Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Temperature: 25 °C

Procedure:
Oxalyl chloride (1 ml) was added dropwise to a solution of methyl sulphoxide (0.82 ml) in anhydrous dichloromethane (4 ml) at -78° C. under a nitrogen atmosphere. A solution of 1-t-butoxycarbonyl-3-hydroxy-2-phenyl piperidine (1.6 g, Example 2c) in anhydrous dichloromethane (10 ml) was added, and the reaction stirred for 1.75 h before triethylamine (4 ml) was added and the reaction allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water, the organic phase washed with brine, dried and evaporated in vacuo to provide 1-t-butoxycarbonyl-2-phenylpiperidin-3-one as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:11][C:4]2[CH:5]=[CH:9][CH:10]=[CH:2][CH:3]=2)=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Yield: 165.7 %

Procedure:
4-Hydroxyphthalic acid (3.50 g, 19.2 mmol) and K2CO3 (23.9 g, 173 mmol) in acetone (100 mL) and water (50 mL) were stirred at rt for 15 min. Benzyl bromide (20.6 mL, 173 mmol) was added and the mixture was heated under reflux for 3 d. Vacuum distillation (45°-50° C./1.1 mm) removed residual benzyl alcohol and the distillation residue was purified by gradient flash chromatography (10-30% ethyl acetate:hexane) to give dibenzyl 4-benzyloxyphthalate (7.20 g, 83%) as a pale yellow oil. TLC Rf 0.65 (25% ethyl acetate:hexane). ##STR413## Step 2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH3:14][N:15]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[CH:17]=[CH:16]1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][N:15]3[CH3:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Cn1ccc2c(N)cccc21
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cccc2c1ccn2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (328 mg, 1.48 mmol) and 1-methyl-1H-indol-4-amine (260 mg, 1.78 mmol) in CH3CN (6 mL) at room temperature, DIEA (0.4 mL, 2.22 mmol) was added. The mixture was stirred at room temperature for 24 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxylate as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 90.6 %

Procedure:
Palladium on BaSO4 (5%, 4.0 g) was added to a degassed solution of the benzyl hydroxamate 7 (4.6 g) in MeOH (200 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 8 (3.5 g, 93%). 1H NMR (DMSO-d6): 10.37 (s, 1H), 8.71 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.54 (ddd, J=14.8, 8.8, and 6.0 Hz, 1H), 2.91 (s, 3H), 2.70-2.87 (m, 7H), 2.24 (t, J=7.2 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C@@H:10]2[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:27]1([CH2:26][O:25][CH2:24][C@H:14]2[O:13][C@H:10]([CH2:11][OH:12])[C@@H:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@@H:15]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart E, 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 is reacted with lithium aluminum hydride in ether at reflux temperature under argon, giving 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-mannitol 38. Compound 38 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 2,5-anhydro-D-mannitol 39, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving the product of Formula I where R', R",R'" and R"" are phenyl, 2,5-anhydro-D-mannitol, 1,6-bis(diphenyl phosphate) 40. Compound 40 is hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R",R'" and R"" are hydrogen, 2,5-anhydro-D-mannitol, 1,6-bis(dihydrogen phosphate) 41. Compounds 40 and 41 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. Substituting other phosphorylating agents in the reaction from 39 to 40, as described in Flowchart A, will result in the corresponding tetraesters and mixed tetraesters. ##STR18##
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][O:44]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:32][C@H:10]2[CH2:11][O:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][OH:44])[O:32][C@H:10]2[CH2:11][OH:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: OC[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart C, 2,5-anhydro-D-glucitol 19 is reacted with trityl chloride in pyridine, giving 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol 20, which is then reacted with sodium hydride and benzyl bromide in dimethylformamide, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-1,6-bis-O-(triphenylmethyl)-D-glucitol 21. Compound 21 is then reacted with acetic acid at about 80° C., giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol 22, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-bis(diphenyl phosphate) 23. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 23 is then hydrogenated in methanol/acetic acid over palladium on carbon, giving the product of Formula I where R', R", R'" and R"are phenyl, 2,5-anhydro-D-glucitol, 1,6-bis(diphenyl phosphate) 24. which may then be hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R", R'" and R"" are hydrogen, 2,5-anhydro-D-glucitol, 1,6-bis(dihydrogen phosphate) 25. Compounds 24 and 25 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. ##STR16##
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][C:37](O)=[O:38])=[N:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][C:37]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:38])=[N:28]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (107 mg, 88%), MS (ISP) m/z=488.4 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([O:12]C)=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:3]=1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([OH:12])=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:3]=1
Reactant: COCOCc1nc(N)c2ncc(OC)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCOCc1nc(N)c2ncc(O)nc2n1
Temperature: 80 °C

Procedure:
8.1 g (0.0322 mole) of 4-amino-7-methoxy-2-(methoxymethoxymethyl)pteridine are added to a solution of 3.2 g (0.080 mole) of sodium hydroxide in 130 ml of water. The suspension obtained is heated at 80° C. for 2 hours. After filtration while hot, the solution is allowed to return to room temperature and is then acidified with acetic acid. The precipitate formed is isolated by filtration. It is purified by washing with water and then with acetone and is recrystallized from a mixture of methanol and N,N-dimethylformamide. Yld: 4.4 g (58%), m.p. 210°-212° C.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][N:8]([C:10](=[O:12])[CH3:11])[CH2:7][N:6]1[C:13](=[O:23])[CH:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:4].[Li+].[OH-].Cl.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.Cl.[NH2:61][CH2:62][C:63]([C:65]1[CH:70]=[CH:69][C:68]([Br:71])=[CH:67][CH:66]=1)=[O:64]>C1COCC1.CO>[CH3:22][O:21][C:19](=[O:20])[NH:18][CH:14]([C:13]([N:6]1[CH:5]([C:3](=[O:4])[NH:61][CH2:62][C:63]([C:65]2[CH:70]=[CH:69][C:68]([Br:71])=[CH:67][CH:66]=2)=[O:64])[CH2:9][N:8]([C:10](=[O:12])[CH3:11])[CH2:7]1)=[O:23])[CH:15]([CH3:16])[CH3:17]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)OC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester (273 mg, 0.829 mmol) was dissolved in THF (1.8 mL) and MeOH (1.2 mL). An aqueous solution of LiOH (34.8 mg, 0.829 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCl (0.83 mL, 1M). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (3 mL) and HATU (315 mg, 0.829 mmol) and DIEA (106 mg, 0.829 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4′ bromo) acetophenone hydrochloride salt (207 mg, 0.829 mmol) was added. Stirring at room temperature was continued. After 120 minutes, all volatiles were removed in vacuo and the crude material was dissolved in DCM. The organic layer was washed with aqueous HCl (0.5 M), aqueous lithium chloride solution (5%), brine and was dried over sodium sulfate. Filtration and evaporation of solvents yielded crude product which was purified via silica gel chromatography (eluent EtOAc/hexanes) to yield the product (1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol): LCMS-ESI+: calc'd for C21H27BrN4O6: 511.4 (M+). Found: 511.3/513.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.CC(C)([O-])C.[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.C1(C)C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COC(=O)C1CCNCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 130 °C
Yield: 46.1 %

Procedure:
Methyl piperidine-4-carboxylate (2.0 g, 14 mmol), 1-bromo-3-(trifluoromethyl)benzene (1.5 g, 6.8 mmol), and potassium tert-butoxide (0.76 g, 6.8 mmol) in a mixed solvent of toluene (20 mL) and DMF (4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.3 g, 0.4 mmol) under nitrogen. The mixture was heated at 130° C. in an oil bath overnight. After cooling to room temperature, the mixture was filtered through celite and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed with EtOAc/hexanes (20% to 40%) to give 0.90 g of product. MS (M+H) 288.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH:3]=[C:4]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1)[C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1>CO.O1CCCC1.[Pd]>[CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1)[C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1
Reactant: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
A solution of 1-(3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (0.85 g, 2.8 mmol) in methanol (20 mL) and tetrahydrofuran (30 mL) was treated with 10% palladium on carbon (300 mg). The reaction was stirred for 16 h at 25° C. under hydrogen atmosphere. At this time, the reaction mixture was filtered. The filtrate was concentrated in vacuo. Silica gel column chromatography (20 g, 200-300 mesh, 10% ethyl acetate/petroleum ether) afforded 1-{3-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-butyl]-phenyl}-ethanone (0.50 g, 58.3%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.63 (s, 1H), 8.09 (d, 1H, J=3.6 Hz), 7.96 (s, 1H), 7.81 (d, 2H, J=7.5 Hz), 7.66 (d, 1H, J=7.5 Hz), 7.46 (t, 1H, J=7.5 Hz), 6.98 (dd, 1H, J1=4.5 Hz, J2=8.1 Hz), 6.31 (s, 1H), 4.30 (t, 1H, J=8.1 Hz), 2.57 (s, 3H), 2.17-2.10 (m, 1H), 1.91-1.86 (m, 1H), 1.41-1.39 (m, 1H), 0.92 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH3:41]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:41])[CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:38])[F:39]
Reactant: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)c2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cc(Cc2cn(C)c3ccccc23)c(=O)nc1SCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-[({5-[(1-methyl-1H-indol-3-yl)methyl]-4-oxo-1,4-dihydro-2-pyrimidinyl}thio)methyl]benzonitrile (60 mg, 0.103 mmol), DIPEA (0.054 mL, 0.310 mmol) and zinc bromide (23.26 mg, 0.103 mmol) in chloroform (2 mL) was added MeI (0.013 mL, 0.207 mmol). The mixture was heated at 60° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (8.3 mg, 13.51% yield). LCMS: rt=3.78 min, [M+H+]=595
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:28]([C:31]1[C:32]([CH:37]=O)=[N:33][CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:37][C:32]2[C:31]([CH:28]([CH3:30])[CH3:29])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)c1cccnc1C=O
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)C)c2)cc1

Procedure:
Using General Procedure B: Reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine and 3-isopropyl-pyridine-2-carbaldehyde in CH2Cl2 (5 mL) with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine. 1H NMR (CDCl3) δ 0.91 (d, 6H, J=6.51 Hz), 2.04 (s, 3H), 2.24 (s, 1H), 2.26 (s, 3H), 2.41 (s, 3H), 2.71 (m, 2H), 2.82 (m, 2H), 3.75 (d, 4H, J=4.50 Hz), 6.63 (s, 1H), 7.14 (q, 1H, J=4.25 Hz), 7.22 (s, 1H), 7.30 (d, 2H, 7.86 Hz), 7.49 (d, 1H, J=7.0 Hz), 7.70 (d, 2H, J=8.40 Hz), 7.80 (s, 1H), 8.19 (s, 1H), 8.32 (d, 1H, J=4.19 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:5])C.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:11][O:10][CH2:9][CH2:8][CH2:7][O:16][C:14]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:15]=1
Reactant: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)O)cc2c1OCCO2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The mixture of 8-hydroxy-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (1.85 g, 6.24 mmol) in dioxane (10 mL) and 2N NaOH (5.0 mL) is stirred at 60° C. over 1 h, then cooled to room temperature and acidified (pH 1) with 2N HCl. Volatiles are removed under reduced pressure to afford a suspension. The precipitate is filtered, washed with ice-water and dried in vacuo overnight to give the title product as white solid. TLC, Rf (hexane/AcOEt 2:1+1% AcOH)=0.07. MS: 267.0 [M−H]+. 1H-NMR (DMSO-d6): δ 1.96 (m, 2H), 3.26 (s, 3H), 3.48 (m, 2H), 4.05 (m, 2H), 4.27 (m, 2H), 4.31 (m, 2H), 7.07 (d, 1H9, 7.11 (d, 1H), 12.8 (s, br, 1H) ppm.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
A 100 ml round bottom flask was loaded with Fluvastatin methyl ester (3.0 g, 7.08 mmole), water (30 ml) and NaOH (0.29 g). The mixture was stirred for 3 h at room temperature then extracted with ethyl acetate (30 ml). The aqueous solution was evaporated, acetonitrile (12 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile (20 ml) and dried at 40EC in a vacuum oven for 24 h to obtain 0.37 g (12%) of fluvastatin sodium crystal Form LXXVIII.
Reaction SMILES: [C:1]12([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([NH:15][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:17]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mL of THF was added to 400 mg (1.76 mmol) of 4-(adamantan-1-yl)aniline, after which 292 mg (2.11 mmol) of potassium carbonate was added. 291 mg (1.94 mmol) of ethyl chloroglyoxylate was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was filtered using silica gel, and the filtrate was condensed. The obtained crude product was then separated and purified by silica gel column chromatography, thereby quantitatively giving ethyl {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]([OH:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g (0.062 mole) of 4-[5-(4-bromophenyl)-2-furanyl]-4-oxobutanoic acid in 350 ml of 95% dioxane/water was treated portionwise with 5.9 g (0.155 mole) of NaBH4 while maintaining the temperature at 15°-20° by means of an ice bath. The reaction was stirred at ambient temperature for 1 1/2 hrs and then filtered. The filtrate was added to ice/H2O and made acidic with 20% hydrochloric acid. The resulting solid was filtered, dissolved in ethyl acetate (Darco) and refiltered. The filtrate solid was filtered, dissolved in ethyl acetate (Darco) and refiltered. The filtrate was treated with hexane and the resulting solid filtered and air-dried to yield 8 g (40%).