Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].O>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([N:4]([O:3][CH3:2])[CH3:5])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 32.6 g of N-methoxymethanamine hydrochloride and 91.2 ml of triethylamine in 500 ml of DCM is cooled in an ice bath, and then 47 ml of 2,4-dichlorobenzoyl chloride are added slowly and the mixture is left to stir while allowing the temperature to rise to AT. After stirring for 1 hour at AT, water is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 53 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(F)cnn1C
Yield: 27 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-chlorophenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) was necessary, providing a 10 mg (27% yield) of Compound 83: LCMS m/z (%)=377 (M+H37Cl, 25), 375 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.28 (s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.64 (dd, J1=8.8 Hz, J2=2.8 Hz 1H), 7.48 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.34 (dd, J1=9.2 Hz, J2=0.8 Hz, 1H), 7.26 (dd, J1=8.2, J2=8.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.00 (dd, J1=8.8 Hz, J2=0.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.35 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:4][CH2:3][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH3:1]
Reactant: CC(C)(CO)N1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)N1CCCC1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-Methyl-2-pyrrolidin-1-ylpropan-1-ol (0.3776 g, 2.0682 mmol) was taken up in anhydrous DMF (5 mL). Sodium hydride (0.083 g of a 60% dispersion, 2.0682 mmol) was added. The reaction was stirred at RT until gas evolution was complete. 1-Chloro-2-methoxy-4-nitrobenzene (0.3578 g, 2.0682 mmol) was added. The reaction was heated to 80° C. and stirred for 72 h. Cooled to RT and diluted with EtOAc, (50 mL) and washed with water (3×50 mL). Organics were dried over MgSO4, filtered and concentrated. Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH) to give 0.075 g (0.2551 mmol, 12%) of the product. 1H NMR (CDCl3) δ 7.81 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 7.15 (d, 1H, J=8.8 Hz), 3.88 (s, 3H), 2.76 (s, 2H), 2.68 (bs, 4H), 1.75 (bs, 4H), 1.38 (s, 6H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6]>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1Cl
Yield: 189.5 %

Procedure:
2-Chloro-4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D27) (1.0 g) was heated at reflux in thionyl chloride (20 ml) for 1.5 h. The thionyl chloride was removed by evaporation and the residue evaporated from DCM (3×30 ml) to give the title compound (D28) (1.0 g).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:50][S:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)(=[O:49])=[O:48])=[O:26])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21

Procedure:
Using a similar procedure to the described in Example 2, but starting from 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(morpholinocarbonyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid and phenylsulfonamide, the title compound was obtained as a white solid (69%); mp 244°-245°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:2]1.N1C=CC=CC=1.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[CH2:2]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCNC3)nc3ccccc23)CC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.15 g), pyridine (60 mg), and chloroform was added phenylacetic acid chloride (87 mg), and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=2:1−ethyl acetate) to obtain t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g). (2) To t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g) was added a mixed solution (7.5 mL) of chloroform and trifluoroacetic acid (10:1), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, then the solvent was evaporated, and the residue was purified by preparative TLC to obtain title compound (69 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH2:28]>C(#N)C>[CH3:27][NH:28][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=2)[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), methanamine (33% in EtOH, 0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 255 (M+, 92), 132 (52), 131 (bp), 77 (76), 70 (48).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.CI.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: COc1ccc(-c2cc(C)c(=O)[nH]n2)cc1

Procedure:
The product of step 2 (6-(4-methoxy-phenyl)-2,4-dimethyl-2H-pyridazin-3-one) was prepared as described for example 22 step 2 using 6-(4-methoxy-phenyl)-4-methyl-4,5-dihydro-2H-pyridazin-3-one, MeI and Cs2CO3.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1
Reactant: O=C([O-])O
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N(C)C)cc1

Procedure:
23 g of 4-dimethylaminobenzoic acid was dissolved in 200 ml of methanol to which was added 2 ml of concentrated sulfuric acid and the mixture was refluxed with heating for 2 days. After cooling, the reaction mixture was poured into an aqueous solution of sodium bicarbonate and the crystals thus deposited were collected by filtration, washed with water and dried to obtain 24 g of 4-dimethylaminobenzoic acid methyl ester having a melting point of 101° to 102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[C:15]([CH3:22])=[N:14]1.Cl.[OH-].[Na+].C1(C)C=CC=CC=1>O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:22])=[N:14]1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
1-(2-fluoro-4-chloro-5-isopropoxyphenyl)-3,5-dimethyl-4-nitropyrazole (32.8 g) and metallic iron (33.5 g) were suspended in water (140 ml), and the resultant suspension was heated at 80° C., to which 35% aqueous hydrochloric acid (3.2 g) was then added dropwise. After the completion of addition, the reaction mixture was stirred for further 30 minutes at 80° C. Subsequent to cooling, the reaction mixture was brought to pH 9 with aqueous sodium hydroxide solution, followed by addition of toluene to form two layers. The organic layer as separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (27.7 g) as a pale yellow oil which soon crystallized on standing at room temperature. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 94°-96.5° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[CH3:12][C@@H:13](O)[CH2:14][CH:15]=[CH2:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][C@H:15]([CH2:14][CH:13]=[CH2:12])[CH3:16])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(F)cc1F
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.7 %

Procedure:
To a solution of 2,4-difluoro-6-hydroxybenzaldehyde (1.0 g, 6.33 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.090 g, 12.65 mmol) and triphenylphosphine (2.157 g, 8.22 mmol). To this mixture was added dropwise DIAD (1.599 ml, 8.22 mmol) (exotherm) and stirred at rt. After 20 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The crude was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 10 CV) to give (S)-2,4-difluoro-6-(pent-4-en-2-yloxy)benzaldehyde (0.3394 g, 1.500 mmol, 23.72% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 10.33 (s, 1H), 6.67-6.32 (m, 2H), 6.04-5.63 (m, 1H), 5.32-5.00 (m, 2H), 4.66-4.40 (m, 1H), 2.68-2.28 (m, 2H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:19]([O:31]COC)=[CH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[CH2:8]([O:15][C:16]1[N:17]=[CH:18][C:19]([OH:31])=[C:20]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCOc1cnc(OCc2ccccc2)cc1C#Cc1ccc(F)cc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cnc(OCc2ccccc2)cc1C#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (0.95 mL, 12.4 mmol) was added to a stirring solution of 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5-(methoxymethoxy)pyridine (450 mg, 1.24 mmol) in dichloroethane (5 mL) at room temperature. It was allowed to stir for 5 hours and then concentrated to dryness to give 6-(benzyloxy)-4-((4-fluorophenyl)ethynyl)pyridin-3-ol (395 mg, 1.24 mmol, 100% yield) consistent by LCMS. LC-MS retention time: 2.49 min; m/z (MH+): 320. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](OCC)=O)=[CH:4][CH:3]=1.[H-].[Na+].[I:22][C:23]1[CH:30]=[CH:29][C:26](CBr)=[CH:25][CH:24]=1.[Cl-].[NH4+].[Cl-].[Li+]>O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:8][C:26]2[CH:29]=[CH:30][C:23]([I:22])=[CH:24][CH:25]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(Br)cc1)Cc1ccc(I)cc1
Temperature: 160 °C
Yield: 84 %

Procedure:
A mixed liquid containing diethyl 4-bromobenzylmalonate (9.88 g, 30.0 mmol) and anhydrous N,N-dimethylformamide (12.0 mL) was added gradually at 0° C. to a mixed liquid containing sodium hydride (62 wt % in oil, 1.74 g, 45 mmol) and anhydrous N,N-dimethylformamide (18.0 mL). Following stirring of the resulting mixed liquid at this temperature for 30 minutes, a mixed liquid containing 4-iodobenzyl bromide (11.6 g, 39.0 mmol) and anhydrous N,N-dimethylformamide (30 mL) was added. The resulting mixed liquid was stirred at room temperature for 3 hours, and a saturated aqueous solution of ammonium chloride was then added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with ethyl acetate. The thus obtained organic layer was washed with a saturated saline solution and then dried using anhydrous magnesium sulfate. The organic layer was filtered, the filtrate was concentrated under reduced pressure, to the thus obtained residue were added lithium chloride (5.09 g, 120 mmol), water (1.08 mL) and N,N-dimethylformamide (100 mL), and the resulting mixture was heated for 12 hours at 160° C. The thus obtained mixed liquid was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The thus obtained organic layer was dried using anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:1), yielding the title compound (4h) (11.9 g, 25.2 mmol) as a yellow liquid in a yield of 84%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[N:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([O:18][CH2:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)[N:8]=1)=[O:6].CO>O1CCCC1>[CH:20]1([CH2:19][O:18][C:9]2[N:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=[N:11][C:10]=2[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Sodium hydroxide 2M (10 mL) was added to a solution of the 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester (2.2 g, 7.4 mmol) in a (1:1) mixture of methanol and tetrahydrofuran (30 mL), the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ether (30 mL) and extracted with water (50 mL), the aqueous layer was washed with ether (2×50 mL) until only product remained in the aqueous layer. The aqueous layer was cooled to 0° C. and acidified with concentrated hydrochloric acid until precipitation was observed. The precipitate was filtered and dried in vacuo to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid as a cream solid 1.65 g (80% yield) LC@215 nm; Rt 1.98: 93%, m/z (ES+): 278 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:21]C(=O)C1C=CC=CC=1)[CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7].O1CCCC1>C(N(CC)CC)C>[NH2:21][C@@H:4]([CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7])[C:3]([O:2][CH3:1])=[O:30]
Reactant: COC(=O)[C@H](CC(=O)c1ccc2oc3ccccc3c2c1)NC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)CC(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid methyl ester, prepared as described in Step (b) of Example 6, was dissolved in tetrahydrofuran containing one equivalent of triethylamine. The solution was stirred at room temperature for 1 hour, and then the solvent was removed by evaporation to give a solid. The solid was washed with water to give methyl (S)-2-amino-4-dibenzofuran-2-yl-4-oxo-butyrate as a mono-hydrate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[C@H:22]([C:37]([OH:38])([CH3:39])[CH3:36])[CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(=O)O1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a cooled solution of (5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2-one (compound 40d, 5.00 g, 14.0 mmol) in dry tetrahydrofuran (28 mL) was added a solution of lithium bis(trimethylsilyl)azanide (1.3 M in THF, 11.8 mL, 15.4 mmol) dropwise at −78° C. under argon. After addition, the mixture was stirred at −78° C. for 1 hour. Then distilled acetone (1.23 mL, 15.4 mmol) was added dropwise to the mixture and the resulting mixture was stirred at −78° C. for another 2 hours. The reaction was quenched by saturated NH4Cl solution and extracted with EtOAc (30 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 5.7 g of (3S,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40e) as a light yellow oil. MS obsd. (ESI+) [(M+NH4)+]: 430. (For the synthesis, please refer to: Tetrahedron 1997, 53, 6281-6294).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:22](=[O:25])[N:21]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@@H:34]([CH:36]5[CH2:38][CH2:37]5)[OH:35])=[C:28]([O:39][CH3:40])[CH:27]=4)[CH:20]=[N:19][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:22](=[O:25])[N:21]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@@H:34]([CH:36]5[CH2:37][CH2:38]5)[O:35][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[C:28]([O:39][CH3:40])[CH:27]=4)[CH:20]=[N:19][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](O)C1CC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](OC(=O)CCCC(=O)O)C1CC1
Temperature: 40 °C
Reaction time: 25 h
Yield: 77.7 %

Procedure:
A mixture of glutaric anhydride (73.0 mg, 0.640 mmol), (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (60 mg, 0.128 mmol) prepared in Example 1 and 4-pyrrolidinopyridine (18.96 mg, 0.128 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. for 25 hours. LC-MS indicated about 35% conversion. Additional portions of glutaric anhydride (130 mg) and 4-pyrrolidinopyridine (20 mg) were added. After stirring at 40° C. for another 16h, conversion was complete according to HP LC. The mixture was cooled to RT, diluted with CH2Cl2 (10 mL), washed with 1N HCl, brine-, died (Na2SO4), filtered, and evaporated to yield a white solid, which was purified by Preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 inn) to yield impure title compound (58 mg, 78%) as a white solid. The product was further purified by Preparative HPLC using CH3CN-system (PHENOMENEX® Luna Axia 5® C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A: 100% B (A 90% H2O/10% CH3CN+0.1% TFA); (B=90% CH3CN/10% H2O+0.1% TFA); detection at 220 nm) to yield the title compound (40 mg, 0.069 mmol, 53.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 0.33-0.43 (m, 1H), 0.45-0.55 (m, 1H), 0.55-0.68 (m, 2H), 1.06-1.18 (m, 1H), 1.85-1.95 (m, 2H), 2.30-2.45 (m, 4H), 3.86 (s, 3H), 4.23-4.35 (m, 2H), 4.64-4.73 (m, 1H), 6.87-6.96 (m, 2H), 7.03 (d, J=7.9 Hz, 2H), 7.44 (d, J=8.35 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.35 Hz, 2H), 8.24 (s, 1H). LC-MS, [M+H]-4=583.5. HPLC Method: Gradient solvent system from 100% A:0% B to 0% A:100% B (A=90% H2O/10% MeOH+0.2% H3PO4; B=90% MeOH/10% H2O+0.2% H3PO4) for 4 min; detection at 220 nm. YMC S3 ODS 4.6×50 mm Ballistic column; Retention time=4.35 min.