Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.Cl.[NH2:18][OH:19]>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13](=[N:18][OH:19])[NH2:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
Triethylamine (68 mL, 498 mmol) was added to a solution of 6-chloronicotinonitrile (30.0 g, 217 mmol), hydroxylamine hydrochloride (33.0 g, 476 mmol) and ethanol (325 mL) and stirred for 12 hours at 75° C. The reaction mixture was cooled to room temperature, quenched with H2O (400 mL) and the partially concentrated in vacuo. The resulting slurry was filtered and dried to provide the title compound as a crude white solid (37.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25]>CC#N>[CH2:27]([N:26]([CH2:29][CH3:30])[C:24](=[O:25])[CH2:23][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=2[N:6]=[CH:7]1)[CH3:28]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)OC)c(C)c2c1=O
Yield: 97.8 %

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (2.24 g, 10 mmol) in CH3CN (20 mL) was added K2CO3 (1.38 g, 10 mmol), KI (1.61 g, 10 mmol), and 2-chloro-N,N-diethylacetamide (1.4 mL, 10 mmol). The reaction mixture was refluxed overnight and quenched with H2O (50 mL). The resulting precipitate was filtered and dried to afford 3.3 g of methyl 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate as a solid (yield: quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[OH-].[K+].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1.CO>[N+:17]([CH2:20][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:13]=1)[OH:12])([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a cooled (0° C.) solution consisting of 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) in THF (5 mL) and NO2CH3 (0.3 mL) and MeOH (2.5 mL) was added KOH (2.5 M, 1.13 mL). The reaction mixture was stirred at 0° C. for 30 min. and then quenched with a saturated NH4Cl solution. The aqueous mixture was extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (257 mg, 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:26])[C:10]=1[C:11](=[O:25])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]([CH3:24])[CH3:23])[N:21]=2)[CH:18]=1)=[O:5])C.CN1C(C(=O)NC2C=CC3N(N=C(N4CCOCC4)N=3)C=2)=C(C(O)=O)C=N1>>[CH3:23][N:22]([CH3:24])[C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:11]([C:10]3[N:9]([CH3:26])[N:8]=[CH:7][C:6]=3[C:4]([OH:5])=[O:3])=[O:25])=[CH:18][N:17]2[N:19]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N(C)C)nn2c1
Agent: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1

Procedure:
Using 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, this compound was prepared following the same method as for the synthesis of 1-Methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid. Brown solid (41 mg, 70%). MS: m/z=330 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH2:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: [H][H]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (14 mg) in ethyl acetate (400 μl) was added rhodium on carbon (4 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was removed in vacuo. Purification by flash chromatography (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg). partial 1H NMR d: 7.17 (s, 1H); 7.15 (d, J=9 Hz, 1H); 6.97 (d, J=3 Hz, 1H); 6.92 (dd, J=9, 3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.56 (brd, J=4 Hz, 1H); 4.40 (brd, J= 14 Hz, 1H); 3.71 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:7]=2[OH:6])[CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(OC)ccc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(O)c(C(=O)Nc2cc(-c3ccco3)ccc2C(=O)O)c1
Temperature: 52.5 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Dioxane (2.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.22 mL) were added to the obtained methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(furan-2-yl)benzoate (0.073 g), followed by stirring at 50 to 55° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid (6 mL) was added thereto. The solid substance was collected by filtration to obtain 0.062 g of 4-(furan-2-yl)-2-(2-hydroxy-5-methoxybenzamido)benzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH2:26]([C:28](B1OC2C=CC=CC=2O1)=[CH:29][CH2:30][CH3:31])[CH3:27]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:28]([CH2:26][CH3:27])=[CH:29][CH2:30][CH3:31])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: CCC=C(CC)B1Oc2ccccc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 146.8 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.89 mmol) and 2-(1-Ethyl-but-1-enyl)-benzo[1,3,2]dioxaborole (709 μL, 3.56 mmol) in dioxane (15 mL) is added Pd(PPh3)4 (103 mg, 8.9% mmol) and 2M aqueous solution of CsCO3 (1.34 mL, 2.67 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 2 h. After concentration in vacuo, the residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (128) as a brown semi-solid (530 mg, 73%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:25].Cl.[NH+]1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:25]
Reactant: COc1cccc(-c2ccc3c(-c4cccc(C(=O)NS(C)(=O)=O)c4)c(OC)ccc3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: CS(=O)(=O)NC(=O)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Yield: 42 %

Procedure:
The compound was prepared by refluxing 3-(2-methoxy-6-(3-methoxyphenyl)-naphthalene-1-yl)-N-(methylsulfonyl)benzamide (80 mg, 0.17 mmol, 1 eq) with pyridinium hydrochloride (302 mg, 15 eq) for two hours. After cooling, 2 ml of 1 N HCl was added, and the water phase was extracted with ethyl acetate. The organic phase was dried and concentrated in vacuum. After purification by column chromatography with 10% methanol in dichloromethane, the desired compound was obtained in 42% yield, 31 mg.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][O-:20].[Na+]>S1(CCCC1)(=O)=O.O>[CH3:19][O:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 100 °C
Yield: 78.9 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 1.5 ml sulfolane was added g sodium methylate (0.55, 1.0 mmol). The reaction mixture was heated for 10 min at 100° C. under microwave irradiation. The reaction mixture was diluted with water and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with two portions of water, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.043 g, 79%) as an off-white solid, MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH3:22])=[N:10][C:9]=1[OH:23].[C:29](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CCOCC>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH3:22])=[N:10][C:9]=1[O:23][CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cc2c(O)nc(C)c3cc(OC)c(OC)cc23)cc1OC
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1ccc(Cc2c(OC)nc(C)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 90 °C
Reaction time: 0.37 h
Yield: 53.1 %

Procedure:
A mixture of 4-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol (compound 2 free base, 60 mg, 162 μmol), cesium carbonate (70 mg, 215 μmol) and iodomethane (13 μL, 208 μmol) in dry DMF (2 mL) in a 5 mL microwave vial equipped with a magnetic stirrer was stirred at 90° C. for 22 min under microwave irradiation. After cooling to RT, the mixture was diluted with Et2O (50 mL) before washing with water (10 mL) then with brine (10 mL), drying over Na2SO4, filtration and concentration at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 4-(3,4-dimethoxybenzyl)-3,6,7-trimethoxy-1-methylisoquinoline as a colorless oil (33 mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (1.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum. The solid was then washed with Et2O to afford, after drying, 4-(3,4-dimethoxybenzyl)-3,6,7-trimethoxy-1-methylisoquinoline hydrochloride 3 as a pale brown solid (23 mg, 34% yield).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH3:9][S:10][CH2:11]Cl.C(N(CC)CC)C>>[CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([O:5][CH2:9][S:10][CH3:11])=[O:4]
Reactant: CCC=C(C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCC=C(C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-methyl-2-pentenoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 56°-57° C./2 mm Hg, n20 1.4861.
Reaction SMILES: C([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][CH:16]1[O:18][CH2:17]1)C1C=CC=CC=1.[Li+].[OH-].O>CO>[CH2:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:19])=[O:8])[CH:16]1[O:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1CC1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1CC1CO1

Procedure:
N-Glycidyl-L-proline is prepared from compound 120 by hydrolyzing the benzyl ester with LiOH/H2O in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][C:21](=[O:38])[CH:22](OS(C(F)(F)F)(=O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCCCCC>CC(C)=O.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:38])[CH:22]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 5 h

Procedure:
To 5-nitro-1H-indole (5.18 g, 31.93 mmol) in acetone (200 ml) at ambient temperature under a nitrogen atmosphere was added cesium carbonate (21.80 g, 67.06 mmol) followed by 3-phenyl-2-trifluoromethanesulfonyloxy-propionic acid methyl ester (10.96 g, 35.13 mmol). The resulting dark red mixture was stirred for 5 hours, concentrated in vacuo to a brown powder which was then partitioned between H2O (100 ml) and EtOAc (300 ml). All organics were combined, extracted with brine (250 ml), dried with MgSO4, filtered, and concentrated in vacuo. Gradient SiO2 chromatography (Hexane:EtOAc) afforded 2-(5-nitro-indol-1-yl)-3-phenyl-propionic acid methyl ester as an opaque syrup (5.91 g, 57% yield): MS (ESI) m/z 325, MS (ESI) m/z 323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][P:15](=[O:19])([CH3:18])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][P:15]([CH3:18])(=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a pressure vessel was added 1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide (272 mg, 0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The vessel was connected to a Parr apparatus, evacuated, and refilled with nitrogen. The vessel was then evacuated and filled with hydrogen gas to a pressure of 50 psi. The reaction mixture was shaken under 50 psi for 4 h. The mixture was filtered through Celite to a flask containing HCl in ethanol. Concentration of the filtrate afforded 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a gray solid (211 mg, 87% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCC(C)CC=NO

Procedure:
3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alchohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyloct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10% solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102-103/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.
Reaction SMILES: C[C@@](O)(CC([S:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][NH:18][C:19]([C@H:21]([OH:57])[C:22]([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][C@H:36]1[O:40][C@@H:39]([N:41]2[C:45]3[N:46]=[CH:47][N:48]=[C:49]([NH2:50])[C:44]=3[N:43]=[CH:42]2)[C@H:38]([OH:51])[C@@H:37]1[O:52][P:53]([OH:56])([OH:55])=[O:54])([OH:33])=[O:32])([OH:29])=[O:28])([CH3:24])[CH3:23])=[O:20])=[O:15])=O)CC(O)=O.C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.SC[C@H]([C@@H](CS)O)O.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)CC(C)=O.Cl>CS(C)=O>[CH3:24][C:22]([C@@H:21]([OH:57])[C:19]([NH:18][CH2:17][CH2:16][C:14]([NH:13][CH2:12][CH2:11][SH:10])=[O:15])=[O:20])([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][C@H:36]1[O:40][C@@H:39]([N:41]2[C:45]3[N:46]=[CH:47][N:48]=[C:49]([NH2:50])[C:44]=3[N:43]=[CH:42]2)[C@H:38]([OH:51])[C@@H:37]1[O:52][P:53]([OH:56])([OH:55])=[O:54])([OH:33])=[O:32])([OH:29])=[O:28])[CH3:23]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](C)(O)CC(=O)O
Agent: CC(=O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CS(C)=O
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Reaction time: 0.08 h

Procedure:
Intrinsic activity of HMG-CoA synthase is measured in the following in vitro assay. Enzyme protein (ca. 12.2 μg) is added to a solution containing 117 mM Tris-HCl (pH 8.0), 11.7 mM MgCl2, 1.17 mM Ethylenediaminetetraacetic acid (EDTA), 0.58 mM dithiothreitol, in the presence or absence of the test compound (added as, e.g., a 2 μg/ml solution in dimethylsulfoxide). The incubation is in a volume of 0.085 ml at 30° C. in a shaking water bath. After 5 minutes, 15 μl of a solution containing acetoacetyl-CoA and 0.1 μCi of 1[14C]-acetyl-CoA is added to give final concentrations of 0.1 and 0.4 mM, respectively. The incubation is continued for 2 more minutes and the reaction stopped by the addition of 50 μl of the assay mixture to 0.2 ml of 6N HCl in a glass scintillation vial. The vial is heated for 1 hour at 110° C. after which time 0.2 ml more of 6N HCl is again added to each vial and the heating continued for another hour. Following this, 1.0 ml of 0.9% saline is added to each vial and finally 10 ml of scintillation liquid. Radioactivity is determined in a Packard Tri-Carb liquid scintillation counter. Percent inhibition is calculated a standard formula. IC50 values are determined by plotting the log of the concentration of the test compound verses the percentage inhibition and fitting a straight line to the resulting data by using the least squares method.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cn2)CC1
Yield: 86.1 %

Procedure:
Stir a mixture of 4-(5-Nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (2.7 g, 8.35 mmol) and 10% palladium on carbon (0.5 g) in ethanol (100 mL) at room temperature under hydrogen for 4 hours. Filter to remove palladium catalyst. Concentrate the filtrate and subject the resultant colorless oil to silica gel chromatography eluting with hexanes and ethyl acetate to give the title compound as a white solid (2.11 g, 86% (ES+(m/z) 194.2 [M+H—BOC]).
Reaction SMILES: [CH2:1]([Si:11]([CH3:14])([CH3:13])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CN(C)C=O.C(Cl)([Cl:22])=O>ClCCCl>[CH2:1]([Si:11]([CH3:14])([CH3:13])[Cl:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC[Si](C)(C)O
Reactant: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCC[Si](C)(C)Cl
Yield: 88 %

Procedure:
To the same reactor as used in Example 1 were added 54.1 g (0.25 mole) of decyldimethylsilanol, 215 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 51.7 g of decyldimethylchlorosilane.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[C:4]([F:15])[CH:3]=1.[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11]3([O:18][CH2:17][CH2:16][O:14]3)[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: OCCO
Reactant: O=C1CCC(c2cc(F)c(Br)cc2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(C2CCC3(C2)OCCO3)c(F)cc1Br
Yield: 88.4 %

Procedure:
A solution of 27.5 g (0.1 mol) of 3-(4-bromo-2,5-difluorophenyl)cyclopentanone, 18.6 g (0.3 mol) of ethylene glycol, 1 g of p-toluenesulfonic acid and 500 ml of toluene was heated at reflux with a Dean-Stark trap for 18 hours. The cooled solution was washed with 5% sodium bicarbonate solution (2×250 ml), dried (MgSO4), and evaporated in vacuo to give 28.2 g of the title compound which was used without further purification.