Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1([Mg]Br)CCCC1.[Si:14]([O:21][CH2:22][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24]O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOCC>[Si:14]([O:21][CH2:22][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: BrC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CO[Si](C)(C)C(C)(C)C
Agent: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC1CCCC1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A 100 mL, three-neck round bottom flask was charged with Mg powder (720 mg, 30 mmol), then a solution of cyclopentylbromide (3.73 g, 25 mmol) in THF (25 mL) was added dropwise while a heat gun heated the flask. After stirring for 2 h, most of the Mg was consumed. The cyclopentylmagnesium bromide was added to a suspension of CuBr—SMe2 (307.5 mg, 1.5 mmol) in THF (80 mL) at −78° C., the cuprate was stirred for 30 min and a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-hydroxypropan-2-ylcarbamate (2.87 g, 10 mmol) in Et2O (30 mL) was added. After stirring for 2 h, the reaction mixture was washed with saturated NaHCO3 (2×20 mL) and brine (30 mL). The organic layer was dried with MgSO4, the solvent evaporated, and the residue purified by silica gel chromatography to obtain (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopentylpropan-2-ylcarbamate as an oil (2.9 g, yield 81%). 1H NMR (CDCl3, 400 MHz) δ 4.60 (brs, 1H), 3.58 (m, 3H), 1.81 (m, 3H), 1.60 (m, 3H), 1.50 (m, 3H), 1.44 (s, 9H), 1.10 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:25])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([O:17][CH3:25])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.1 parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one, 25 parts of tetrahydrofuran and 5 parts of 10% aqueous sodium hydroxide was reacted with 1.29 parts of dimethyl sulfate. The reaction was stirred at ambient temperature for 20 hours and evaporated at 25° and 100 mm. Hg to yield 2.8 parts of a glass. This glass was chromatographed on 75 parts of Mallinckrodt Silicar CC-7 Special silica gel. The benzene eluent gave a solid which was recrystallized from etherhexane at -70° to yield 0.2 part of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-3-methoxy-2H-indazole melting at 100°-102°. The infrared spectrum contained no absorptions for a carbonyl, NH, or OH and the nuclear magnetic reasonance spectrum contained singlet absorption at 4.0 δ characteristic of a methoxy moiety.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(I)cc2)nn1-c1ncccn1
Product: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ncccn1
Yield: 95 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of each of 3-(4-iodophenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (25) prepared in Example B-6 and phenylboronic acid (manufactured by Aldrich) was used in place of Compound 21 prepared in Example B-2 and phenylboronic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[C:21]1([C:27](=[N:30][OH:31])[CH2:28][CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:32]([O:39][CH2:40][CH3:41])(=[O:38])[C:33]([O:35]CC)=O>C1COCC1>[OH:31][N:30]=[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:28]([CH3:29])[C:33](=[O:35])[C:32]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 131.7 %

Procedure:
Diisopropylamine (21 mL, 148 mmol) was added to 50 mL of THF and cooled with an external ice bath. Butyllithium (56 mL, 141 mmol, 2.5 M in hexanes) was added and the mixture was stirred at 0° C. for 30 min, and brought to room temperature. The resulting LDA solution was added to a mixture of 1-phenyl-propan-1-one oxime (10 g, 67 mmol) and THF (50 mL) at 0° C. Following the addition, the reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (46 mL, 336 mmol) and THF (150 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 3M hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 22 g of the title compound. MS: (+) m/z 250.48 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N:12]=1.Cl>C(OCC)C.C1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[NH:12][C:11](=[O:16])[CH3:10])=[O:17])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Cc1ccc2nc(C)oc(=O)c2c1
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A Grignard reagent prepared from 87.5 g (0.5 mole) of p-bromofluorobenzene and excess magnesium in 800 ml of diethyl ether was slowly added to a solution of 2,6-dimethyl-3,1-benzoxazine-4-one in 300 ml of dry benzene and 200 ml of dry diethyl ether at 0° C. The mixture was allowed to warm to room temperature and stirring was continued for 2 hr. The reaction mixture was cooled to -15° C. and 500 ml of 3N hydrochloric acid was added. After about 10 min additional stirring, the organic layer was separated and washed with dilute sodium hydroxide solution. The organic layer was concentrated and the residue was dissolved in a mixture of 600 ml of 95% ethanol and 300 ml of 6N hydrochloric acid. The precipitate (crude titled product) in the amount of 123 g (ca 91%) was recrystallized from cyclohexane to give tan crystals, m.p. 140°-145° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:7][CH:6]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(OCCO)cc1
Yield: 69.3 %

Procedure:
A solution of 113 (1.7 g, 5.1 mmol) in a mixture of methanol/ethyl acetate (80 and 10 mL correspondingly) was placed in a 0.5 L Parr flask and palladium on carbon (1.1 g, 5% wet. Pd/C) was added. The reaction mixture was shaken at 50 psi of hydrogen pressure at room temperature overnight. After this time, the mixture was filtered through a silica gel pad and the solvent was removed at reduced pressure to give crude 114 (1.2 g) as a brown oil. The crude 114 was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:22])([CH3:21])[CH2:5]1.[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[CH2:25]([O:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:21])([CH3:22])[CH2:5]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Temperature: 35 °C
Yield: 69.9 %

Procedure:
Sodium hydride (2.65 grams, 110 mmol) is added to a solution of 30.0 grams (105 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (as prepared in Example 5) in 150 ml of tetrahydrofuran under nitrogen. The reaction mixture is heated at reflux for three hours, cooled to 35° C., and treated with 12.7 grams (110 mmol) of allyl bromide. The reaction mixture is heated at reflux for one hour, then partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer is washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in heptane (50 ml) and passed through a pad of silica gel (eluent 5:1 heptane:ethyl acetate). The crude product is purified by flash chromatography (silica gel; 9:1 heptane:ethyl acetate) to afford 23.9 grams (70% yield) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][NH:103][CH2:102]1)([CH3:97])([CH3:96])[CH3:95]>>[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][N:103]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:3]=2)[CH2:102]1)([CH3:97])([CH3:95])[CH3:96]
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol. (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) by replacing the trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:13][C:14]2[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: COc1cc(Cl)ccc1CO
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Cl)cc1OC

Procedure:
Using (4-chloro-2-methoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(4-chloro-2-methoxybenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: C([N:4](C(=O)C)[C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=O)C.[O:18]1[CH2:22][CH2:21][O:20][C:19]1(CC([O-])=O)CC([O-])=O>>[CH:10]1[N:11]([CH2:19][O:18][CH2:22][CH2:21][OH:20])[C:12]2[N:13]=[C:5]([NH2:4])[N:6]=[C:7]([OH:14])[C:8]=2[N:9]=1
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=C([O-])CC1(CC(=O)[O-])OCCO1
Product: Nc1nc(O)c2ncn(COCCO)c2n1

Procedure:
On monitoring this reaction by thin layer chromatography, it was determined that the condensation of diacetyl guanine with dioxolane-diacetate in the presence of acidic catalyst produced N7 -isomer first, which was partially converted to N9 -isomers to reach an equilibrium in the ratio of 3/2 in favor of N9 -isomers. Under these condensation conditions, pure N7 - or N9 -acyclovir diacetate could be converted to give the same equilibrated mixture. This observation resulted in one of the embodiments of the improved process for the production of acyclovir of the present invention. When diacetyl quanine (4) almost disappeared during the condensation reaction, the reaction mixture was concentrated to dryness in vacuo, during which time the ratio of N9 /N7 -isomer continuously changed from approximately 3/2 to nearly one spot (N9 -isomer) as indicated by thin layer chromatography. The pure acyclovir diacetate (5) was obtained by simply washing with chloroform in good yield. It was surprising to learn that the ratio of N9 /N7 -isomers could be significantly manipulated in this manner.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>[Cu]I.[Pd].COCCOC>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:40]#[C:39][C:37]([CH3:38])([OH:41])[CH3:36])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: C#CC(C)(C)O
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(O)C#Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-iodoindole (25 g, 102.9 mmol), triphenylphosphine (2.70 g, 10.3 mmol), CuI (1.96 g, 10.3 mmol), potassium carbonate (35.5 g, 257.2 mmol), palladium (5 wt. % on calcium carbonate, poisoned with lead) (0.55 g, 5.14 mmol) and 1,2-dimethoxyethane (250 ml) was stirred at room temperature for 0.5 hour. 2-Methyl-3-butyn-2-ol (21.6 g, 257 mmol) was added and the mixture was stirred for 15 hours at 100° C. The crude mixture was filtered through silica gel and aqueous hydrochloric acid (250 ml, 2 M) was added and extracted with toluene. The organic phase was dried and evaporated. Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. Yield 6.7 g (33%). Mp. 119-123° C.
Reaction SMILES: Cl.[OH:2][NH2:3].C(O)C.C1COCC1.[O:12]=[C:13]([NH:43][CH2:44][C:45](=O)[CH3:46])[CH:14]([NH:27][C:28](=[O:42])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:31][CH:30]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1>CCCCCC>[OH:2][N:3]=[C:45]([CH3:46])[CH2:44][NH:43][C:13](=[O:12])[CH:14]([NH:27][C:28](=[O:42])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:31][CH:30]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1
Reactant: NO
Reactant: CC(=O)CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1)=NO
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.7 %

Procedure:
Hydroxyamine hydrochloride (20 mg, 0.288 mmol) was added to a solution mixture of ethanol:THF (2:1, V/V, 7.5 mL) containing N-{2-oxo-2-[(2-oxo-propyl)amino]-1-[4-(trifluoromethoxy)benzyl]ethyl}-4-(3,3,3-trifluoropropoxy)benzamide (100 mg, 0.192 mmol) prepared in Example 76. The mixture was stirred at room temperature for 6 hours, and the solvent was evaporated. The residue was purified by thin layer chromatography for separation (ethyl acetate:n-hexane, 2:1, V/V, developed once) to give 49 mg of the title compound (white powder, yield: 48%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3].[C:27]([OH:36])(=[O:35])[C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29].O>CO>[C:32]([C@@H:30]([C@H:28]([C:27]([OH:36])=[O:35])[OH:29])[OH:31])([OH:34])=[O:33].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][C@H:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: O
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1
Reaction time: 96 h

Procedure:
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione hydrochloride (100 mg) in MeOH (2 mL) was stirred for 5 min. using brief sonication to give a clear solution. L-tartaric acid (38 mg, 1 eq) was added followed by dropwise addition of water until a haziness persisted (up to 2 mL used). The reaction was stirred in closed vial for 96 h, the precipitated solid was collected on a filter cup and washed with H2O-MeOH (2:1, 3 ml) and then dried under vacuum (42 mg). (Method 13) 48.30%, Rt 9.62 min.; 51.60%, Rt 14.30 min.; d.e. 3.3%. 1H NMR (400 MHz, DMSO-d6): δ 8.34-8.29 (1H, d, J 1.9), 7.55-7.49 (1 H, dd, J 2.2, 7.9), 7.24-7.20 (1 H, d, J 7.8), 7.12-7.05 (2 H, d, J 8.6), 6.84-6.77 (2 H, d, J 8.6), 4.78-4.71 (1 H, dd, J 4.3, 9.1), 4.30-4.19 (1 H, d, J 4.3), 3.24-3.18 (2 H, d), 3.11-3.03 (2 H, t, J 6.6), 3.00-2.92 (1 H, dd, J 9.2, 14.2), 2.59-2.50 (2 H, q, J 7.6), 1.17-1.09 (3 H, t, J 7.7).
Reaction SMILES: [C:1]([C:6](=[CH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:1]([C:6](=[CH:12][O:15][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C(=O)OCC)C(=O)C(C)C
Reactant: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(C)C

Procedure:
A mixture of ethyl isobutyrylacrylate (60.5 g, 0.38 mol) triethyl orthoformate (126 ml, 0.76 mol) and acetic anhydride (36 ml, 0.38 mol) was heated at reflux for 24 hours, then the volatile components removed in vacuo, finally at 100°/0.5 mm. The residue consisted mainly of ethyl 2-isobutyryl-3-ethoxyacrylate as a mixture of E/Z isomers, and was used without further purification.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[Li]CCCC.CCCCCC.[CH:44]([C:46]1[CH:47]=[C:48]([CH:52]([S:60][CH2:61][CH2:62][C:63](=[O:67])[N:64]([CH3:66])[CH3:65])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:50][CH:51]=1)=O.C([O-])(=O)C.[NH4+]>C1COCC1>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:44][C:46]3[CH:47]=[C:48]([CH:52]([S:60][CH2:61][CH2:62][C:63](=[O:67])[N:64]([CH3:66])[CH3:65])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:50][CH:51]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Reactant: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-chloroquinolin-2-ylmethyltriphenylphosphonium bromide (809 mg, 1.56 mmol.) (Example 4, Step 2) in THF (15 mL) at -78° C., was added a solution of n-BuLi (1.6M) in hexane (0.89 mL, 1.43 mmol.). The mixture was stirred for 0.5 hrs at -78° C. Then, (-)-methyl 5-(3-formylphenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 7) (480 mg, 1.3 mmol.) in THF (4 mL) was slowly added. The mixture was stirred for 0.5 hr at -78° C. and then warmed up to room temperature and stirred for an additional 2 hrs. A solution of 25% ammonium acetate was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[I:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:10]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 645.2 %

Procedure:
N-lodosuccinimide (144.0 g, 0.641 mole) was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL). The reaction mixture was stirred for 2 days at room temperature. Additional N-iodosuccinimide (20.0 g) was added and stirring was continued for additional 2 days. The reaction mixture was diluted with ethyl acetate (1 L), washed with hydrochloric acid (300 mL, 0.1 N), water (300 mL), sodium thiosulfate (5%, 300 mL), brine (300 mL), dried (MgSO4) and was concentrated to dryness to afford the desired aldehyde as a pale yellow solid (162 g, 90% yield).
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7](C(=O)C)=[CH:6][CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[Li+].[OH-].Cl>ClCCl.C1COCC1.CO.O>[F:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:21])=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(OCF)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(OCF)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
To a solution of 1-(4-fluoromethoxy-phenyl)-ethanone (1.5 g; 8.9 mmol) in dichloromethane (30 mL) was added mCPBA (4.0 g; 17.8 mmol). The resulting mixture was stirred at room temperature for 4 h, then washed with saturated NaHCO3 (3×). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the crude material (3.77 g). The crude material (3.77 g) was dissolved in THF/MeOH/H2O (5/5/5 mL), then treated with LiOH (4.0 g; 108 mmol) at room temperature for 4 h. The reaction mixture was acidified with 2N HCl solution to pH 5. The mixture was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.3 g). This compound was used directly without further purification.
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br[CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C.O>C(O)C>[CH3:2][C:1]1[S:4][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g of ethanethioamide was suspended in 50 mL of ethanol, to which 9.3 mL of ethyl 3-bromo-2-oxopropanoate was added dropwise at room temperature, and this suspension was stirred for one hour while heating it under reflux. The reaction mixture was cooled to room temperature and added to a mixture of ethyl acetate and water, followed by separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 2.30 g of ethyl 2-methyl-1,3-thiazole-4-carboxylate as white solid.