Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27]O)[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:31]#[N:33])[CH:24]=[N:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CO)c2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CC#N)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.2 %

Procedure:
To a mixture of [5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (1.68 g), triethylamine (0.85 g) and ethyl acetate (100 mL) was dropwise added methanesulfonyl chloride (0.96 g) at room temperature, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give pale-yellow crystals. To a mixture of the crystals and dimethyl sulfoxide (20 mL) was added an aqueous solution (2 mL) of sodium cyanide (0.41 g) at room temperature and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.76 g, 44%) of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 137-138° C.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([O:26][CH3:25])[CH:28]=3)=[O:23])[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(N)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3cccc(OC)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 27 mg (0.22 mmol, 1.1 eq.) of 3-methoxyaniline were reacted according to General Method 1. Yield: 52 mg (60% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:19]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:29]=[O:30])[C:23]=2[CH:22]=[CH:21][N:20]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[C:3]=1[CH:29]([C:24]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:28]=2[CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=Cc1cccc2cnccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1c(Br)ccc2c1OCO2)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a solution of 4-bromo-1,2-(methylendioxy)benzene (3.01 g, 15 mmol) in THF (20 mL) at −78° C. was added dropwise lithium diisopropylamide (10.6 mL of 1.5 M in cyclohexane, 16 mmol). The reaction mixture was stirred at −78° C. under argon for 20 minutes. A brown solution was formed. A solution of 5-isoquinolinecarboxaldehyde (1.90 g, 12 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes and warmed to room temperature. Stirring was continued for 30 minutes at room temperature, and then the mixture was quenched with saturated NH4Cl solution. The product was extracted with EtOAc and the solvent was removed under reduced pressure. Chromatography (SiO2 Type-H, 35% EtOAc in Hexanes) of the residue yielded the title compound as a yellow solid (2.8 g, 7.8 mmol, 65% yield): mp 173–175° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:16][CH2:17][CH3:18])[CH3:27]
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF (7 mL) is cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol, 60% oil dispersion). The ice bath is removed, ethyl bromoacetate (0.43 mL, 3.9 mmol) is added, and the mixture is placed in an oil bath (T=85° C.). After 18 h, the reaction mixture is cooled and concentrated in vacuo. The residue is diluted with EtOAc, washed with brine (2×), dried (Na2SO4), and concentrated. The crude product is purified by radial chromatography using 10% ethyl acetate in hexanes to give a tan solid (0.62 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.82 (d, J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 329 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][CH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH3:13]O>>[CH3:13][O:9][C:8](=[O:10])[C@H:6]([CH2:5][CH2:4][S:3][C:2]([F:11])([F:1])[F:12])[NH2:7]
Reactant: N[C@@H](CCSC(F)(F)F)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)CCSC(F)(F)F

Procedure:
The compounds of the present invention can be synthesized from trifluoromethionine, for example. For example, trifluoromethionine amide(WY-200) can be obtained by: reacting trifluoromethionine with methanol to produce trifluoromethionine methyl ester; and reacting ammonia with the trifluoromethionine methyl ester.
Reaction SMILES: ClC[N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]([CH3:14])[S:4]1(=[O:16])=[O:15].N1C=CC=NC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:6]1[N:5]([CH3:14])[S:4](=[O:16])(=[O:15])[NH:3][C:7]1=[O:8]
Reactant: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1cncnc1
Solvent: CN(C)C=O
Product: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Temperature: 0 °C

Procedure:
A mixture of 2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 3.72 mmol), 2,4-dioxo-4-H-pyrido 1,2-a!pyrimidine (Formula IV: X=H; Y= ##STR18## (0.72 g; 4.44 mmol), and potassium carbonate (0.67 g; 4.84 mmol) in 35 ml of DMF was stirred at room temperature for 24 hours. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The solvent was concentrated in vacuo and the residue purified by silica gel flash chromatography (70% hexane/ethyl acetate, 5% methanol/ethyl acetate) to afford 0.29 g of 2-(4-oxo-4-H-pyrido 1,2-a!pyrimidin-2-yl-oxymethyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =(CH2)2CH(CH3); R3 =CH3 ; ##STR19## Example 1J) as a solid, m.p. 106.5°-107.5° C., and 0.34 g of 2-(4-oxo-4-H-2-hydroxypyrido 1,2-a!pyrimidin-3-yl-methyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a solid, m.p. 165°-170° C.
Reaction SMILES: [Li+].[OH-].[CH2:3]([N:9]([CH3:20])[C:10]([CH:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[C:14](=[O:19])[O:15]2)=[O:11])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Cl.Cl.[NH2:23][C@:24]1([C:29]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[O:30])[CH2:26][C@H:25]1[CH:27]=[CH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:35]1([S:32]([NH:31][C:29]([C:24]2([NH:23][C:14]([CH:13]3[CH2:18][CH:16]([OH:15])[CH2:17][CH:12]3[C:10]([N:9]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:20])=[O:11])=[O:19])[CH2:26][CH:25]2[CH:27]=[CH2:28])=[O:30])(=[O:34])=[O:33])[CH2:37][CH2:36]1
Reactant: C=CCCCCN(C)C(=O)C1CC2CC1C(=O)O2
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
LiOH solution (0.15M, 53 mL, 8 mmol) was added to the lactone amide 24a (996 mg, 3.96 mmol) in an ice bath and stirred for 1 h. The mixture was acidified to pH 2-3 with 1N HCl and evaporated, co-evaporated with toluene several times, and dried under vacuum overnight. (1R,2S)-cyclopropanesulfonic acid (1-amino-2-vinyl-cyclopropane-carbonyl)amide hydrochloride (4.21 mmol) and HATU (1.78 g, 4.68 mmol) were added. The mixture was cooled in an ice bath under argon, DMF (25 mL) and then DIEA (2.0 mL, 11.5 mmol) were added. After stirring for 30 min, the mixture was stirred at rt for 3 h. After evaporation of solvent, the residue was dissolved in EtOAc (120 mL), washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2×20 mL), and dried over Na2SO4. Flash column chromatography (200 g YMC silica gel, 2-4% MeOH in CH2Cl2 gave white solids (1.25 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[OH:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:17][CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][NH:14][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCC(O)c1cccnc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)c1cccnc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 296 mg, 1.51 mmol) and 2-amino-1-pyridin-3-ylethanol (Preparation 98, 214 mg, 1.55 mmol) in DMF (10 mL) was added HOBt (225 mg, 1.47 mmol), DIPEA (0.55 mL, 3.16 mmol) and EDCI (340 mg, 1.77 mmol). After stirring at rt for 12 h the solvent was removed in vacuo and the residue then taken up in THF (150 mL) and washed with diluted sodium hydroxide solution (1M, 50 mL) and brine (2×50 mL). The solution was dried (MgSO4) and concentrated to an oil that was further purified by flash chromatography on silica gel (eluent: DCM/methanol: 90/10+0.5% triethylamine) to give the title compound as off-white solid. δH (d6 DMSO): 3.53 (2H, m), 4.85 (1H, m), 5.75 (1H, d), 7.15 (1H, s), 7.37 (1H, dd), 7.75 (2H, m), 8.47 (1H, m), 8.57 (1H, s), 8.89 (1H, appt), 12.24 (1H, s); m/z (ES+)=317.17 [M+H]+; RT=2.71 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:14])[C:12]#[N:13].[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:14][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH3:15])[C:12]#[N:13]
Reactant: [Li]CCCC
Reactant: CC(C#N)c1ccc2ccccc2c1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc2ccccc2c1
Temperature: -78 °C

Procedure:
To a stirred solution of naphth-2-ylpropionitrile (25 mmol, 4.52 g) in dry tetrahydrofuran (250 ml) at -78° C. was added n-butyl lithium (30 mmol, 18.75 ml; 1.6M solution in hexane) dropwise over a twenty minute period. After stirring the solution for twenty minutes at -78° C. methyl iodide (30 mmol, 4.26 g) was added in one portion. The reaction mixture was stirred for twenty minutes at -78° C. and the reaction was quenched with saturated NH4Cl (35 ml). The reaction mixture was warmed to room temperature, the volatiles were removed in vacuo, the residue diluted with water (200 ml) and extracted with diethyl ether (2×250 ml). The organic phase was washed with water (250 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative high pressure liquid chromatography (SiO2 :hexane/dichloromethane) to give α-methyl-naphth-2-ylpropionitrile as a white solid (3.21 g, 66 percent of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a 150 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (5 g, 18 mmol) was dissolved in dimethylformamide (30 ml). N-Chlorosuccinimide (2.4 g, 18 mmol) was added and the mixture was stirred at 60° C. for 1 h. The reaction mixture was poured into ethyl acetate and extracted with saturated sodium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 30% ethyl acetate in heptane) to yield a light yellow solid (4.0 g, 71%) MS (ISP): 313.1 ([{35Cl}M+H]+), 315.1 ([{37Cl}M+H]+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][N+:31]#[C-:32])[O:27][N:26]=2)[CH2:24][CH2:23]1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH:22]1([C:25]2[N:29]=[C:28]([C:30]3[N:31]=[CH:32][N:3]4[C:4]5[C:9](=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=[CH:6][CH:5]=5)[C:10]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:11][C:2]=34)[O:27][N:26]=2)[CH2:24][CH2:23]1
Reactant: [C-]#[N+]Cc1nc(C2CC2)no1
Reactant: FC(F)(F)c1cccc2nc(Cl)nc(N3CCOCC3)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c1c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a stirred solution of 2-chloro-4-morpholino-5-trifluoromethyl-quinazoline (600 mg, 1.9 mmol) and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole (440 mg, 2.9 mmol) in dry DMF (15 ml) under nitrogen at 5°-10° C. was added solid potassium t-butoxide (330 mg, 2.9 mmol). The mixture was stirred at 5°-10° C. for 0.5 h and triturated with water (20 ml). The crystals were filtered off and washed with water (10 ml) and ethyl acetate. A final purification was done by stirring the crystals in acetone (10 ml) to give 330 mg of the title compounds, m.p. 197°-199° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Sc1nc2ccccc2s1
Product: O=C1CCc2cc(OCCCCSc3nc4ccccc4s3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p.: 147°-148° C.) and 2-mercapto-benzthiazole.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]([C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[CH3:23][NH:24][CH3:25]>C(O)C>[CH3:23][N:24]([CH3:25])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]([C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccccc1N(C/C=C/CBr)c1nccnc1Cl
Solvent: CCO
Product: CN(C)C/C=C/CN(c1ccccc1[N+](=O)[O-])c1nccnc1Cl

Procedure:
Similar to Example 1094, 0.34 g of (E)-2-[N-(4-bromo-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazine was treated with 20 ml of a 0.86 M ethanol solution of dimethylamine in 5 ml of ethanol to thereby give 0.17 g of the title compound as a yellow oily substance.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:32][C:26]1[C:25]([CH3:33])=[C:24]([NH:23][C@@H:10]([C:11]2[S:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)s2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)s2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (347 mg, 0.67 mmol) was deprotected using tetrabutylammonium fluoride (1.0 M solution in THF, 0.8 mL, 0.8 mmol) in a procedure analogous to that used for the preparation of example 7. After column chromatography (50% EtOAc/hexanes) the title compound was isolated as a white solid (269 mg, quant). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.88 (m, 2H), 7.29 (d, J=8.5 Hz, 1H), 7.13 (m, 2H), 6.63 (d, J=8.7 Hz, 1H), 5.47 (d, J=7.6 Hz, 1H), 4.99 (dd, J=3.4, 7.5 Hz, 1H), 4.49 (m, 1H), 3.09 (br s, 1H), 2.30 (s, 3H), 1.31 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][C@@H:48]([CH2:50][CH3:51])[CH3:49]>>[C@H:48]([NH:47][C:41](=[O:43])[CH2:40][CH:37]1[CH2:36][CH2:35][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:39][CH2:38]1)([CH2:50][CH3:51])[CH3:49]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC[C@@H](C)N
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(-)-2-aminobutane (Alfa) to give the title product. LC-MS (ES+) 720 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]#[C:17][C:18](O)([CH3:20])[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CC)CC.CC[OH:30]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:22][C:18]([CH3:19])([CH3:20])[C:17](=[O:30])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=CC1=O
Reaction time: 1 h
Yield: 98 %

Procedure:
To a RT solution of 1-(4-(benzyloxy)phenyl)-4-hydroxy-4-methylpent-2-yn-1-one (1.5 g, 0.005 mol) in EtOH (10 mL) was added a solution of Et2NH (0.86 mL) in EtOH (10 mL) under an inert atmosphere. The reaction mixture was stirred for 1 hr and then concentrated in vacuo to obtain the crude product. The crude material was partitioned between water and DCM and the organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to afford 5-(4-(benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one (1.4 g, 98%) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][CH2:5][CH:6]([CH:12](O)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=O)C.CN(C1C=CC=CN=1)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH:12](=[C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:15])[CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CCOC(=O)C(CCC=C(C)C)C(C)O
Agent: CN(C)c1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC=C(CCC=C(C)C)C(=O)OCC
Reaction time: 6 h
Yield: 47.3 %

Procedure:
A mixture of ethyl 2-(4-methyl-3-pentenyl)-3-hydroxybutyrate (23.0g, 0.107 mol), acetic anhydride (14.28g, 0.14 mol), dimethylaminopyridine (0.714g, 0.0058 mol), 1,8diazabicyclo[5.4.0]undec-7-ene (42.5g, 0.28 mol) and toluene (250 mL) was heated in a stainless steel autoclave at 110° C. for 4h and then at 150° C. for 6h. The mixture was cooled, washed sequentially with water (50 mL), 2N HCl (3×50 mL), sodium bicarbonate solution until neutral, and dried (sodium sulfate). The solvent was evaporated and the residue distilled to provide 9.93g of ethyl 2-ethylidene-6-methyl-5-heptenoate (GLC purity 94%, about an 8:1 mixture of E:Z isomers). NMR (CDCl3 60 MHz) δ 1.28 (3H, t, J=7Hz, 1.62 (3H, s), 1.68 (3H, s), 1.80 (3H, d, J=7Hz), 1.6-2.4 (4H, m), 4.21 (2H, q, J=7Hz), 4.9-5.3 (1H, m), 6.87 (1H, q, J=7Hz), IR 2960, 2910, 1715, 1640, 440, 1370, 1270 cm-1 ; MS m/e 196, 167, 150, 69.