Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:8]([C:11]1[N:16]=[C:15]([N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:34])[CH2:32][OH:33])[N:12]=1)(=O)=O)C1C=CC=CC=1.O.[SH-].[Na+:37].[SH-].[Na+]>CS(C)=O>[OH:33][CH2:32][C@H:31]([NH:30][C:13]1[CH:14]=[C:15]([N:17]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[N:16]=[C:11]([S-:8])[N:12]=1)[CH3:34].[Na+:37]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc([S-])n1
Reaction time: 2 h

Procedure:
To a solution of the product of step iii) (3.97 g) in DMSO (30 ml) was added sodium hydrosulphide hydrate (0.84 g). Stirring was continued for a further 2 h and additional aliquots of 0.42 g of sodium hydrosulphide were added until complete disappearance of starting material as assessed by reverse phase HPLC-MS. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides described in examples 43-53 and 137.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:15][CH:14]=1)=[NH:12])C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[ClH:32].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:18]=1)(=[NH:10])[NH2:12]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N=C(N)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Yield: 165.4 %

Procedure:
To a solution of the compound obtained from Step H (50 mg) in methanol (2.0 mL) was added HCl in dioxane (4.0 M, 0.13 mL) and 10% Pd/C (20 mg). This mixture was hydrogenated with a hydrogen ballon for 1.0 h. Removal of Pd/C and solvent gave the desired product as a white solid (34 mg, 82%). 1HNMR (300 MHz, DMSO-d6) δ 9.34 (br, 2H), 9.05 (m, 3H), 7.78 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 5.02 (m 1H), 4.43–4.31 (m, 3H), 3.5 (s, br), 2.90 (m, 2H), 2.21–2.05 (m, 6H), 1.65 (m, 2H). MS m/e 415(M+1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]=[C:17]([CH2:20][OH:21])[C:16]=2[CH:22]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]=[C:17]([CH:20]=[O:21])[C:16]=2[CH:22]=1
Reactant: OCc1coc2ccc(F)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1coc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At a constant temperature of −60° C. dimethylsulfoxide (3.27 g, 41.8 mmol) in dichloromethane (10 mL) was added to a solution of oxalylchloride (2.65 g, 20.9 mmol) in dichloromethane (30 mL) and the solution was stirred for 15 minutes. 1-(5-Fluorobenzofuran-3-yl)methanol (3.16 g, 19.0 mmol) dissolved in dichloromethane (60 mL) was added dropwise at −60° C. The mixture was stirred for 20 minutes followed by addition of triethylamine (9.61 g, 0.095 mmol). After stirring for 10 minutes, the reaction mixture was allowed to heat to ambient temperature and stirred for additional 20 minutes. The organic fraction was washed successively with 50 mL portions of water, 1N aqueous HCl, saturated aqueous sodium bicarbonate and brine, then dried (MgSO4) and concentrated in vacuo to furnish crude title compound in quantitative yield as a beige crystalline solid. 1H NMR (CDCl3): 7.13 (dt, 1H); 7.50 (dd, 1H); 7.86 (dd, 1H); 8.30 (s, 1H); 10.15 (s, 1H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[CH2:19]([N:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([CH3:10])=[CH:9][C:4]=1[Br:3])[C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N(Cc2ccccc2)C(=O)C(C)C)c(Br)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
A mixture of powdered KOH (1.3 g, 23.13 mmol) in DMSO (25 mL) was stirred at 0° C. for 5 minutes. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (3.30 g, 11.56 mmol) was added cautiously followed immediately by the addition of benzylbromide (2.75 mL, 23.13 mmol) and the reaction stirred at room temperature for 48 hrs. Water was added and the mixture extracted with ethyl acetate. The organic extract was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 4.3 g of N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). 1H NMR (300 MHz; CDCl3): 1.02 (d, J=6.6 Hz, 3 H), 1.15 (d, J=6.6 Hz, 3 H), 2.16 (s, 3 H), 2.29 (m, 1 H), 3.43 (s, 3 H), 3.85 (d, J=14.1 Hz, 1 H), 5.75 (d, J=14.1 Hz, 1 H), 6.02 (s, 1 H), 7.18–7.27 (m, 5 H), 7.38 (s, 1 H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:21]([OH:38])[CH:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 min and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*, 2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 188-189° C.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH3:34])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:35])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
2-Methyl-2-{[4-({[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}methyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (900 mg) obtained in Example 152-2 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (420 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH2:6][CH3:7])[C:4]1=[O:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH3:2].O>C(O)(=O)C.Cl>[CH2:1]([C@@H:3]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH2:6][CH3:7])[C@H:4]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(CC)C1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(CC)[C@H]1O
Yield: 47.4 %

Procedure:
A solution of 1.3 g of 16β-ethyl-3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one in 14.5 ml of glacial acetic acid and 2 ml of concentrated hydrochloric acid is stirred for 16 hours at room temperature. Then the mixture is poured into water, extracted with ethyl acetate, the ethyl acetate extracts washed in succession with saturated NaHCO3 solution and saturated NaCl solution, dried over sodium sulfate, and concentrated under vacuum. The oily crude product is reduced according to 1(d) with sodium borohydride. Chromatography on silica gel with petroleum ether/ethyl acetate yields 620 mg of 16α-ethyl-3-methoxy-18-methyl-1,3,5(10)-estratrien-17β-ol, m.p. 112°-114° C. (from methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:32])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][C:12]([Cl:32])=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ncc[n+]([O-])c2-c2ccc(OC)cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ncc(Cl)nc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
To 20 ml of phosphorus oxychloride was added with stirring 3.918 g of 2,3-bis(p-methoxyphenyl)pyrazine oxide. The mixture was heated under reflux for 30 minutes. After allowed to cool, the reaction mixture was poured into ice water and then made basic with potassium carbonate to precipitate the product, which was collected by filtration. There was obtained 2.823 g of 2,3-bis(p-methoxyphenyl)-5-chloropyrazine. A mixture of 653 mg of said compound, 414 mg of anhydrous potassium carbonate and 116 mg of tetrakis(triphenylphosphine)palladium was suspended in an atmosphere of argon in 10 ml of dry N,N-dimethylformamide. To the suspension was added 2 ml of a hexane solution of triethylborane (15%). The resulting mixture was heated under reflux for 2 hours, followed by removal of the solvent by distillation under reduced pressure. Water was added to the residue, and the resulting mixture was extracted three times with methylene chloride. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure afforded 850 mg of an extraction residue. The residue was subjected to column chromatography on silica gel. There was obtained 555 mg of 2,3-bis(p-methoxyphenyl)-5-ethylpyrazine from the eluates with a 1:1 hexane:methylene chloride mixture. M.P. 76.5°-78° C. (colorless needles, recrystallized from ethanol). Physical properties of the product support a chemical structure of the below formula (XII).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.6 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (15 g, 90 mmol), benzyl alcohol (10.8 g, 100 mmol) and potassium carbonate (18.7 g, 135 mmol) in DMF (20 ml) was stirred at room temperature for 60 h. Water (60 ml) was added to the reaction, and the resultant yellow precipitate out filtered, washed with water, and dried under reduced pressure to provide 17.3 g (75.4%) of 5-benzyloxy-2-nitrobenzonitrile. The compound was used directly for the next step without further purification. MS GC-MS M+=211, RT=6.15 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:12](=[O:17])[NH:13][CH:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.Br[C:21]1[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[C:23]([CH3:33])[CH:22]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][O:25][C:24]1[CH:31]=[CH:32][C:21]([N:13]2[CH:14]=[CH:15][N:16]=[C:11]([S:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:19])=[CH:9][CH:8]=3)[C:12]2=[O:17])=[CH:22][C:23]=1[CH3:33]
Reactant: Cc1cc(Br)ccc1OCC(C)(C)O
Reactant: O=c1[nH]ccnc1Sc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC(C)(C)O
Temperature: 115 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A mixture of 3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (100 mg, 0.347 mmol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (90 mg, 0.347 mmol), N1,N2-dimethylethane-1,2-diamine (92 mg, 1.041 mmol), copper(I) iodide (19.82 mg, 0.104 mmol) and K3PO4 (221 mg, 1.041 mmol) in dioxane (1.0 mL) was stirred at 115° C. in a sealed tube for 2 hours. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 100% EtOAc) to elute 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-(trifluoromethoxy)phenylthio)-pyrazin-2(1H)-one (18.65 mg, 0.040 mmol, 11.52% yield) as off-white solid. 1H NMR (500 MHz, methanol-d3) δ ppm 7.62-7.68 (2H, m), 7.37 (2H, d, J=7.97 Hz), 7.21-7.28 (3H, m), 7.16 (1H, d, J=4.40 Hz), 7.02 (1H, d, J=8.25 Hz), 3.84 (2H, s), 2.31 (3H, s), 1.36 (6H, s).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)(=O)=O>CN(C)C=O>[O:9]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OCC1=CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(COc2ccccc2)OCCC1
Reaction time: 0.5 h

Procedure:
6.0 g (0.25 mol) of sodium hydride are added a little at a time at room temperature to 20.5 g (0.22 mol) of phenol in 200 ml of dimethylformamide. Stirring is carried out for 30 minutes at room temperature, after which 42 g (0.22 mol) of 2,3-dihydropyran-6-ylmethyl methanesulfonate (Example 7b) are added dropwise with slight cooling. Stirring is carried out for 4 hours at room temperature, after which the reaction mixture is poured onto water. The aqueous phase is extracted three times with diethyl ether and the organic phase is dried over MgSO4 and evaporated down under reduced pressure. The residue is distilled. 27 g (0.14 mol=57%, based on 6-formyl-2,3-dihydropyran) of the title compound are obtained as a pale yellow oil.
Reaction SMILES: Br.[N:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:28][O:29][C:30]([C:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([NH:38][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]3[N:18]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([N:2]5[CH2:3][CH2:4][O:5][CH2:6][CH2:7]5)[CH2:13][CH2:12]4)[S:15][CH:16]=3)=[CH:20][CH:21]=2)=[O:24])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:31]
Reactant: O=C(O)c1ccc(-c2csc(N3CCN(N4CCOCC4)CC3)n2)cc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Br
Product: COC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(N5CCOCC5)CC4)n3)cc2)CCCCC1

Procedure:
4.50 g (9.90 mmol) of 4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acid hydrobromide was used instead of 4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide and 1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference Example 160 to obtain 5.08 g (quantitative) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:25].Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([NH:51][C:52]([CH3:66])([CH3:65])[CH2:53][CH:54]([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=1)[C:55](O)=[O:56])=O)(C)(C)C.Cl>C(Cl)Cl>[NH2:51][C:52]([CH3:66])([CH3:65])[CH2:53][CH:54]([C:58]1[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=1)[C:55]([N:40]1[CH2:39][CH2:38][N:37]([C:35]2[C:36]3[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:42][CH2:41]1)=[O:56].[ClH:25]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C(CC(C)(C)N)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (33 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (50 mL) and washed with brine (5×50 mL). The organic phase was dried and concentrated to afford the product. The product was treated with HCl to afford 4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as HCl salt (22 mg, 49%).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([C:21]5([CH2:30][C:31]#[N:32])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:22]5)[CH:20]=4)[N:13]4[CH:33]=[CH:34][N:35]=[C:12]4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:42]>>[Cl:42][C:33]1[N:13]2[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:30][C:31]#[N:32])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:22]4)[CH:20]=3)=[N:15][C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH:9]=3)=[CH:11][C:12]2=[N:35][CH:34]=1
Reactant: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4ncc(Cl)n34)cn2)CN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
2-(3-(4-(7-(1-(Oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (Example 105; 0.040 g, 0.08274 mmol) was suspended in DCM (3 mL) and saturated aqueous NaHCO3 (1 mL). n-Chlorosuccinimide (0.017 g, 0.124 mmol) was added in one portion and the reaction mixture stirred at ambient temperature overnight. Additional n-chlorosuccinimide (0.033 g, 0.248 mmol) was added and the reaction was allowed to stir at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/DCM to provide 2-(3-(4-(3-chloro-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (0.012 g, 0.023 mmol, 28% yield). MS (apci) m/z=518.1 (M+H).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[N:22]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:21]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[C:52]1[CH:84]=[CH:83][C:55]([CH2:56][CH:57]2[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]2=[O:82])=[CH:54][CH:53]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[N:22]([C@@H:26]([CH3:29])[CH2:27][O:28][C:52]2[CH:84]=[CH:83][C:55]([CH2:56][CH:57]3[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)([C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]3=[O:82])=[CH:54][CH:53]=2)[CH2:21]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 29 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 405 mg of tributylphosphine, 25 ml of anhydrous benzene, 700 mg of 2(S)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 40), 505 mg of azodicarbonyldipiperidine and 745 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione were used, to give 340 mg of the title compound, melting at 80° C. to 84° C. and having [α]D =+25.9° (methanol, c=0.96).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[CH2:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)[CH:8]=[CH:9][CH:10]=1)=[CH2:2]
Reactant: OCCO
Reactant: C=Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=Cc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-ethenylbenzaldehyde from Step 1 (3.77 g) and ethylene glycol (1.8 mL) in benzene (40 mL) was added p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was heated to reflux for 6 hours. The water produced by the reaction was collected in a Dean-Stark trap. The reaction was allowed to cool to room temperature. The reaction was diluted with NH4OAc buffer and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. Flash chromatography of the residue using 15% diethyl ether in hexane afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]2([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]2)=[N:5][N:6]=1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (100 mg, 0.289 mmol), ethyl 1-bromocyclobutanecarboxylate (47 μL, 0.289 mmol) and diisopropylethylamine (151 μL, 0.866 mmol) in DMF (1 mL) was heated at 60° C. for 4 days. After cooling to room temperature, the mixture was concentrated and partitioned between dichloromethane (15 mL) and HCl (1N aqueous, 15 mL). The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic extracts dried over sodium sulfate, concentrated and purified by column chromatography (40% EtOAc/hexanes) to provide ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate as a light yellow sticky foam (75 mg, 55% yield).