Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.[CH2:4]1[C:6](=O)[CH2:5]1.B.[CH2:9]([O:11]BO)[CH3:10]>>[C:9]12([OH:11])[CH2:4][CH:6]([C:5]1([CH3:5])[CH3:6])[CH2:10][CH2:9][C:10]2([OH:11])[CH3:4]
Reactant: CCOBO
Reactant: O=C1CC1
Agent: B
Agent: OBO
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
Scheme 12 illustrates the preparation of boronic acid analogs containing a substituted cyclohexyl ring in the P1 site. Cyclohexadione monoethylene ketone 38 was converted to the alkene 39 using a Wittig reaction. 39 was hydroboronated using diiisopinocamphyl borane and converted to the boronic acid ethyl ester using the general procedure described by Brown et al. J. Org. Chem. 47, 5065, 1982. Transesterification with pinanediol gave 40. The α-chloro compound 41 was prepared by the homologation reaction of 40 with the anion of methylene chloride using the procedure of Matteson et al. J. Am. Chem. Soc. 105, 2077, 1983. Nucleophillic displacement of the α-chloride with the lithium salt of hexamethyldisilazane gave the bis-silyl protected amine 42. The trimethylsilyl protecting groups were removed by treatment with anhydrous HCl. The α-amino group was coupled to either an acyl group or N-protected peptide or amino acid using the mixed anhydride or other standard peptide coupling reaction conditions. The peptide 43 was treated with an aqueous suspension of a sulfonic acid substituted ion exchange resin to yield the side chain ketone which was converted to the amino cyclohexylpeptide 44 by reductive amination using ammonium acetate and sodium cyanoborohydride. ##STR35##
Reaction SMILES: C(OC([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:13][C:12](=[O:21])[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:31][C:32](C)([O-])C.[K+].C(I)C>C1COCC1>[CH2:31]([N:13]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:9]([NH:8][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:10][CH2:11][C:12]1=[O:21])[CH3:32]
Reactant: COc1ccccc1CN(C(=O)OC(C)(C)C)[C@@H]1CCC(=O)N[C@@H]1c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1C(=O)CC[C@@H](NCc2ccccc2OC)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 50 ml (0.12 mmol) of cis-5-(N-tert-butoxycarbonyl-2-methoxybenzylamino)-2-oxo-6-phenylpiperidine and 0.2 mL of THF. To the system were added 13.5 mg (0.12 mmol) of potassium tert-butoxide and 20 μL (0.24 mmol) of ethyl iodide. The reaction mixture was stirred at room temperature for 3 hours (during this period, additional potassium tert-butoxide (13.5 mg) and ethyl iodide (20 μL) were added to the system). The mixture was partitioned between methylene chloride and aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of methylene chloride. The combined organic fractions were dried (sodium sulfate) and concentrated with a rotary evaporator. The crude material was purified by flash column chromatography using 3:97 methanol/chloroform as the eluant to obtain 42 mg of cis-N-ethyl-5-(2-methoxybenzylamino)-2-oxo-6-phenylpiperidine.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:12])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[CH:11]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[I:1][C:2]1[C@H:3]([OH:12])[C@@H:4]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]2[CH:11]=1
Reactant: CC1(C)O[C@@H]2C=C(I)C(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O)O1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
(3aR,6aR)-5-iodo-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-2) (1.5 g, 5.4 mmol, 1 equiv) was dissolved in MeOH (54 mL). The solution was cooled to −78° C. and cerium(III) chloride (1.4 g, 5.7 mmol, 1.05 equiv) was added followed by sodium borohydride (216 mg, 5.7 mmol, 1.05 equiv). The resulting mixture was stirred at the same temperature for 5 minutes. Upon disappearance of the starting material, the reaction was quenched with the addition of water (10 mL) and concentrated. The residue was partitioned between EtOAc (100 mL) and water (40 mL), the organics were dried over MgSO4, filtered and concentrated to afford (3aS,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-3) as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 6.31 (s, 1 II); 4.92 (dd, J=5.5, 2.0 Hz, 1H); 4.69 (t, J=5.5 Hz, 1H); 4.41 (dd, J=10.5, 5.5 Hz, 1H); 1.43 (s, 3H); 1.40 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][O:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)CO
Solvent: c1ccncc1
Product: CC(C)(C)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
Add 4-bromobenzenesulfonyl chloride (2.20 g, 8.61 mmol) and pyridine (30 mL) to a round bottom flask. At ambient temperature, with stirring, add neopentyl alcohol (1.39 mL, 12.91 mmol). After stirring the reaction overnight at ambient temperature quench the reaction with saturated aqueous sodium bicarbonate and extract it with ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, 0.05 N aqueous hydrochloric acid and brine, then dry (sodium sulfate), and concentrate in vacuo. Purify the resulting material on a flash column (silica gel; 30%-50% gradient of CH2Cl2 in hexanes) to provide 2.24 g of 4-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (85%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Temperature: 18 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
Acetophenone (5 ml, 42.9 mmol) was added to a dry Schlenck flask containing 250 ml 2-propanol. Then a portion (2 ml) of the catalyst solution was added followed by sodium 2-propoxide solution (0.3 ml of 0.1 M solution in 2-propanol). The mixture was stirred at 18° C. under vacuum (28 mmHg) for 5 h. This gave (R)-1-phenylethanol Yield 74%, ee 86.8%. The initial turnover number, integrated over 1 h, was 1947 h−1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.CON(C)[C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28]>C1COCC1>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: CON(C)C(=O)CC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly a solution of N-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allow the mixture to warm to room temperature. Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M+).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C([O:15][C:16](=[O:47])[CH:17]([C:35]1[S:36][C:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][CH:39]=1)[NH:18][C:19](=[O:34])[CH:20]([CH2:29][S:30]C(=O)C)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C.Cl>O.CO>[CH2:40]([C:37]1[S:36][C:35]([CH:17]([C:16]([OH:47])=[O:15])[NH:18][C:19](=[O:34])[CH:20]([CH2:29][SH:30])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:39][CH:38]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cc2ccccc2)s1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: O=C(NC(C(=O)O)c1ccc(Cc2ccccc2)s1)C(CS)CCc1ccccc1
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
A solution of sodium sulphide nonahydrate (464 mg) in water (3 ml) was added to a stirred solution of 2-[(5-benzyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 40) (330 mg) in methanol (3 ml) under argon. Further portions of methanol (totalling 5 ml) were added over 45 min. The mixture was stirred for a further 20 min. and then dilute hydrochloric acid (2 ml) was added and the mixture partitioned between ethyl acetate and water. The organic phase was washed with water and brined, dried over magnesium sulphate and evaporated. The product (209 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel:5% going to 10% methanol in chloroform). vmax (CHCl3) 3423, 3295, 1723 and 1674 cm-1. δ (CD3SOCD3) 1.70-1.90 (2H, m), 2.43-2.70 (5H, m), 4.07 and 4.09 (2H, two s's), 5.43 (1H, d, J 7.77 Hz), 6.73-6.75 (1H, m), 6.88 and 6.91 (1H, two d's, J 3.42 Hz), 7.09-7.35 (10H, m). m/z 439 (M+). [Found (HRMS): m/z 439.1281. Calc. for C24H25NO3S2 : 439.1276].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].[CH3:18][S:19][CH3:20].ClN1C(=O)CCC1=O.C(N(CC)CC)C>[Cl-].[Na+].O.C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH2:18][S:19][CH3:20])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCOC(=O)c1ccc(OC)c(N)c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)c1ccc(OC)c(N)c1CSC
Temperature: -30 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Pentyl 3-amino-4-methoxybenzoate (0.744 g, 4.45 mmol), methylene chloride (15 ml) and dimethylsulfide (0.33 ml, 4.50 mmol) were mixed, and after cooling to -30° C., N-chlorosuccinimide (601 mg, 4.5 mmol) was added to this solution. After sti ring for 1 hour, triethylamine (0.627 ml, 4.5 mmol) was added, and the mixture was refluxed under heating for 0.5 hour. Saturated brine (0.5 ml) was added to stop the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hemne/ethyl acetate=4/1) to give pentyl 3-amino-4-methoxy-2-methylthiomethylbenzoate (0.83 g, 82%) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
2-Chloroquinoline (0.12 moles, 20.0 g), 4-nitrothiophenol (0.13 moles, 20.8 g), and potassium carbonate (0.13 moles, 18.5 g) were dissolved in 800 ml ethanol and stirred at room temperature for 1.5 hr. The mixture was filtered and the solid washed with ethanol. The solid was dissolved with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to yield 2-(4-nitrophenylthio)quinoline 26.0 g, 77%. Mass Spec (FD) 282. Calculated for C15H10N2O2S: C, 63.82, H 3.57; N, 9.92. Found: C, 63.55, H 3.59; N, 9.71.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[C:36]([O:38]CC2C=CC=CC=2)[CH:35]=[CH:34][C:10]=1[C:11]([NH:13][C@H:14]([C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12])C1C=CC=CC=1>[H][H].[C].[Pd]>[OH:8][C:9]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:10]=1[C:11]([NH:13][C@H:14]([C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12]
Reactant: [H][H]
Reactant: NC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(c2ccccc2)CC1
Agent: [Pd]
Product: NC(=O)CC[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCN(c2ccccc2)CC1
Yield: 66.1 %

Procedure:
10% Palladium-carbon (120 mg) was added to an ethanolic solution (20 ml) of 1-(2,4-dibenzyloxybenzoyl-L-glutaminyl)-4-phenylpiperazine (364 mg) and catalytic reduction was carried out for 6 hours at room temperature and under atmospheric pressure in hydrogen stream. Thereafter, treatments were effected in the same manner as in Example 5 (ii) to obtain powdery 1-(2,4-dihydroxybenzoyl-L-glutaminyl)-4-phenylpiperazine (169 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:13][NH:14][CH:15]2[CH:22]3[CH2:23][C:18]4([OH:26])[CH2:19][C:20]([OH:25])([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>CO>[NH2:7][C:8]1([CH2:13][NH:14][CH:15]2[CH:22]3[CH2:21][C:20]4([OH:25])[CH2:19][C:18]([OH:26])([CH2:17][CH:16]2[CH2:24]4)[CH2:23]3)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(CNC2C3CC4(O)CC2CC(O)(C3)C4)CCCC1
Agent: Cl
Solvent: CO
Product: NC1(CNC2C3CC4(O)CC2CC(O)(C3)C4)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
A mixture of {1-[(5,7-dihydroxy-adamantan-2-ylamino)-methyl]-cyclopentyl}-carbamic acid tert-butyl ester (350 mg, obtained in examples 122, step A) and 6N HCl solution (1.0 ml) in MeOH (2.0 ml) was stirred at room temperature for 16 hr. The mixture was evaporated. The residue was purified with amine-coated silica gel chromatography (CH2Cl2:MeOH=from 100:0 to 9:1) to obtain the title compound (250 mg, 97%) as a dark brown solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:45]=[C:44]([O:46][CH3:47])[C:38]2[O:39][CH2:40][CH2:41][CH2:42][O:43][C:37]=2[C:36]=1[F:48])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:48][C:36]1[C:37]2[O:43][CH2:42][CH2:41][CH2:40][O:39][C:38]=2[C:44]([O:46][CH3:47])=[CH:45][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCCO2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
After adding 20 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 103 mg of [2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (67 mg) as a light brown solid.
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]([O:15]C)=[O:14])[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH3:12][O:11][C:9]([C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][O:6][C:7]=1[C:13]([OH:15])=[O:14])=[O:10]
Reactant: COC(=O)c1onc(C(C)C)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(C)C)noc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
40 g of dimethyl 3-isopropylisoxazole-4,5-dicarboxylate are dissolved in 200 ml of methanol. A solution of 7.05 g of sodium hydroxide in 50 ml of water is added dropwise at 0° C. to this solution. It is stirred for 14 hours and allowed to warm to room temperature. The reaction selution is diluted with water and extracted twice with ethyl acetate. The alkaline solution is then acidified with conc. hydrochloric acid and extracted several times with ethyl acetate, and the organic phase is dried and concentrated.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([S:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(S)c1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cc(-c3ccc(C(C)(C)C)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 25-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.20 g, 0.82 mmol), 3-methoxybenzenethiol (0.23 g, 1.6 mmol, Aldrich) and DMF (4 mL) under a N2 atmosphere at room temperature was added NaH (0.066 g, 1.6 mmol, 60% disp. in oil, Aldrich). The mixture turned green and gas evolution was observed. The solution was stirred for 20 h at room temperature under a N2 atmosphere. The reaction was quenched with H2O (50 mL), and the resulting solution was extracted with EtOAc (3×25 mL). The combined extracts were washed with H2O (3×25 mL) and brine, dried over Na2SO4, and adsorbed onto silica. The crude material was purified by chromatography (0 to 15% ethyl acetate/hexanes) on silica gel to afford the title compound as a colorless oil. MS (ESI, pos. ion.) m/z: 351.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32](O)=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35]([O:42][CH2:43][CH2:44][NH:45][CH:46]([CH3:48])[CH3:47])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[Si:35]([O:42][CH2:43][CH2:44][N:45]([CH:46]([CH3:48])[CH3:47])[C:32]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:33])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: O=C(O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 24.5 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (219) (300.0 mg, 24.5%) was synthesized as a colorless liquid from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (218) (850.0 mg, 1.87 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (610.5 mg, 2.80 mmol) following the procedure described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (206).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][CH2:27]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:26][CH3:27])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: CCO
Reactant: COc1cc(O)ccc1CCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCc1ccc(O)cc1OC
Temperature: 25 °C

Procedure:
To a stirring solution of 3-[4-hydroxy-2-(methyloxy)phenyl]propanoic acid (229 mg, 1.17 mmol) in EtOH (14 mL) was added concentrated H2SO4 (0.031 mL, 0.58 mmol) and the reaction heated at reflux under nitrogen for 1 h. The mixture was then cooled to ambient temperature poured into ice (ca. 30 mL) and saturated aqueous Na2CO3 (60 mL) added. The mixture was then extracted with EtOAc (2×50 mL) and the combined organic layer washed with brine (70 mL) and concentrated under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title compound (217 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][CH:24]5[CH2:28][O:27]C(C)(C)[O:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:36])([F:35])[F:37])[CH:3]=1
Reactant: CC1(C)OCC(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC(O)CO
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1,3-thiazolidine-2,4-dione (Example 42; 0.1 mmol) in dioxane (3 mL) was treated with 10% aq. HCl (0.5 mL) and stirred at 45° C. overnight. Concentration of the reaction in vacuo gave a pale yellow solid which was triturated with ether to afford pure (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2,3-dihydroxypropyl)-1,3-thiazolidine-2,4-dione as a pale yellow crystalline solid.