Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COCC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(N=[N+]=[N-])c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Fluoro-4-(1-methoxy-2-methylpropan-2-yl)-2-nitrobenzene (2.227 g, 9.80 mmol) was dissolved in DMF (25 ml) and sodium azide (1.274 g, 19.6 mmol) was added at r.t. and the reaction stirred overnight. The reaction was quenched with water (75 ml) and the mixture was extracted with TBME (3×75 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 15% EtOAc:85% heptane as eluent to give the product as a yellow oil (2.301 g, 75%, 80% pure): LC purity 79% (ret. time, 2.15 min); 1H NMR (500 MHz, CDCl3) δH 7.97 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.2 Hz, 1H), 7.33-7.22 (m, 1H), 3.40 (s, 2H), 3.33 (s, 3H), 1.36 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19].O>N1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
To a solution of 2-phenyl-1H-indol-6-amine (54 mg, 0.26 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (30 μL, 0.29 mmol). The resulting mixture was stirred at room temperature for 2 days. When water was added, a precipitate was formed. This solid was recrystallised from hot ethyl acetate to afford 15 mg (21%) of the title compound (LCMS RT=6.27 min, MH+ 279.0)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[C:30](N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C(OC)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=[O:32])C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:21][CH2:22]4)[CH:19]=3)=[C:11]([O:32][CH3:30])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: COc1cc2c(cc1-c1ccc(S(C)(=O)=O)cc1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Product: COc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methoxy-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-methoxy-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 244). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.O.[OH-].[Na+].[I:14]I>C(O)C>[ClH:1].[ClH:1].[I:14][C:7]1[NH:8][CH:9]=[N:10][C:6]=1[CH2:5][CH2:4][NH2:3]
Reactant: NCCc1c[nH]cn1
Reactant: II
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCc1nc[nH]c1I
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 250 ml round-bottomed flask equipped with a stir bar and addition funnel was added 4.0 g (21.7 mmol) of histamine dihydrochloride and 6.0 ml of distilled water and the pH adjusted to 8.0 with concentrated NaOH. The addition funnel was charged with a solution of 2.76 g (10.86 mmol, 0.5 equivalent) of I2 in 100 ml of ethanol (abs.) and the solution added slowly dropwise with stirring at room temperature over 6 hours. The pH was periodically monitored and maintained at an apparent pH=8.0 with concentrated NaOH. The dark suspension was then stirred overnight, readjusted to pH=8.0 and allowed to stir an additional 3 hours. The suspension was filtered and evaporated to a red oil. Purification of this material was accomplished by electrophoresis using a 1M HOAc buffer titrated to pH 5 with pyridine. Approximately 400 mg of crude material, dissolved in methanol, was applied in a 1 cm band to an 8"×16" paper which was run for 1 hour at 20 V/cm and 150-180 mA. A thin strip was then removed from the paper and visualized with ninhydrin spray. The iodohistamine band was then cut out of the remaining sheet and eluted with several portions of methanol. The methanol extracts were acidified (con.HCl) and evaporated in vacuo. The remaining residue was re-evaporated with one volume of absolute ethanol followed by recrystallization from absolute ethanol. in this manner 620 mg (19%) of the analytically pure title compound was isolated, m.p. 210° C. with decomposition. The mother liquor was pooled, evaporated, and the residue recrystallized to yield an additional 205 mg of somewhat inferior material.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=C([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)C(N(C)C)=O.CO.C[CH2:20][O:21][C:22]([CH3:24])=[O:23].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:24]([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:22]([O:21][CH3:20])=[O:23]
Reactant: CN(C)C(=O)c1cc(CO)nc(N(C)C)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(CO)nc(N(C)C)c1
Temperature: 135 °C
Reaction time: 12.5 h
Yield: 65 %

Procedure:
A mixture of 167 mg of 2-(dimethylamino)-6-(hydroxymethyl)-N,N-dimethylisonicotinamide in 2 mL of H2SO4 and 1.2 mL of H2O was stirred at 135° C. for 12.5 h. The temperature was decreased to 95° C., methanol (5 mL) was added, and the solution was heated for 1 h. The solution was added to ice with H2O and EtOAc, and solid NaHCO3 and sat. NaHCO3 solution were added to pH=8. The aqueous layer was extracted with EtOAc (4×), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 102 mg of methyl 2-(dimethylamino)-6-(hydroxymethyl)isonicotinate as a yellow solid in 65% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][C:10]=1[F:32])=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][C:10]=1[F:32])=[O:8]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3Cl)c(F)c2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)c(F)c1
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a stirred solution of tert-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetate (15 mg, 0.0276 mmol) in dichloromethane was added TFA. The reaction was stirred for 2 hours and then concentrated. The crude material was purified by preparative TLC (10% methanol/0.5% AcOH/dichloromethane). The appropriate section was collected and then purified a second time by preparative TLC to provide 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetic acid (0.0042 g). 1H NMR (400 MHz, CD3OD) δ 7.70-7.74 (m, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.88-6.94 (m, 2H), 3.52-3.65 (m, 4H), 3.05 (t, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].[Cl:26][C:27]([F:31])=[C:28]([F:30])[F:29]>O1CCOCC1>[C:1]([C:6]1[C:10]([O:11][C:28]([F:30])([F:29])[CH:27]([Cl:26])[F:31])=[CH:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:22])[F:21])=[CH:14][C:13]=2[Cl:23])[N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: FC(F)=C(F)Cl
Reactant: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Reaction time: 6 h

Procedure:
3-Carboethoxy-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole (2.0 g) was added to a stirred suspension of sodium hydride (80% dispersion in oil; 0.2 g) in dry dioxan (20 ml). When the resultant effervescence had subsided, the solution was heated to 80°-900 °C. and stirred while 2-chloro-1,1,2-trifluoroethylene was passed through. After 6 hours, the reaction was complete and the solvent was evaporated to dryness. The residue was dissolved in dilute hydrochloric acid (2M; 10 ml) and dichloromethane (20 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (30 ml) and the combined organic layers were washed with water (20 ml), dried over magnesium sulfate, filtered and evaporated. The residue was purified by dry-column chromatography (eluant ether:hexane 1:3) to give (RS)-3-carboethoxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (1.0 g). This was recrystallised from hexane to yield colorless needles, m.p. 105°-106.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([C:25]([F:28])([F:27])[F:26])[NH:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[C:25]([F:26])([F:28])[F:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1cccc2c1C(C(F)(F)F)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cccc(F)c2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]([CH3:18])([CH2:16][CH3:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(COC)OC>[CH3:8][C:9]([CH3:18])([CH2:16][CH3:17])[CH2:10][C:11]1[N:12]=[CH:13][N:14]([S:21]([N:20]([CH3:25])[CH3:19])(=[O:23])=[O:22])[CH:15]=1
Reactant: CCC(C)(C)Cc1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)cn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (54 mL, 0.48 mol) was added to a solution of 4-(2,2-dimethylbutyl)-1H-imidazole (36 g, 0.24 mol) in dimethoxyethane (360 mL). After warming to 40° C., N,N-dimethylsulfamoyl chloride (38 mL, 0.36 mol) was added over 15 min. After stirring at 40° C. for 2 h, N-methylmorpholine (11 mL) and N,N-dimethylsulfamoyl chloride (8 mL) were added. After stirring for additional 2 h, the reaction mixture was cooled and filtered rinsing with ether. The filtrate was extracted with ether and the combined extracts were washed with brine, dried (magnesium sulfate), filtered, concentrated in vacuo. Chromatography over silica gel afforded the title compound.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][NH:5][C@H:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])=[N:9]2)[CH2:3]1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C@@H:4]3[CH2:3][C:2]([F:1])([F:32])[CH2:6][N:5]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])[C:11]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@@H]1CC(F)(F)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (850 mg, crude), 2-cyanoacetic acid (120 mg, 1.31 mmol, 1.29 equiv) and TEA (650 mg, 6.45 mmol, 5.00 equiv) in dichloromethane (30 mL), was added HATU (500 mg, 1.32 mmol, 1.29 equiv). The resulting solution was stirred at room temperature overnight. The mixture was diluted with DCM, washed with HCl (2N), sat. NaHCO3, brine, dried over sodium sulfate and concentrated. The residue was submitted to chromatography (SiO2, DCM: MeOH=30:1) to give 0.4 g (77%) of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 635.5 %

Procedure:
To a stirred solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.00 g, 0.42 mmol) in DCM (20 mL), were added 2-methoxyethanamine (0.41 mL, 0.47 mmol), DMAP (620 mg, 0.51 mmol) and EDCI (900 mg, 0.47 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was diluted with EtOAc and washed with water. The organic solution was dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, MeOH/DCM) to yield the title compound as a white solid (780 mg, 63%). LCMS: (FA) ES+ 293.2 (M+1), ES− 291.2 (M−1).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@@H:5]1[CH2:6][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 114.5 %

Procedure:
Ethyl (1S,3R,4S)-4-azido-3-(tert-butoxy-carbonylamino)cyclohexane-1-carboxylate (4.0 g) was dissolved in a mixed solvent of ethanol (150 ml) and ethyl acetate (150 ml), and 5% palladium on carbon (0.5 g) was added to stir the mixture at room temperature for 17 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.2 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].C[O-].[Mg+2:12].[Mg].CO>CCCCCCC>[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2:12].[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CCCCCCC
Solvent: CO
Product: [O-]c1ccccc1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
A mixture of 282 g of phenol and 86 g of magnesium methylate prepared from metallic magnesium and methanol was heated at 70° C. to make a solution, to which 300 ml of n-heptane was added. The mixture was refluxed at 98° C. for 24 hours, then cooled, and evaporated in a rotary evaporator to remove heptane, phenol and methanol, thereby giving 170 g of magnesium phenolate.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: C1COCCN1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CN3CCOCC3)c2)C(=O)N1Cc1ccncc1

Procedure:
50 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-2-chloro-acetamide (raw material, as described above) owere dissolved in 2 ml morpholine and heated for 1 h to 50° C. Subsequently, the mixture was poured on ice and extracted with ethylacetate. The combined organic phases were evaporated to dryness and the residue was purified by flash chromoatography (Silica gel, methylene chloride:methanol=1.98:22.95:5) Yield: 20 mg
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41].O>ClCCl>[C:40]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 0.040 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate in 2 ml of dichloromethane is admixed successively with 0.007 ml of pyridine and 0.011 ml of acetic anhydride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with 1M HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.37 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=17.25 (gradient II).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 3-allyloxy-5-hydroxy-benzoic acid methyl ester (la) (10.25 g, 49.2 mmol) in DMF (20 mL) was added methyl iodide (3.67 mL, 59.1 mmol) and K2CO3 (13.6 g, 98.5 mmol). The reaction mixture was stirred at 70° C. for 2 hr, cooled to room temperature. The mixture was quenched with H2O (150 mL) and extracted with EtOAc (2×150 mL). The organic layers were washed with H2O (2×150 mL), dried over MgSO4 and concentrated to give a pale yellow oil which was purified by flash column chromatography eluting with 10% EtOAc in hexane to give a colorless oil (9.63 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.11-7.24 (m, 2 H) 6.68 (t, J=2.40 Hz, 1 H) 5.91-6.17 (m, 1 H) 5.38-5.51 (m, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.52-4.61 (m, 2 H) 3.91 (s, 3 H) 3.83 (s, 3 H); LCMS for C12H14O4 m/z 223.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([P:19](=[O:26])([O:23]CC)[O:20]CC)=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([P:19](=[O:20])([OH:26])[OH:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc([C@@H](C)NC(=O)c2cnc(-c3ccccn3)nc2O)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cnc(-c2ccccn2)nc1O)c1ccc(P(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-diethyl 4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonate, 3-4, (400 mg, 0.88 mmol) in DCM (10 ml) was added dropwise TMSBr (2.0 g, 13.15 mmol) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, and the residue was treated with MeCN and water at room temperature. The resulting solid was collected via filtration to obtain the product, 3-5, (200 mg). 1H NMR (DMSO-d6, 300 MHz,): δ 11.29 (s, 5H), 9.93-9.96 (m, 1H), 8.80-8.81 (m, 1H), 8.56 (s, 1H), 8.37-8.39 (m, 1H), 8.07-8.12 (m, 1H), 7.61-7.74 (m, 3H), 7.42-7.46 (m, 2H), 5.12-5.16 (m, 1H) 2.07 (s, 1H), 1.48-1.51 (m, 3H), (M+H)+=401.2.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20]C)=[O:19])[N:3]=1.[Li+].[OH-]>CO.O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1
Reactant: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
The product Intermediate 1H (0.85 g, 2.36 mmol) was dissolved in methanol (50 mL) and LiOH (0.79 g, 18.88 mmol) in water (10 mL) was added. The resulting solution was stirred at 50° C. overnight. The reaction mixture was concentrated, cooled on ice and brought to pH 3 using 1N HCl. The resulting white precipitate was filtered, washed with water and air dried to give the desired acid Intermediate 1I as a white solid (0.62 g, 76%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:15][N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:19][C:17]1[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:15][N:14]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH:18]=1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (130 mg, brown solid) from 4-chloro-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-74) and phenyl formate (99 mg, 0.81 mmol) in a similar manner to Intermediate-91.