° C. for 20 min. The tube was cooled and 20 mL of H2O was added to the mixture. The solid which precipitated was collected and dried to yield 4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[H][H]>[OH-].[Na+].[Pd]>[CH2:7]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CCC(Cc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
A solution of 35.2 gm (0.2 mol) of α-ethyl cinnamic acid in 450 ml of 3% sodium hydroxide was reduced in a hydrogen atmosphere at 60 psi using 4 gm of 5% palladium on charcoal. After hydrogen uptake had ceased, the reaction mixture was filtered, acidified with hydrochloric acid and extracted with ether. Evaporation gave 36 gm (0.2 mol) of 2-benzyl butanoic acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH3:29])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:20]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCN(C)c1ccc(N)cn1
Product: CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H17F3N4O2 (m/e) 390, obsd 391 (M+H).
Reaction SMILES: C([C:3]1([C:16]([O-:18])=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)C.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:16]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[NH2:21]
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (21 g), hydrazine monohydrate (40 mL), and ethanol (200 mL) was heated and refluxed for 22 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, to the residue were added saturated brine and ethyl acetate, and the organic phase was separated. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether, followed by stirring for 1 hour, and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (17.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:35])=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=2[F:35])[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/CC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(CC2CCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 25.8 %

Procedure:
In a manner similar to the method described in Example 1c, [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was vented with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].Cl[CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:4][CH2:3][CH2:2][OH:1]
Reactant: Nc1ccccc1OCCO
Reactant: OCCOCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCOCCNc1ccccc1OCCO
Temperature: 90 °C
Reaction time: 96 h
Yield: 53 %

Procedure:
6 g (39.17 mmol) 2-(2-hydroxyethoxy)aniline A3, 5 ml (5.85 g, 47 mmol) 2-(2-chloroethoxy)ethanol and 8.19 ml (5.95 g, 58.75 mmol) triethylamine were dissolved in 20 ml dimethylformamide and stirred for 4 days at 90° C. After cooling, the solution was filtered, the precipitate washed with dichioromethane and the filtrate concentrated in vacuo. The residue was taken up in chloroform and washed twice with a small quantity of water. The chloroform solution was then dried over sodium sulfate and concentrated. The viscous crude product was purified by column chromatography on silica gel 60 with toluene/acetone 1:2 as the mobile phase. 5 g of brown, viscous oil were obtained; yield 53%.
Reaction SMILES: [C:1]1([C:7]2([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:18]#[N:19].[Na+]>CS(C)=O.O>[C:1]1([C:7]2([CH2:12][C:18]#[N:19])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccccc2)CCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (10 g, 39.37 mmol) in DMSO (30 ml) were added KI (0.6 g, 3.9 mmol) and NaCN (2.89 g, 59.05 mmol). It was then stirred at 140° C. for 16 h. After completion of the reaction, it was diluted with water, extracted with EtOAc and the organic layer was washed with water and brine. It was then dried over Na2SO4, concentrated and purified by normal column chromatography (15% EtOAc in hexanes) to afford the title compound as a colorless liquid (2.5 g, 34%).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:21]([O:30][CH3:31])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]([O:30][CH3:31])=[O:29]
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Reactant: COC(=O)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCC(C)C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 115°-116° C.). 1H NMR (DMSO-d6) δ 0.80 (m, 6 H), 1.0 (m, 1 H), 1.17 (m, 1 H), 1.43 (m, 1 H), 1.96 (m, 2 H), 3.4 (2 H+H2O), 3.81 (s, 3 H), 6.02 (bd, 1 H), 6.88 (t, 1 H), 7.05 (t, 1 H), 7.42 (m, 5 H), 7.80 (dd, 1 H).