Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:12][CH3:13])[C:8]([F:11])=[N:9][CH:10]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:12]([C:7]1[C:8]([F:11])=[N:9][CH:10]=[C:5]([OH:4])[CH:6]=1)[CH3:13]
Reactant: CCc1cc(OC(C)=O)cnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(O)cnc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
To a stirred solution of the 5-acetoxy-3-ethyl-2-fluoropyridine from Step 126e above (2.22 g, 12.1 mmol) in MeOH (50 mL) was added K2CO3 (0.84 g, 6.10 mmol). The reaction mixture was allowed to stir at room temperature 24 h. The solvent was evaporated and the residue was diluted with Et2O (100 mL) and water (100 mL). The phases were separated and the aqueous phase was neutralized (pH 7) by the addition of 1 N aqueous HCl, and extracted with diethyl ether (2×100 mL). The combined ethereal extracts were washed with brine (50 mL), dried (MgSO4), and the solvent evaporated. The crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the desired material as an off-white solid (1.18 g, 69%): 1H NMR (CDCl3, 300 MHz) δ 1.24 (t, J=7.5 Hz, 3H), 2.63 (q, J=7.5 Hz, 2H), 7.24 (dd, J=2.0, 5.0 Hz, 1H), 7.62 (m, 1H); MS (CI/NH3) m/z 142 (M+H)+, 159 (M+NH4)+.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+](C)([O-])=O.Cl>CCOCC>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
One gram of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 25 ml of nitromethane saturated with hydrogen chloride gas at 0° C. After stirring at 0° C., the reaction mixture is allowed to reach room temperature and stirred for an additional hour. The suspension is diluted with anhydrous ether and suction filtered. The collected solid is washed with ether, methanol, and ether again, and then dried under reduced pressure to give 0.81 g of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a yellowish powder: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (s, 9H), 7.72 (d, 2H, J=8.02 Hz), 7.98 (d, 2H, J=8.02 Hz), 8.52 (d, 1H, J=2.01 Hz), 9.01 (d, 1H, J=2.01 Hz); IR (KBr) 3420, 3000, 1725, 1680, 1425, 1405, 1360, 1250, 1130, 1020, and 800 cm -1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-])=O)[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]>O1CCOCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(F)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1c(N)cc(C(=O)O)cc1F
Yield: 91.2 %

Procedure:
520 g of 3-fluoro-4-methyl-5-nitro-benzoic acid are hydrogenated in 3,500 ml of dioxane with 50 g of Pd-C catalyst (5% strength) at 50° C. and under 30 bar. The catalyst is then filtered off with suction and the solution is concentrated. 403 g of 3-fluoro-4-methyl-5-amino-benzoic acid are obtained as crude material.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]3=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)NCC(=O)O
Reactant: S=C=Nc1ccc2c(c1)CCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Yield: 36.1 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 17.5 g of indan-5-yl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178°-180° C. Anal. Calcd. for. C15H18N2OS: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass spectrum (EI, M.+) m/z 274.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12[CH3:12])[C@:24]1([CH3:25])[C@H:19]([CH:20]=[C:21]([P:29]([O:33][CH3:34])(=[O:32])[O:30][CH3:31])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)(C(C)(C)C)(C)C.CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:31][O:30][P:29]([C:21]1[CH2:22][CH2:23][C@@:24]2([CH3:25])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:26]2[CH2:27][CH2:28][C@@:11]2([CH3:12])[C@H:13]3[CH2:14][CH2:15][C@@H:10]2[C:9]([OH:37])=[O:8])[CH:20]=1)([O:33][CH3:34])=[O:32]
Reactant: CC(C)=O
Reactant: COP(=O)(OC)C1=C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](CO[Si](C)(C)C(C)(C)C)CC[C@@H]34)[C@@]2(C)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COP(=O)(OC)C1=CC2CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Yield: 99 %

Procedure:
Dimethyl 17β-(t-butyldimethylsilyloxymethyl)-5α-androst-3-ene-3-phosphonate (500 mg), was dissolved in 150 ml acetone. Jones reagent was added until a red color persisted. Isopropanol was then added to quench excess Jones reagent. The acetone was decanted off and the residual chromium salts were then dissolved in water and washed 3 times with dichloromethane. The organic layers were combined and passed through a plug of florosil and concentrated to give 360 mg (99%) of 3-dimethylphosphono-3-androstene-17β-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (21 g) in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and benzyl chloroformate (17 g). The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27].CO>O1CCCC1.C(Cl)Cl.O>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-methyl-3-D-glucopyranosylurea prepared in the same manner as described in Example 1-(1) are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is further stirred at the same temperature for 10 minutes. After the reaction, 10 ml of methanol and 3 ml of water are added to the mixture, and the mixture is stirred for 10 minutes. Said mixture is dried, filtered and evaporated to remove solvent. Then, the residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol(5:2:1)). 2.4 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-D-glucopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH3:24])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH3:24])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C2CCC2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C3CCC3)nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[cyclobutyl(methyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (670 mg) in DMF (10 mL) was added potassium tert-butoxide (223 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (530 mg, 87%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH3:3].ClCCl>[O-2].[O-2].[Mn+4].C(#N)C>[C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A mixture of the title compound of Example 56 (160 mg, 0.62 mmol), activated manganese dioxide (1.6 g), dichloromethane (12 ml) and acetonitrile (3 ml) was stirred for 16 hours at room temperature, when a further portion of activated manganese dioxide (0.6 g) was added. After a further 4 days, the reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (1:12:5:86.5), to afford the title compound (35 mg). Rf 0.35 (SS 15). Found: C,73.30; H,7.76; N,10.65. C16H20N2O; 0.17 CH2Cl2 requires C,73.73; H,7.75; N,10.71%.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.C[N:13]1CCOCC1.CC(COC(Cl)=O)C.[OH-].[NH4+]>C1COCC1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH2:13])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C1CCC(F)(F)CC1
Temperature: 0 °C
Yield: 53.1 %

Procedure:
To a solution of compound 4,4-difluorocyclohexanecarboxylic acid (3.5 g, 21 mmol) in 80 mL THF, 4-methylmorpholine (2.51 g, 21 mmol) was added at −70° C., followed by isobutyl chloridocarbonate (2.85 g, 21 mmol). 30 min later, 10 mL ammonium hydroxide was added. The resulting mixture was allowed to warm up to 0° C. After removal of all solvents, the residue was washed with water, PE to afford the compound 4,4-difluorocyclohexanecarboxamide (1.82 g, 40%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[O:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2)[Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1Cc2cccc(O)c2C1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cccc(O[Si](C)(C)C(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-hydroxy-2-methyl-1-indanone (6) (10.2 g, 37 mmol) and imidazole (3.02 g, 44 mmol) dissolved in DMF (200 ml) was added tert-butyldimethylchlorosilane (6.11 g, 41 mmol) in DMF (50 ml). The reaction mixture was stirred overnight at room temperature and treated with water (200 ml) and extracted with diethylether (2×200 ml). The combined organic phases were washed with aqueos NH4Cl (300 ml), brine (100 ml) and dried over sodium sulfate. Evaporation gave (7) as a yellow oil which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1>CN(C=O)C>[Cl:9][C:4]1[N:5]=[CH:6][N:7]([CH3:8])[C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cnc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)ncn2C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The new mixture was stirred at room temperature for 2 hours. DMF was removed under vacuum. The crude compound was purified by column chromatography to provide 2-{[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as the major product (350 mg, 13% overall yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.72 (s, 3H), 4.59 (s, 2H), 6.00 (bs, 1H), 7.59 (s, 1H); M+271.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCCCC5)cc4)cc3)n(C)c(=O)c12
Yield: 68.1 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (399 mg), 1-(2-chloroethyl)piperidine hydrochloride (185 mg) and potassium carbonate (392 mg) in DMF (5 ml) was stirred at 60° C. for 62 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was recovered by filtration to provide the title compound as colorless solid (368 mg).
Reaction SMILES: C1COCC1.B.[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:14])=[CH:11][CH:10]=1.Cl>O>[OH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[C:12]2[CH:26]=[CH:27][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)N(C)c2ccc(C(=O)O)cc2)cc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)c2ccc(CO)cc2)cc1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
THF solution (1M, 16 ml) of borane was added dropwise to THF solution (10 ml) of 4-[N-(4-methoxybenzoyl)-N-methylamino]benzoic acid (1.14 g) under ice-cooling, which was stirred for 15 minutes, and then stirred at room temperature for 1 hour. After water was added to the reaction mixture, 1N hydrochloric acid was further added, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate, and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel chromatography (development solvent; hexane˜hexane:ethyl acetate=1:2), and recrystallized (ethyl acetate-hexane) to give the titled compound (770 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(Cl)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 24 g of 2-chloro-6-methylbenzaldehyde [L. G. Humber, J. Med. Chem., 7, 826 (1964)] in 200 ml of methanol is cooled in an ice bath while 6.0 g of sodium borohydride is added in portions. After stirring overnight at room temperature, the mixture is concentrated to dryness and the residue is partitioned between water and ether. The organic layer is washed with dilute hydrochloric acid, dried, and concentrated to yield the crude product. Recrystallization from benzene/hexane gives 20.8 g of 2-chloro-6-methylbenzyl alcohol, mp 83°-86° C. in two crops.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[O:29])[C:15]([NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][C:22]([OH:27])([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[C:10]2[N:9]=[CH:8]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:28]([C:14]2[C:15]([NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][C:22]([OH:27])([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[C:10]3[N:9]=[CH:8][NH:7][C:11]3=[N:12][CH:13]=2)=[O:29])=[CH:33][CH:34]=1
Reactant: COc1ccc(Cn2cnc3c(NC4C5CC6CC4CC(O)(C6)C5)c(C(=O)NCc4ccc(F)cc4)cnc32)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1cnc2[nH]cnc2c1NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To 3-(3,4-dimethoxybenzyl)-N-(4-fluorobenzyl)-7-{(5-hydroxyadamantan-2-yl)amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide (170 mg) was added trifluoroacetic acid (1.7 ml), and the mixture was stirred at ambient temperature for overnight. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-(4-fluorobenzyl)-7-{(5-hydroxyadamantan-2-yl)amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide (31 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 78.3 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 286 mg of 5-[4-{2(S)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propoxy}benzyl]-3-triphenylmethylthiazolidine -2,4-dione (prepared as described in Preparation 41), 1 ml of trifluoroacetic acid and 1 ml of methylene chloride were used, to give 150 mg of the title compound, melting at 54° C. to 56° C. and having [α]D =+41.8° (methanol, c=0.975).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3.66 g, 30 mmol) and potassium carbonate (8.24 g, 60 mmol) in DMF (75 mL) was added 2-chloromethylquinoline hydrochloride (6.42 g, 30 mmol), and the resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to afford 4-(2-quinolylmethoxy)benzaldehyde (5.8 g, 74%) as a crystalline compound.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26](O)=[O:27])[CH:19]=[CH:18]2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26]([O:1][N:2]1[C:3](=[O:12])[C:4]3[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=3[C:6]1=[O:7])=[O:27])[CH:19]=[CH:18]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)ON3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of N-hydroxyphthalimide (7.1 g, 43.4 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 10 g, 43.4 mmol) and N,N-dimethylaminopyridine (DMAP, 5.3 g, 43.4 mmol) in CH2Cl2 (70 mL) and DMF (30 mL) at 0° C. was treated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (8.3 g, 43.4 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under vacuum. The residue was then dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to give the title compound (7.6 g, 47% yield) as a white solid. Mp 110-112° C. 1H NMR (300 MHz, d6-DMSO) δ 7.80-8.06 (m, 7H), 7.50 (dd, J=1.7 and 8.5 Hz, 1H), 7.32-7.37 (m, 1H), 7.20 (dd, J=2.5 and 9.0 Hz, 1H), 4.50 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 171.2, 161.8, 157.5, 153.0, 135.5, 133.6, 133.5, 129.3, 128.4, 128.2, 127.3, 126.1, 126.0, 124.0, 119.0, 105.8, 55.2, 41.8, 18.6. Mass spectrum (API-TIS) m/z 376 (MH+), 393 (MNH4+).