Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:3]([O:5][CH3:6])=[O:4].ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([S:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:29])=[CH:12][CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1ccc(Sc2ccccc2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(Cl)Cc1ccc(S(=O)c2ccccc2)nc1

Procedure:
Methyl 2-chloro-3-(6-phenylthio-3-pyridyl)propionate (10.5 g), prepared in substantially the same manner as in Reference Example 5 using the corresponding starting materials, is dissolved in 100 ml of dichloromethane. To the solution, 7.1 g of m-chloroperbenzoic acid is added slowly with stirring under cooling in an ice-water bath. The mixture is stirred at room temperature for 1 hour, washed with saturated sodium carbonate solution, dried over magnesium sulfate, and concentrated to give crude methyl 2-chloro-3-(6-phenylsulfinyl-3-pyridyl)propionate. To the sulfinyl compound is added 170 ml of 4N sodium hydroxide solution, and the mixture is refluxed with stirring for 4 hours. After cooling, the resulting precipitate is collected to give 4.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)c1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-methoxyphenylboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5](S(C)(=O)=O)=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:34]([NH:37][C:5]1[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[N:4]=1)[CH:35]=[CH2:36]
Reactant: COC(=O)c1ccc(C)c(-n2c(S(C)(=O)=O)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Reactant: C=CCN
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of methyl 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylsulfonyl)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (3.02 g, 6.05 mmol), allyl amine (0.55 mL, 7.26 mmol), and DMAP (0.07 g, 0.61 mmol) in dioxane (8 mL) was stirred at ambient temperature overnight. Observed product and impurity (1:1 ratio). Added ethyl acetate (4 mL), cooled (0° C.) the reaction mixture, filtered the precipitate, and dried in vacuo to give the product as a white solid (1.17 g, 41%). 1H NMR (CD3OD/400 MHz) δ8.08 (m, 1H) , 7.82 (s, 1H), 7.57 (m, 2H), 7.00 (t, 2H, J=8.8 Hz), 5.80 (m, 1H), 5.51 (m, 2H), 5.07 (m, 2H), 4.56 (s, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 3.65 (s, 3H). ESHRMS m/z 476.1184 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][OH:28])C>CS(C)=O>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][OH:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CCO
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CS(C)=O
Product: O=c1cc(CO)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-hydroxy-but-2-ynoic acid ethyl ester (G. Cai et al., Tetrahedron, 2006, 5697-5708) employing the procedure described in Example 99. [α]D25 +5.80 (c 0.5, DMSO)
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]1([N:14]2[C:18]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:17](=[O:24])[NH:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:21]1[CH2:20][CH2:19][C:18]2([N:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][NH:16][C:17]2=[O:24])[CH2:23][CH2:22]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: C1CCC2OC2C1
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1O)CC2

Procedure:
The title compound was prepared from cyclohexene oxide and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one in analogy of the procedure described for the synthesis of (rac,trans)-8-(2-hydroxy-cyclohexyl)-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73c). (rac,trans) 8-(2-Hydroxy-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid, MS (ISP): 330.3 MH+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][CH:16]=[O:17])[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[CH:7]([NH:15][CH:16]=[O:17])[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC=O)CC1C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)C(NC=O)CC(C)N3C(C)=O)cc1
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a suspension of intermediate 3 (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (62.24 g) in DME (600 ml) was added palladium tetrakis (11.56 g) at room temperature. After 10 min of stirring, were added {4-[(methyloxy)carbonyl]phenyl}boronic acid (54 g) and a 2N solution of Na2CO3 (300 mL) and the mixture was stirred heated to reflux for 16 h. The mixture was concentrated under reduced pressure. After addition of 200 ml of DCM to the residue, the product precipitated, it was filtered and washed with water (3*100 mL). To remove the rest of the water, the solid was washed with isopropyl ether (100 ml), the solid was then added to 220 ml of warm isopropyl ether and the resulting mixture was left in the sonicator. The solid was filtered off and dried to afford the title compound as a beige solid (64.7 g)
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]1[O:21][C:20]2[CH:19]=[CH:18][C:8]([O:9][CH:10](Cl)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:6]=2[O:5]1>CN(C=O)C>[CH2:4]1[O:21][C:20]2[CH:19]=[CH:18][C:8]([O:9][C:14]3[CH:15]=[CH:16][CH:11]=[C:10]([O:9][C:8]4[CH:18]=[CH:19][C:20]5[O:21][CH2:4][O:5][C:6]=5[CH:7]=4)[C:13]=3[CH2:12][C:1]#[N:2])=[CH:7][C:6]=2[O:5]1
Reactant: [C-]#N
Reactant: ClC(Oc1ccc2c(c1)OCO2)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1c(Oc2ccc3c(c2)OCO3)cccc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
Sodium cyanide (85 mg, 1.6 mmol) was added to a solution of 2,6-bis-[(3,4-(methylenedioxy)phenoxy]-benzyl chloride (435 mg, 1.1 mmol) in DMF (3 ml) at room temperature. The resulting dark brown solution was stirred at room temperature for 18 hours. The DMF was removed under high vacuum and the remaining brown residue was extracted into ethyl acetate and washed with brine (1×5 ml). After drying over MgSO4, the solvent was removed by evaporation and the remaining solid was purified by column chromatography using 10% ethyl acetate-hexanes which yielded 217 mg (51% yield) of the pure benzyl cyanide as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: O[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O[C@@H]1CCN(Cc2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
4-bromo-2-fluorobenzaldehyde (203.0 mg, 1.0 mmol) was mixed with (3R)-pyrrolidin-3-ol (87.1 mg, 1.0 mmol) in 1,2-dichloroethane (10 mL). The mixture was stirred at RT for 5 min, and then was treated with sodium triacetoxyborohydride (318 mg, 1.5 mmol). The mixture was stirred at RT for 2 h, and quenched by adding 1N NaOH. The organic phase was separated. The aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (252 mg, 91.9%) which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1.[ClH:29]>C(O)(=O)C>[ClH:29].[N:20]1([CH2:25][CH2:26][CH2:27][N:28]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[CH2:6][N:5]2[C:4](=[O:14])[C:3]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]3[C:1]2=[O:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: NCCCn1ccnc1
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CCCn1ccnc1

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione and 2.5 g (0.02 mol) of 3-(1-imidazolyl)-propylamine are stirred in 70 ml of acetic acid at 80° C. for 2 hours and the mixture is worked up as in Example 1. After ethanolic hydrochloric acid has been added, the product is filtered off and recrystallised from ethanol.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C1CNCCNC1
Solvent: CCO
Product: c1cnc(N2CCCNCC2)nc1
Reaction time: 1 h

Procedure:
To a solution of homopiperazine (3.5 g, 35 mmol) in ethanol (100 ml) at 40° C., was added portionwise 2-chloropyrimidine (2.0 g, 17.5 mmol). The mixture was stirred for 1 hour then concentrated in vacuo. The residue was dissolved in methylene chloride (75 ml) and washed with a saturated solution of sodium bicarbonate and brine. Layers were separated, and the organic layer was dried over magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography and a semi-solid (1.0 g) was collected and used as is.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=CO[CH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29].C(O)(=O)C>ClC(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:21][C:25]3=[N:26][C:27](=[O:30])[O:28][CH3:29])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)NCOC=N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:39]2([OH:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:41])[N:31]2[CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 2 (4.0 g, 13.7 mmol) in dry THF (40 mL) at −78° C. was treated with n-BuLi (2.5 M, 6.0 mL, 15.0 mmol) for 15 min to produce 3. To this solution, 5 (3.1 g, 12.2 mmol) in dry THF (40 mL) was added slowly over a 10 min period. The reaction mixture turned light brown in color and stirring was continued for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layer was washed with brine (15 mL). Volatiles were evaporated under reduced pressure and the crude residue was purified by column chromatography using 20% acetone/hexane as the eluent to afford the title compound 6 as a white solid (2.6 g, 46%).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH:18]=[O:19]>O1CCOCC1>[CH3:14][N:13]1[C:8]([S:4][CH2:1][CH2:2][CH3:3])=[C:9]([CH:18]=[O:19])[C:10](=[O:17])[N:11]([CH3:16])[C:12]1=[O:15]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCSc1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C

Procedure:
To a stirred solution of propane-1-thiol (2.30 mmol) in dry 1,4-dioxane (4 ml), NaH (2.30 mmol) was added under argon. To the mixture, a solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (2 mmol) in dry 1,4-dioxane (8 ml) was added at 5-8° C. in one portion. The mixture was stirred at room temperature until the starting material was consumed (monitored by TLC). Then the mixture was poured onto ice water (50 ml) and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with water and dried over anhydrous MgSO4. The solvent was evaporated in vacuo and the crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (1:1) as the eluent.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[ClH:30]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[ClH:30]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O

Procedure:
3.01 Grams of Z-Asn-Leu-OEt was dissolved in 50 ml of methanol and 7.4 ml of 1N-HCl, the solution was subjected to catalytical reduction in the presence of 500 mg of palladium black at a room temperature, under an atmospheric pressure to obtain H-Asn-Leu-OEt.HCl.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.C(N(CC)CC)C.[CH2:32](I)[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH2:32]([O:23][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:24])[CH2:33][CH2:34][CH3:35]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CCCCI
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (521 mg.) in dry acetone (50 ml.) was refluxed with triethylamine (1.04 ml.) and n-butyl iodide (0.87 ml.) for 16 hours. The mixture was evaporated to a residue which was dissolved in chloroform, washed with water, dried (Na2SO4) and evaporated to a foam (534 mg.). A solution of the foam in ether was washed with saturated sodium bicarbonate solution and with water, dried (Na2SO4) and evaporated to give title compound (443 mg.) as a white foam, [α]D + 51°.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:38]5[CH2:39][CH2:40][C:35]6([O:34][CH2:33][CH2:32][O:31]6)[CH2:36][CH2:37]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCC5(CC4)OCCO5)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 1,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.1 (m, 20H), 2.05 (m, 4H); MS (DCI) m/z 478 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N+:3]=1[O-:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccnc(Cl)c3)nc2c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)cc1Cl
Temperature: 50 °C
Yield: 90.2 %

Procedure:
To a mixture of 0.40 g of 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.53 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred while ice-cooling for 30 minutes, then stirred at room temperature for three hours, and then stirred while heating at 50° C. for 1.5 hours. To the mixture, 0.53 g of 65% m-chloroperbenzoic acid and 2 ml of chloroform were added and stirred while heating at 60° C. for five hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 0.38 g of 2-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 22”).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:32])[C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:30][C:28]5[CH:27]=[CH:26][N:25]=[C:24]([N:23]([CH3:32])[CH3:22])[N:29]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)c1nccc(C=O)n1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: C[C@@H]1CN(Cc2ccnc(N(C)C)n2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 2-(dimethylamino)pyrimidine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.24-8.21 (m, 1H), 8.00-7.99 (m, 1H), 6.52-6.50 (m, 1H), 5.13-5.10 (m, 1H), 3.72-3.68 (m, 1H), 3.56-3.52 (m, 1H), 3.46-3.40 (m, 3H), 3.17-3.11 (m, 7H), 2.84-2.82 (m, 1H), 2.64-2.60 (m, 1H), 2.44-2.38 (m, 1H), 2.06-1.92 (m, 5H), 1.66-1.65 (m, 2H), 1.20-1.16 (m, 3H). MS: (M+H m/z=423.1).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Br:17])=[CH:12][C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:16][C:13]1[CH:12]=[C:11]([Br:17])[C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[C:14]=1[Br:15]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Br)cc(Cl)c(Br)c2n1
Product: CC(C#N)(Cn1nc2c(Br)cc(Cl)c(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile (44 mg, described in Example 53) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (15 mg, 22%). MS (ES): M/Z [M−H]=594. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.43 (d, J=13.4 Hz, 1H), 5.61 (d, J=13.3 Hz, 1H), 7.88 (q, J=8.5 Hz, 4H), 8.04 (s, 1H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[Cl:18])=[CH:34][CH:33]=2)=[O:39])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Reactant: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Yield: 93.1 %

Procedure:
1.84 g (7.0 mmol) of 4-benzyloxy-2-chloro-benzoic acid, 1.90 g (6.7 mmol) of 4-hydroxy-benzoic acid 4-pentyl-phenyl ester and 0.082 g (0.67 mmol) of 4-dimethylaminopyridine were dissolved in 50 mL of methylene chloride followed by the addition of 1.45 g (7.0 mmol) of dicyclohexylcarbodiimide while stirring in the presence of argon. After stirring for 8 hours in the presence of argon, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 3.3 g of a white solid.