Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 34, Compound 122) as starting materials. Product as a light brown solid (17%). LC/MS (Method B) 2.57 min, [M+1]+ 427.0. Potency class A.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[N:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[CH3:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([N:19]([CH3:20])[CH3:18])=[N:6][C:5](=[O:10])[N:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:17]
Reactant: CNC
Reactant: CSc1nc(=O)n(C2CCCCC2)c(=O)n1C
Solvent: Cc1ccccc1
Product: CN(C)c1nc(=O)n(C2CCCCC2)c(=O)n1C

Procedure:
A suspension of 300 parts of 1-methyl-3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione in 887 parts of toluene is stirred at 25°-30° for three hours with 150 parts of dimethylamine. Toluene is distilled from the reaction until a pot temperature of 125° is attained. The reaction mass is cooled to 50° at which time 480 parts of hexane is added over 0.66 hours. The slurry at 25° is filtered to give 282 parts of crystalline 1-methyl-3-cyclohexyl-6-dimethylamino-s-triazine-2,4(1H,3H)-dione, m.p. 110°-115°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[NH2:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(OCC)(=O)C>O.O1CCOCC1>[NH2:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:40]=[CH:39][CH:38]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(N)c4)cc23)CC1
Yield: 36.2 %

Procedure:
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.0965 mmol), potassium carbonate (80 mg, 0.578 mmol) and (3-aminophenyl)boronic acid sulfate (145 mg, 0.386 mmol). The mixture was taken up in water (1.2 mL) and dioxane (2.8 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol) was added. The mixture was then reacted in a CEM microwave for 10 min at 150° C. Ethyl acetate (2 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (1×2 mL). The organic layers were pooled, concentrated under a stream of nitrogen, and taken up in dimethyl sulfoxide (0.89 mL) and trifluoroacetic acid (0.15 mL). This solution of crude product was purified on an Agilent MDAP eluting with a linear gradient of 30% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) at 20 mL/min over 9 min. To the HPLC fraction containing product was added a solution of saturated K2CO3 (1 mL), a 1 M solution of sodium hydroxide (1 mL), and ethyl acetate (2 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 mL). The organic layers were pooled, filtered through a plug of magnesium sulfate, and concentrated under a stream of nitrogen to give 14.9 mg of the title compound (36%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[CH:10][C:9]([NH:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])=[CH:8][CH:7]=2)#[N:2].FC(F)(F)C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:3]1[C:4]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[CH:10][C:9]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:8][CH:7]=2)#[N:2]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(NCC(=O)OC(C)(C)C)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a solution of tert-butyl N-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (3.0 g, 7.0 mmol) in tetrahydrofuran (10 ml) was added trifluoroacetic acid (820 ml), and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl-acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue (3.0 g) was dissolved in N,N-dimethylformamide (10 ml). Thereto were added methyl iodide (1.5 g, 5.3 mmol) and potassium carbonate (0.73 g, 5.3 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with 0.1 M aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl N-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (1.6 g, yield 79%) as a pale-yellow powder. Subsequently, methyl N-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (1.0 g, yield 62%, pale-yellow powder) was synthesized by a method similar to the method shown in Example 25(2).
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][C:11]2([N:15]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][NH:13][C:12]2=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:15]1[C:11]2([CH2:22][CH2:23][NH:8][CH2:9][CH2:10]2)[C:12](=[O:21])[NH:13][CH2:14]1
Reactant: CC(C)CCN1CNC(=O)C12CCN(Cc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CCN1CNC(=O)C12CCNCC2

Procedure:
A solution of 130 mg (0.412 mmol) 8-benzyl-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one in 2 ml methanol was debenzylated with hydrogen in presence of 30 mg 10% Pd/C at ambient temperature over night. Then the reaction mixture was filtered through a silica gel pad and the filtrate evaporated: 70 mg 1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one as colorless solid: m.p. 103–105° C., MS (ISP): 226.3 MH+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1CC(OCC)=O.[O-:17][CH2:18][CH3:19].[Na+].[N:21](OCCCC)=O.C(O)(=O)C>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:21][CH2:19][CH2:18][OH:17]
Reactant: CCCCON=O
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: OCCNc1ccc2ccccc2c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Ethyl 2-naphthylacetate (11.6 g) was dissolved in ethanol (100 mL) and treated with solid sodium ethoxide (3.5 g) and then dropwise with n-butyl nitrite (7.6 mL). The reaction was stirred at 23° C. for 18 h and treated with acetic acid (5 mL) and stirred for 1 h. The ethanol was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The crude residue (5.6 g) was taken up in ether (300 mL) cooled to 0° C. and treated with lithium aluminum hydride solution (45 mL, 1M in tetrahydrofuran) dropwise. The mixture was heated to reflux for 5 h and cooled. It was quenched by the sequential addition of ethyl acetate (5 mL) water (1.5 mL), sodium hydroxide solution (3M, 1.5 mL) and water (4 mL). The solid was filtered and the solution was dried with magnesium sulfate. The solvent was removed at reduced pressure and the solid was triturated with hexanes/butyl chloride (1:1, 100 mL). Of the crude 2-naphthylglycinol (2.6 g) thus obtained, 1.2 g was dissolved in tetrahydrofuran and treated with triethylamine (1 mL) and cooled in an ice water bath. Treatment of the mixture with 2,6-difluorobenzoyl chloride (1 mL) was followed by stirring at room temperature for 1 h. The mixture was diluted with dichloromethane and water. The organic phase was washed sequentially with sodium bicarbonate solution (saturated aqueous) and 1N hydrochloric acid. The solvent was dried with magnesium sulfate and removed under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (5:1 to 1:1) as eluent. The product was treated with benzene (20 mL), thionyl chloride (3 mL) was added and the mixture heated at reflux for 2.5 h. The solvent was removed under reduced pressure and the residue was treated with methanol (20 mL) and NaOH (50% aqueous, 1.5 mL), and heated at reflux for 1 h. The mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using hexanes/ethyl acetate (5:1) as eluent to afford the title compound (0.68 g) as an oil which quickly solidified: mp 68°-70° C., 1H NMR (CDCl3): 15 8.0-7.0 (m,10H, aryl H), 5.6 (m, 1H,CH), 4.9 (m, 1H,CH), 4.4 (m, 1H,CH).
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A cooled (0° C.) solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 1; 164 mg, 0.57 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.43 mL, 0.86 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.42 mL, 2.0 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-acetamide (116 mg, 71% yield) as a white solid, mp 88.3-91.4° C.; FAB-HRMS m/e calcd for C13H15NCl2O2 (M+) 288.0558, found 288.0572.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(4-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[ClH:1].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:3]=[C:2]([NH:24][CH2:23][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: COc1ccc2c(Cl)cc(-c3ccc(Cl)cc3)nc2c1
Product: COc1ccc2c(NCCO)cc(-c3ccc(Cl)cc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 271-272° C., and MS: m/e=328 (M+), was prepared from 4-chloro-2-(4-chloro-phenyl)-7-methoxy-quinoline and ethanolamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(Cc2ccc3ccccc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(Cc2ccc3ccccc3n2)CCNC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-quinolylmethyl)-1,2,5,6-tetrahydropyridine (1.98 g) was dissolved in dichloromethane (5 ml), and TFA (5 ml) was added to the solution under cooling on ice. The mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. A saturated solution of sodium hydrogencarbonate was added to the residue to neutralize, the mixture was then extracted with chloroform. The organic phase was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The title compound was recovered from an ether-hexane solvent as white powder. This powder was also used for subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-:21])=[C:7]([CH3:11])[C:6]=1[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nccc(C(C)(C)C)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(C)(C)C)cc[n+]([O-])c1C

Procedure:
A solution of 10.5 g of 4-tert-butyl-2,3-dimethylpyridine in 120 ml of methylene chloride is treated at room temperature with 14.4 g of m-chloroperbenzoic acid. The reaction mixture is made basic with a saturated sodium carbonate solution and extracted. The organic solution is dried and concentrated. The residue is purified on a silica qel column, whereby the medium pressure flash chromatography method (solvent: methylene chloride/ethyl acetate, with increasing ethyl acetate concentrations) is used and the pressure is produced with nitrogen gas. The 4-tert-butyl-2,3-dimethylpyridine N-oxide obtained is processed directly.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1[CH:13]=CC=C[CH:9]=1.CC(C)C(=O)C(=NO)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>>[I:1][CH2:2][C:3]1[N:4]=[C:36]([C:35]2[CH:38]=[CH:39][C:32]([C:31]([F:40])([F:41])[F:30])=[CH:33][CH:34]=2)[O:37][C:7]=1[CH:8]([CH3:13])[CH3:9]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=NO)C(=O)C(C)C
Product: CC(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 4-methylpentane-2,3-dione-2-oxime and 4-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-isopropyl-2-(4-trifluoromethylphenyl)-oxazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][CH:8]([O:10][CH3:11])[CH3:9])[CH3:2].C(N(CC)CC)C.[N:20]#[N:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[C:29]([S:36]([NH:39][C@H:40]([C:48](Cl)=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46])(=[O:38])=[O:37])[CH:28]=[CH:27]2>C(Cl)(Cl)Cl>[N:20]#[N:21].[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]([C:48](=[O:49])[C@H:40]([CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])[NH:39][S:36]([C:29]1[CH:28]=[CH:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:30]=1)(=[O:38])=[O:37])[CH2:7][CH:8]([O:10][CH3:11])[CH3:9])[CH3:2]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: CCOC(=O)CNCC(C)OC
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(C)OC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1.3 g of N-(2-methoxypropyl)glycine ethyl ester and 1.7 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride which was obtained in Example 3. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ether to give 2.4 g of powdery N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxypropyl)glycine ethyl ester.
Reaction SMILES: OC1C=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=O)=[N:6]C=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=O)=[N:21][CH:22]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[NH3:6].[N:26]1([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:4][CH2:5][CH2:8][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:22][N:21]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(c1ccc(O)cn1)N1CCCCC1
Reactant: O=C(O)c1ccc(O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: N
Product: c1cc(CN2CCCCC2)ncc1OCCCN1CCCCC1
Yield: 43 %
Yield: 5 %

Procedure:
(5-Hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone. To a solution of 5-hydroxy-2-pyridine carboxylic acid (2.00 g, 14.0 mmol) and piperidine (1.5 mL, 15 mmol) in DCM (150 mL) was added HOBt (2.80 g, 21.0 mmol), EDC (4.00 g, 21.0 mmol), and N-methyl morpholine (8.5 mL, 84 mmol). After 18 h the reaction mixture was concentrated. Chromatography of the residue (SiO2; 5-10% 2 M NH3 in MeOH/DCM) gave the title compound as a solid (1.30 g, 43%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[O-]C1C=CC=CC=1.[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCCCCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1ccc(C(C)(C)C)cc1

Procedure:
To a stirred slurry of 1.6 g sodium hydride (as 50% dispersion in oil) in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g p-tert-butylphenol (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution stirred under nitrogen until the phenoxide had totally formed. To the phenoxide was added a solution of 5.0 g 4-chlorobutyl acetate (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution was stirred for fourteen hours. The reaction mixture was partitioned between water/toluene. The organic layer was removed, washed with water, then 1N sodium bicarbonate. The organic layer was removed, dried and evaporated to an orange oil, 5.6 g. The oil was chromatographed on 500 g, 90 to 200 mesh silica gel (CH2Cl2 eluent) yielding pure 4-(p-tert-butylphenoxy)-butyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH:9]([N:11]([CH3:13])[CH3:12])[CH3:10])=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([N:11]([CH3:13])[CH3:12])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)c1ccc(F)cc1)N(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 105 °C

Procedure:
11.2 g of sodium hydride (66%) are washed with hexane to remove oil, and added to 200 ml of dry dimethylacetamide. 50.0 g (0.256 mol) of 1-(4-fluorophenyl)-2-dimethylamino-propan-1-one (prepared by the method described in U.S. Pat. No. 5,534,629) are dissolved in 50 ml of dry dimethylacetamide and added dropwise to the above described solution. Successively, 48.2 g (0.282 mol) of benzyl bromide are slowly added dropwise with stirring and warmed up to 105° C. When the mixture has been stirred at this temperature for 12 h, the reaction mixture is poured to 500 ml of ice/water and extracted with toluene. The organic phase is washed with water, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:20) as eluent. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.17 (s,3H), 2.33 (s,6H), 2.96 (d, 1H), 3.39 (d, 1H), 6.87 (m,2H), 7.03-7.13 (m,5H), 8.55 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:21]([N:40]1[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=2)=[N:43][N:42]=[N:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[C:44]3[N:40]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:41]=[N:42][N:43]=3)=[CH:58][CH:57]=2)[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 37.5 %

Procedure:
Following a procedure similar to that described in Example 18(a), but using 0.26 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 8), 45.5 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 0.63 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.28 g of the title compound were obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18]1([C:21](=O)[CH2:22][C:23](OCC)=[O:24])[CH2:20][CH2:19]1.C[O-].[Na+].C(O)(=O)C>COCCO.O>[CH:18]1([C:21]2[CH:22]=[C:23]([OH:24])[N:14]3[N:13]=[C:12]([C:3]4[C:2]([CH3:1])=[N:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH:16]=[C:15]3[N:17]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Cc1nc2ccccc2nc1-c1cc(N)[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: COCCO
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3CC3)cc(O)n2n1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine (Example 1.001 (c)) (200 mg, 0.888 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (416 mg, 2.66 mmol), and sodium methoxide (28% in methanol, 1.03 g, 5.34 mmol) in 2-methoxyethanol (2.0 mL) was refluxed for 10 h. After being cooled to ambient temperature, the reaction mixture was acidified to pH 3-4 with acetic acid. The mixture was diluted with water and the resulting precipitate was collected and washed with diisopropyl ether to give 5-cyclopropyl-2-(3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ol. MS (APCI): m/z 318 (M+H).