Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:8])([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[SH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:2]([CH3:8])([CH3:3])[C:4](=[O:7])[CH2:5][CH3:6])[CH3:15]
Reactant: CCC(=O)C(C)(C)Br
Reactant: CCOC(=O)CS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(C)(C)C(=O)CC
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-2-methyl-pentan-3-one (A1) (13.5 g, 75 mmol) in CH2Cl2 (400 ml) were added ethyl 2-mercaptoacetate (9 g, 8.2 ml, 75 mmol) and 10.42 ml triethylamine at 0° C. and stirred for 3 h. The solution was allowed to come to room temperature (12 h). The resulting suspension was filtered, the filtrate washed with water (100 ml) and brine (100 ml) and dried over Na2SO4. Removal of the solvent in vacuo gave a slightly yellow oil, which was purified by flash chromatography (ethyl acetate-petroleum ether 1:25).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=O)[CH2:6][CH2:7][O:8][CH3:9].CO.[BH3-]C#[N:16].[Na+].C(Cl)Cl>Cl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([NH2:16])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: [BH3-]C#N
Reactant: COCCC(=O)CC(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCC(N)CC(=O)OC
Yield: 101.1 %

Procedure:
Methyl-5-methoxy-3-oxovalerate (10 g, 62.5 mmol) was added to methanol (200 ml) followed by ammonium formats (39.4 g, 620 mmol) and NaBH3CN (3.9 g, 46 mmol) at 25° C. After 24 h the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride dried over Na2SO4 and evaporated to give methyl-5-methoxy-3-aminovalerate (7.5 g). 1H NMR (d6-DMSO) δ 1.25 (m, 3H) 1.66 (m, 2H), 1.86 (bs, 2H), 2.9 (M, 2H), 3.33 (s, 3H), 3.49 (M, 2H), 3.7 (s, 3H); MS (FAB) m/z 161.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1C

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4-dimethylaniline to yield 2-[(3,4-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[O:8].[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[OH:21])#[N:15]>C(#N)C>[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])#[N:15]
Reactant: CCCCOc1cc(O)c(C#N)s1
Reactant: COP(=O)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=O)(OC)OC)c(C#N)s1
Temperature: 20 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
7.7 g of potassium carbonate and 7.7 g of O,O-dimethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in ether. The ether solution was washed with water containing 100 g/l of sodium chloride and then with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride. The ether phase was dried and treated with activated carbon, filtered and concentrated to dryness to obtain 12.5 g of 2-cyano-3-(dimethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.511.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([Cl:19])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CCC=C[C@H]1c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@H]1CCC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 155 mg (1.02 mmol) of 1(R)-phenyl-2(S)-carboxy cyclohex-5-ene (See U.S. Pat. No. 5,750,549, Example 158, Step B) in 3 mL of CH2Cl2 at 0° C. was added oxalyl chloride (100 uL) followed by DMF (1 drop). The reaction was allowed to warm to room temperature. After stirring 1 hour the reaction was concentrated in vacuo, redissolved in CH2Cl2 and concentrated to a yellow solid which was used directly in the next step.
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[N:12][CH:13]=2)=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: COC(=O)COc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a mixture of 0.4 g of an iron powder, 2 ml of acetic acid and 0.2 ml of water was added a solution of 0.393 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxypyrimidine in 1 ml of acetic acid and 2 ml of ethyl acetate dropwise. After completion of the addition, the mixture was stirred for 1 hour at room temperature, for 2 hours at 30-40° C. Water was added to the mixture, then, the mixture was filtrated through Celite, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was subjected to silica gel chromatography to obtain 0.315 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]I)[N:12]=2)=[CH:4][CH:3]=1.S1CCCCS1.[Li]CCCC.[S:28]1[CH2:33][CH2:32][CH2:31][S:30][CH2:29]1.CN1CCCN(C)C1=O>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][CH:29]3[S:30][CH2:31][CH2:32][CH2:33][S:28]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCI
Reactant: C1CSCSC1
Agent: C1CCSSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCC1SCCCS1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
Add a cold (−78° C.) solution of 2-(4-bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-oxazole (See Intermediate 30) (1.05 g, 2.67 mmol) in 15 mL THF to a cold (−78° C.) solution of dithiane anion [Preparation: Add n-BuLi (7.5 mL, 12 mmol, 1.6M in hexanes) to a −20° C. solution of 1,3-dithiane (1.92 g, 15.9 mmol) in 25 mL THF. Stir 20 min at −78° C. and add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 4.03 g, 31.4 mmol).] Stir the reaction mixture at −78° C. for 15 min. Add water and warm to room temperature. Add dichloromethane, and separate the layers. Dry the crude organic extracts over MgSO4, filter and concentrate. Purify on silica gel 0-10% EtOAc/Hexanes to give 2-(4-bromo-phenyl)-4-(2-[1,3]dithian-2-yl-ethyl)-5-methyl-oxazole (0.672 g, 66%). MS (m/e): 384 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CCl)cc1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(C#N)cc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide (0.20 g, 0.63 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added potassium carbonate (0.10 g, 0.69 mmol), followed by the addition of 4-(chloromethyl)benzonitrile (0.11 g, 0.69 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The solvent was concentrated in vacuo to one-fourth, then diluted with ethyl acetate (150 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford the title compound as a colorless solid in 40% yield (0.11 g): mp 176-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.65-7.63 (m, 2H), 7.40-7.24 (m, 7H), 5.88 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.51 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.44 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.0, 155.5, 152.8, 141.1, 137.8, 132.7, 129.0, 128.8, 128.7, 127.8, 118.3, 117.6, 112.1, 47.7, 44.1, 42.0, 17.2; MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH:15](OCC)=[O:16]>C(O)C.O1CCCC1>[OH:16][CH:15]=[C:10]1[C:11](=[O:12])[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC=O
Reactant: Cn1ncc2c1CCCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ncc2c1CCCC(=CO)C2=O

Procedure:
A mixture of 7 grams of 5,6,7,8-tetrahydro-1-methyl4(1H)-cycloheptapyrazolone, 2.3 grams of sodium hydride (97%), 12 ml of ethyl formate, 2 drops of ethanol and 100 ml of tetrahydrofuran was heated at reflux for 3 hours. The mixture was then cooled and partitioned between water and ether. The aqueous layer was washed once with ether and acidified to a pH of 5 with 1 N hydrochloric acid. The white precipitate which formed was separated by filtration and dried to give 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H)-cycloheptapyrazolone as a cream colored powder melting at about 133°-135° C.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][CH:15]=1.Cl>C(OCC)C.CCCCCC>[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([C:12]2[CH:11]=[C:10]3[C:6]([CH:7]=[CH:8][NH:9]3)=[CH:5][CH:4]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(c1ccc(Br)cc1)c1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To hexane washed potassium hydride (0.30 g, 1.5 mmol), suspended in anhydrous diethylether (1.5 mL), was added 5-bromoindole (0.241 g, 1.23 mmol) dissolved in diethyl ether (2.0 mL) at 0° C. After 15 min, the mixture was cooled to −78 ° C. and tert-buthyllithium (1.5 mL, 2.55 mmol), pre-cooled to −78° C., was added via cannula. After 10 min 4-bromo-N-methoxy-N-methylbenzamide (0.30 g, 1.2 mmol) in diethylether (2.0 mL), pre-cooled to −78° C., was added. The reaction mixture was kept at −78° C. for 10 min and then allowed to warm up to room temperature and stirred for another hour. HCl (1M, 5 mL) was added and the mixture stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO4, and the solvent was evaporated. The crude product was purified by flash column chromatography on silica using methylene chloride as the eluent affording 176 mg (48% yield) of the title compound as a pale yellow solid: mp 47-49° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (br s, 1 H), 8.01 (s, 1 H), 7.87 (m, 2 H), 7.72 (m, 2 H), 7.68 (dd, J=8.2 Hz, J=1.4 Hz, 1 H), 7.52 (m, 1 H), 7.35 (s, 1 H), 6.74 (m, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 196.5, 138.0, 135.4, 132.0, 131.9, 131.8, 131.4, 128.5, 127.1, 122.4, 120.8, 114.6, 103.6; MS TSP) m/z 300, 302 (M+1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:11]=[C:12]([N:19]=[C:20]=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].[NH2:24][C:25]([C:28]#[N:29])([CH3:27])[CH3:26]>O1CCCC1>[F:8][C:9]([F:22])([F:23])[C:10]1[CH:11]=[C:12]([N:19]2[C:28](=[NH:29])[C:25]([CH3:27])([CH3:26])[NH:24][C:20]2=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(C)(N)C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=N
Temperature: 20 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
1 ml of triethylamine was added to a mixture of 49.6g of 3-trifluoromethyl-4-nitrophenyl isocyanate in 500 ml of tetrahydrofuran and then 18 g of 2-amino-2-cyanopropane were rapidly added thereto. The mixture was stirred for 72 hours at 20° C and was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 27 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4 -dimethyl-5-imino-imidazoline-2-one melting at 168° C.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11]N(P(N(C)C)(N(C)C)=O)C.CI>O.[Cl-].[Na+].O>[CH2:2]([O:9][NH:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CNOCc1ccccc1

Procedure:
To a stirred solution of O-benzylhydroxyl amine hydrochloride (1.59 g, 10 mmole) in 15 ml of dry HMPA containing dry sodium bicarbonate (3.36 g, 40 mmole) was added methyl iodide (1.5 g, 11 mmole). After 5 hours the resulting mixture was diluted with 30 ml of water and 20 ml of brine and extracted three times with ethyl ether. The extracts were combined, washed, dried and evaporated to produce the crude product as an oil. The oil was chromatographed to afford 800 mg of title C compound, with consistent spectral data.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:7][C:6]=1[C:31]([F:34])([F:33])[F:32])[NH2:4].[CH:35]1([C:38](Cl)=O)[CH2:37][CH2:36]1>N1C=CC=CC=1>[CH:35]1([C:38]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[C:17]([F:19])([F:20])[F:18])=[O:14])=[CH:7][C:6]=3[C:31]([F:32])([F:33])[F:34])[N:4]=2)[CH2:37][CH2:36]1
Reactant: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(-c2noc(C3CC3)n2)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
80 mg (0.16 mmol) of (2E)-3-[4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Stage 1 were initially charged in 2 ml of pyridine, admixed at room temperature with 16.7 mg (0.16 mmol) of cyclopropanecarbonyl chloride and heated under reflux for 18 hours. The pyridine was for the most part distilled off under reduced pressure, and the residue was admixed with water and extracted with ethyl acetate. After drying over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C@@H:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1.[C:13]([O:17][C:18](N=[N+]=[N-])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>O1CCOCC1>[C:13]([O:17][C:18]([N:6]1[CH2:7][CH:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 73.7 %

Procedure:
A stirred mixture of 100 g (510 mmol) of 5, 75.0 mL (540 mmol) of t-butoxycarbonylazide, 150 mL of triethylamine, 500 mL of water and 500 mL of p-dioxane was heated under nitrogen to 50° C. for 15 h. The mixture was reduced in volume by one half on a rotary evaporator and extracted with four 100 mL portions of ether. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to a yellow oil under reduced pressure. Distillation of the oil under reduced pressure gave 97.5 g (69.6%) of 6 was a pale yellow oil: bp 126°-128° C. (0.05 mm); 1H NMR (CDCl3) δ1.27 (t, 3H, J=7 Hz), 1.45 (s, 9H), 1.8-2.4 (m), 3.4-3.7 (m), 4.2 (q, 2H, J=7 Hz), 4.4-4.6 (m); 13CNMR (CDCl3) δ14.2, 28.2, 28.3, 38.2, 39.0, 54.4, 57.7, 58.0, 60.9, 68.7, 69.4, 79.9, 80.1, 153.8, 154.3, 172.7, 173.0; IR (neat) 3450, 1735, 1680 cm-1. [α]D20 -68.3° C. (c=2, EtOH) (lit. [α]D20 -67.8° C. (c=1.75, EtOH).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:28]=[CH:27][C:26]([OH:29])=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[O:10])[CH:7]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CCCCCC.CN(C)C=O>[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:28]=[CH:27][C:26]([O:29][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=2)=[O:10])[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
Sodium hydride (60%; 1.04 g, 26 mmol) was washed with n-hexane, and suspended in N,N-dimethylformamide (100 mL). A solution of N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (Compound No. 81; 8.15 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added dropwise under cooling with ice bath. After the addition was finished, the mixture was stirred at room temperature for 1 hour. A solution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice and water, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate/n-hexane) to give the title compound (5.38 g, 54.1%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2O[C:8]2([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:10][C:9]1[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][N:19]=1
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c(-c2ccccc2)c1-c1ccncc1
Yield: 34.4 %

Procedure:
Using the procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1:1 acetone/hexane). The product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid: m. p. 212-214° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (151 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide (83 mg, 32%) as a white solid: mp 127–128° C.; EI-HRMS m/e calcd for C20H24N2OS (M+) 340.1609, found 340.1611.