Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:55][C@@H:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:58][C@@H:57]1[OH:69].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:62]([N:59]1[CH2:60][CH2:61][C@@H:56]([NH:55][C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:13](=[O:14])[C:12]3[CH:29]=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:37][CH2:38]4)=[CH:32][C:11]=3[O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)(=[O:17])=[O:18])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])[C@@H:57]([OH:69])[CH2:58]1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@@H]1O
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@@H]5CCN(Cc6ccccc6)C[C@@H]5O)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of EXAMPLE 187A (0.158 g), (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049 g), and triethylamine (0.1 mL) in dioxane (2 mL) was heated at 100° C. overnight. The solvent was removed, and the residue was re-dissolved in 1:1 methanol:dimethylsulfoxide (3 mL). It was then purified by reverse phase Prep HPLC. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 20-80% acetonitrile/0.1% TFA in water. The desired fractions were collected, and the organic solvent was partially removed under reduced pressure. The resulting mixture was treated with saturated aqueous NaHCO3 mixture. It was then extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give the desired product. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.77 (dd, 1H), 7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13 (m, 1H), 7.13 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 5.21-5.22 (br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (br s, 4H), 2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (br s, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][N:16]=1>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: OB(O)c1cncc2ccccc12
Product: c1ccc(-c2ccc(Cc3cncc4ccccc34)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (109 mg, 0.44 mmol) and isoquinolin-4-ylboronic acid (114 mg, 0.66 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 20 mg, 19%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.43 (s, 2H), 7.37-7.54 (m, 4H), 7.59-7.65 (m, 2H), 7.65-7.75 (m, 1H), 7.89-8.07 (m, 4H), 8.48 (s, 1H), 8.65-8.70 (m, 1H), 9.23 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.2, 120.3, 123.1, 126.7, 127.2, 128.4, 128.6, 128.6, 128.7, 128.9, 130.7, 133.6, 134.6, 136.7, 139.0, 143.7, 149.7, 152.3, 155.7; (ESI): m/z=296.95 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2O)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: OC1CCc2ccc(Br)cc21
Product: Brc1ccc2c(c1)C(N1CCCC1)CC2
Yield: 52.7 %

Procedure:
6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with pyrrolidine (1.16 mL, 14 mmol) to yield the title compound (0.195 g, 52%). 1H NMR (CDCl3): 7.4 (s, 1H), 7.25 (d, 1H), 7.0 (d, 1H), 4.1 (t, 1H), 2.9 (m, 1H), 2.6 (m, 1H), 2.55 (m, 4H), 2.1 (m, 2H), 1.7 (brs, 4H).
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].[K+].O>CN(C=O)C.[Cu]I>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:26]([F:28])([F:27])[F:25])[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2cc(C(F)(F)F)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 19.9 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (1.84 g), (trifluoromethyl)trimethylsilane (1.14 g), copper(I) iodide (1.52 g), potassium fluoride (0.28 g) were stirred in DMF (8 ml) at 100° C. for 8 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous solution of sodium chloride. After drying the organic layer with sodium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitro-benzyl)-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (0.32 g).
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[NH:6]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[NH2:7].OCC[N+](C)(C)C>C(O)C>[NH2:5][C:1]1[CH2:2][CH:3]([CH3:4])[N:6]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[N:7]=1
Reactant: C/C=C/C#N
Reactant: NNc1nc2ccccc2s1
Agent: C[N+](C)(C)CCO
Solvent: CCO
Product: CC1CC(N)=NN1c1nc2ccccc2s1

Procedure:
A mixture of 20.1 g. of crotononitrile, 80 ml. of absolute ethanol, 4.87 g. of 2-hydrazinobenzothiazole and 1.5 ml. of 50% methanolic choline is refluxed for 16 hours. The solvent is removed in vacuo and water is added. The separated solid is collected by filtration, dissolved in dichloromethane, and passed through a short column of hydrous magnesium silicate. The effluent is refluxed with the gradual addition of hexane to give a crystalline product. The crystallization step is repeated to give 0.5 g. of the product of the Example as off-white plates, m.p. 212°-215° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(COC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCC(COC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
2-{2-[4-(1,1-Diphenyl-methoxymethyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (0.95 g, 2.1 mmol) was dissolved in ethanol (5 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×20 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product 2-[4-(1,1-diphenyl-methoxymethyl)-piperidin-1-yl]-ethylamine was obtained (0.335 g, 49.4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH3:11].Cl.[N:13]([O-])=O.[Na+].[Sn](Cl)Cl>C(O)C>[NH:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH3:11])[NH2:13]
Reactant: CSc1cc(C#N)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(C#N)ccc1NN
Yield: 74.4 %

Procedure:
To a solution of 4-amino-3-(methylthio)benzonitrile (71.1 mg) and 5N aqueous hydrochloric acid (2.0 ml)/ethanol (0.5 ml) was added under ice cooling sodium nitrite (32.5 mg) and the resulting mixture was stirred for one and a half hours. To the reaction mixture was added tin(II) chloride (101.4 mg) and the resulting mixture was stirred at 0° C. for two and a half hours. The reaction mixture was filtered, and the mother liquor was basified (pH=about 10) with potassium carbonate and extracted with chloroform (30 ml) three times, and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure to afford 4-hydrazinyl-3-(methylthio)benzonitrile (57.7 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C1COCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]3([OH:29])[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a stirred suspension of 1.54 mmol 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole in 3 ml THF at −78° C. was added dropwise 3.85 mmol butyllithium solution (1.6 M in hexane) and stirring continued at −78° C. for 1 h. To the resulting yellow solution was added dropwise a solution of 3.08 mmol tetrahydro-4H-pyran-4-one in 0.7 ml THF and the mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction was quenched by addition of 1 M aq HCl, diluted with ethyl acetate, and then made basic by addition of 2 M aq NaOH. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid (25% yield). MS (m/e): 310.3 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH2:14])[CH:6]=[CH:7][CH:8]=1.CN1[CH:23]=[CH:22][C:21](=[O:24])N(C)C1=O.[O-]CC.[Na+]>C(O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][N:12]3[CH:23]=[CH:22][C:21](=[O:24])[NH:14][C:13]=23)[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: Nc1[nH]ncc1-c1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccn2ncc(-c3cccc(C(F)(F)F)c3)c2[nH]1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a mixture of 4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (2.7 g, 11.88 mmol) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.999 g, 14.26 mmol) in ethanol (35 ml) was added sodium ethoxide (1.132 g, 16.64 mmol). After heating to reflux 16 hours under Agonr, the reaction was cooled to RT and the volatiles removed in vacuo. The mixture was diluted with 30 mL H2O and acidified to pH=4 with AcOH. The resulting solid was collected by vacuum filtration. The solid was taken up in a 4:1 DCM/2-propanol solution, washed with water, dried over Na2SO4, and rotovaced to give pure 3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (2.07 g, 7.41 mmol, 62.4% yield).
Reaction SMILES: [F:1][C:2]1[C:3](/[CH:8]=[N:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C@H:29]1[C@@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:30]1=[O:31])(=[O:27])[CH3:26]
Reactant: COc1ccc(/N=C/c2ncccc2F)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A solution (2.29 l) of N-[(E)-(3-fluoro-2-pyridyl)methylidene]-4-methoxyaniline (449 g) and triethylamine (204 g) in dichloromethane was cooled to −10° C. Then acetoxyacetyl chloride (250 g) was added dropwise thereinto and the resultant mixture was stirred at the same temperature for 30 minutes. Then it was heated to room temperature and stirred for 16 hours. The liquid reaction mixture was washed with water and the solvent was concentrated under reduced pressure to thereby give a crude product (723 g). This crude product was recrystallized from a solvent mixture of ethanol (6.9 l) and ethyl acetate (350 ml) to thereby give the title compound (486 g) as brown crystals.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:38]3[CH:39]=[C:40]([C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])[CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 30 mg; 0.049 mmol) was treated with 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (intermediate 26; 20 mg; 0.065 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (3.2 mg; 0.0049 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(2-hydroxy-1,1-dimethylethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=664.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.80 (m, 2H), 7.76 (s, 1H), 7.67-7.61 (m, 2H), 7.41-7.37 (m, 2H), 7.21 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.38 (d, J=15.5 Hz, 1H), 4.95 (d, J=11 Hz, 1H), 4.09 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.65-3.63 (m, 1H), 3.58-3.55 (m, 1H), 3.41-3.35 (m, 1H), 2.25-2.20 (m, 1H), 1.80-1.72 (m, 1H), 1.28-1.25 (m, 6H), 1.07-1.03 (m, 3H).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:58])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[N:45]=[C:46]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[O:47][C:48]=3[CH3:49])=[C:38]([O:56][CH3:57])[CH:37]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:57][O:56][C:38]1[CH:37]=[C:36]([CH2:35][C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=2)=[O:58])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:47][C:48]=1[CH3:49]
Reactant: COc1cc(CC(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (357 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 54 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-2-{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetamide (590 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-{3-[({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (159 mg, yield 21%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8]P(=O)([O-])[O-])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][O:18][C:19]1[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1.O>O1CCCC1>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][O:16][CH3:15])=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCc1nc(CP(=O)([O-])[O-])co1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCOC)co1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of diethyl ([(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate (2.97 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-3:7, v/v) to give 2-ethyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.24 g, yield 7.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([CH2:8][O:9]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([CH2:8][OH:9])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Agent: [Pd]
Product: CCOC(=O)CC(=O)CO
Reaction time: 2 h
Yield: 102 %

Procedure:
21.24 g of the 4-benzyloxyacetoacetic ethyl ester dissolved in acetic ester (100 ml) was inserted into a 200 ml steel autoclave provided with a magnetic stirrer and was hydrogenolized in the presence of 1.05 g Pd 5 percent on coal with hydrogen with a pressure of 5 atm. After the reaction was completed, which amounted to a period of about 2 hours, and after a 2 hour post-reaction time, the catalyst was filtered out. The filtrate was evaporated on a vacuum rotation evaporator at 35° C. The residue was dried in the high vacuum. 13.4 g of 4-hydroxyacetoacetic ethyl ester in the form of a slightly yellowish oil resulted.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:19][CH2:18][NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2[C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CCNC1CCCCCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 17 (0.1 mol.) is added to a mixture of dichloromethane (200 ml.), triethylamine (0.11 mol.) and benzyloxycarbonyl chloride. The mixture is stirred for 2 hours at room temperature, washed with 5% potassium bisulfate, water, dried, and concentrated to dryness. The residue, 3-(t-butoxycarbonyl)-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester is dissolved in trifluoroacetic acid and the solution stored at room temperature for 1 hour. The solution is concentrated to dryness in vacuo yielding 3-carboxy-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)C.[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCC1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCC2
Yield: 73 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 73%; IR (KBr) cm−1: 3349, 3236, 3130, 1590, 1549, 1431, 1414, 1269, 975; 1H NMR (CDCl3):δ 2.285 (m, 2H), 2.51 (t, 2H, J=7.4 Hz), 2.70 (t, 2H, J=7.4 Hz), 6.64 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); red solid, mp: 154–156° C. (petroleum ether).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.Cl>C1C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH:9]([Cl:15])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)C1CCC(=O)C(Cl)C1

Procedure:
The compound 4-t-butylcyclohexanone, 154.3 grams, is dissolved in one liter of benzene to which a trace of ferric chloride is added. The mixture is heated and 148.5 grams of sulfuryl chloride is added dropwise in periodic increments. The reaction mixture is slowly heated to its reflux temperature and maintained at that temperature until no further evolution of hydrochloric acid is observed. The solvent is removed in vacuo and the residue dissolved in a small amount of heptane. The solution is passed through an alumina column and the eluate removed by evaporation under reduced presssure to yield 167.6 grams of crude 4-t-butyl-2-chlorocyclohexanone.