Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[C:27]([Cl:32])[CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:32][C:27]1[CH:26]=[C:25]([S:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 29 step (i).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1OC)[C:19]([NH2:21])=[O:20])=O>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20]
Reactant: COc1ccc(C(N)=O)cc1C=O
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Product: NC(=O)c1cccc(/C=C/c2ccc(C(F)(F)F)cc2F)c1

Procedure:
The captioned compound was synthesized from 2-fluoro-4-trifluoromethylbenzyl bromide and 3-formyl-4-methoxybenzamide by the same procedure as in the manufacturing method described in Example 2-3-6.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][CH2:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1F
Yield: 11.4 %

Procedure:
To a solution of 2-fluoroaniline (22.06 g, 0.198 mol) and freshly distilled tert-butyl acrylate (25.45 g, 0.198 mol) in dry benzene (250 ml) was added tin tetrachloride (1 ml) and the mixture was refluxed for 60 h. The resulting suspension was filtered and the filtrate was evaporated to give a semisolid which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (5.4 g, 11%). Anal calcd for C13H18NO2F: C, 65.25; H, 7.58; N, 5.85. Found: C, 65.49; H, 7.75; N, 5.80.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:39]1([C:36]2[N:35]=[CH:34][C:33]([C:29]3[CH:28]=[C:27]([C:25]4[CH2:24][C:23](=[O:42])[NH:22][C:9]5[CH:10]=[C:11]([C:18]([F:19])([F:20])[F:21])[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=5[N:7]=4)[CH:32]=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)[CH2:40][CH2:41]1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M196) (362 mg, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (153 mg, 54%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH3:23])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(Cl)[Cl:59]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH2:23][Cl:59])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc(COCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: ClCCl
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(COCCO)cc(C(=O)CCl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]phenyl}ethanone (O2.063; 2.0 g) was dissolved in methanol/THF (30 ml/30 ml) and admixed while stirring with phenyltrimethylammonium tribromide (2.25 g). After stirring at RT for 3 h, the mixture was diluted with DCM and washed once with 5% sodium thiosulfate solution, and the DCM phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was dissolved in THF (200 ml), and 3 N HCl (30 ml) was added. After standing for 1 h, EA and water were added, and the EA phase was removed. The EA phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 40 min). 774 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]([F:11])=[CH:7][C:6]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1C
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (12.8 g, 69.5 mmol) was suspended in 8 ml of concentrated sulfuric acid and cooled to 0° C. A mixture of concentrated nitric acid (8 ml) in concentrated sulfuric acid (8 ml) was added slowly, maintaining a reaction temperature below 50° C. After addition the mixture was stirred for 2 hours. The reaction mixture was poured into ice-water, forming a precipitate which was filtered and dried to give carbonic acid 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (8.0 g, 50.3%) as a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]1[N:14]=[C:15]([OH:23])[C:16]2[S:22][CH2:21][CH2:20][CH2:19][C:17]=2[N:18]=1>C1COCC1.CN(C=O)C>[CH2:3]([O:10][CH2:12][C:13]1[N:14]=[C:15]([OH:23])[C:16]2[S:22][CH2:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1nc(CCl)nc2c1SCCC2
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1nc(COCc2ccccc2)nc2c1SCCC2

Procedure:
Sodium hydride (0.68 g 53% mineral oil) was suspended in THF (80 ml) and 1.5 ml of benzyl alcohol was added dropwise with stirring. To this clear solution was added product from Example 3, Step A (2.6 g) dissolved in 25 ml of DMF. After stirring for 2 hours at 25° C. the reaction mixture was heated at reflux for 10 minutes. The solvent was removed in vacuo, water was added to the residue followed by enough diluted HCl to render the solution slightly acidic and it was extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give title compound as an oil that was used directly in Step B.
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[N+:10]([CH2:13][C:14]([NH2:16])=[O:15])([O-:12])=[O:11].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH2:6]([C:3]1[CH:4]=[C:13]([N+:10]([O-:12])=[O:11])[C:14](=[O:15])[NH:16][C:1]=1[CH3:2])[CH3:7]
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CCC(C=O)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-ethyl-3-oxobutanal, sodium salt (7.5 g, 55 mmol), nitroacetamide (6.6 g, 63 mmol), aqueous piperidinium acetate (4.4 mL) [prepared from glacial acetic acid (42 mL), water (100 mL) and piperidine (72 mL)] in water (45 mL) was stirred at room temperature for 22 hours. The yellow precipitate was collected by filtration and air dried to yield 5-ethyl-6-methyl-3-nitro-2-(1H)-pyidinone.
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].Cl.[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([OH:27])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH3:7]>C(O)CCC>[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([OH:27])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:1][CH3:2].[ClH:4]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1-Butanol (40 mL, 400 mmol) was cooled in an ice bath and acetyl chloride was added dropwise until a concentration of 4N HCl was achieved. The mixture was warmed to room temperature. (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 250 mg, 710 μmol) was added to the acidified butanol (15 mL) and the mixture was capped and heated to 80° C. for 3 hours. The resulting product was dried under vacuum to yield the title compound as a white/orange flaky solid HCl salt (220 mg).
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2CC[CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17](C)([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](NC1C=C(C=C(N2CCCC2=O)C=1)C(O)=O)(=O)[CH3:45].C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC1C=CC=CC=1>>[C:38]([NH:37][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=1)[C:24]([NH:23][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH:17]2[CH2:18][CH:44]1[CH2:45][CH2:19]2)[CH3:12])=[O:43])(=[O:42])[CH3:39]
Reactant: CC(=O)Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Agent: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Product: CC(=O)Nc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E5, from 3-acetylamino-5-(2-oxopyrrolidin-1-yl)benzoic acid (D13) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35].[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>>[F:38][C:32]1[CH:31]=[CH:30][C:29]([C:10]2[CH:11]=[C:12]3[C:17]([C:18](=[O:21])[NH:19][CH3:20])=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:15][C:13]3=[N:14][C:9]=2[NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[CH:37][C:33]=1[C:34]([OH:36])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3ccc(F)c(C(=O)O)c3)cc12
Reactant: NCC(F)(F)F
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3ccc(F)c(C(=O)O)c3)cc12
Temperature: 90 °C
Yield: 35 %

Procedure:
Sodium 2-methylbutan-2-olate (311 mg, 2.82 mmol), 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (250 mg, 0.565 mmol), 2,2,2-trifluoroethanamine (280 mg, 2.82 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (45 mg, 0.056 mmol) were combined, degassed, and taken up in dioxane (12 ml) at rt and then was heated to 90° C. for 1 h. The mixture was then diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with DCM to give 250 mg crude material which was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (100 mg, 0.198 mmol, 35% yield) consistent by LCMS and NMR. LC-MS retention time: 1.74 min; m/z (MH+): 506. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 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 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 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. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br. s, 1H), 8.38-8.29 (m, 1H), 7.98 (dd, J=8.8, 5.5 Hz, 2H), 7.89 (dd, J=7.0, 2.3 Hz, 1H), 7.70-7.62 (m, 2H), 7.51-7.43 (m, 1H), 7.34 (t, J=8.9 Hz, 2H), 6.72 (s, 1H), 4.23-4.10 (m, 2H), 2.80 (d, J=4.8 Hz, 3H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20].[OH-].[K+].C1COCC1>O>[NH:1]([C:8]1[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#Cc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#Cc1cc(N(C)C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-Anilino-4-chloro-6-(1-propynyl)pyrimidine (1.7 g) prepared in Example 2, 1.9 g of 54% aqueous solution of dimethylamine and 0.7 g of KOH were added to 20 ml of THF and the mixture was stirred at room temperature for 24 hours. The reaction liquid was poured in water and extracted with benzene. Then, the benzen layer was dried over Glauber's salt and concentrated, the residue was recrystallized from n-hexane-ethanol to afford 1.5 g of 2-anilino-4-dimethylamino-6-(1-propynyl)pyrimidine (yield: 85%). Melting point: 150°-152° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37](Cl)=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5ccccc5Cl)noc4C(C)C)cc3)cc2cn1
Temperature: 50 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
A mixture of 174 mg (0.62 mmol) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate, 285 mg (0.92 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 260 mg (1.83 mmol) of K2CO3 in 2 mL of DMF was stirred at 50° C. for 20 hr. EtOAc was added then the mixture washed with three portions of H2O, then brine. The organics were dried over Na2SO4 then evaporated and the residue purified by silica gel chromatography (40 g of silica gel eluting with 0-70% EtOAc in hexanes over 45 minutes) to give 196 mg (58%) of methyl 7-[4-({[3-(2-chlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate as white solid. 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 7.99 (m, 2H), 7.60 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.33 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.80 (s, 2H), 4.06 (s, 3H), 3.36 (septet, 1H, J=7 Hz), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([NH:17][CH2:18][CH2:19][N:20](C(OCC1C=CC=CC=1)=O)[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:25]=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:25]=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(C(CC(=O)OC(C)(C)C)NCCN(CC=Cc2cccc(NCC3CC3)n2)C(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(CC(=O)OC(C)(C)C)NCCNCCCc2cccc(NCC3CC3)n2)cn1
Yield: 57.2 %

Procedure:
A mixture of 2-6 (29.0 g, 47.0 mmol) and 10% Pd/C (7.25 g) in EtOH (500 mL) was stirred under a balloon of hydrogen for 18 h. Filtration through celite and evaporative removal of the solvent followed by purification on silica gel (90:10:1 CHCl3:MeOH:NHOH) afforded 13 g of 2-7.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37](Cl)=[O:38])[C:25]=2[CH3:40])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:38])[C:25]=2[CH3:40])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A mixture of 1.82 g of tert-butyl hydrazinecarboxylate and 2.4 ml of triethylamine in 50 ml of DCM is cooled to 0° C., a solution of 5.24 g of the compound obtained in stage A in 50 ml of DCM is added and the mixture is left stirring while allowing the temperature to rise to AT. The reaction mixture is washed with water, with a buffer solution at pH=2 and with a saturated NaHCO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is taken up in isopropyl ether, pentane is added and the precipitate formed is filtered off. 6.2 g of the expected compound are obtained.
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1)(=O)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.CO>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1ccc(O)cc1
Reaction time: 20 h

Procedure:
Into a flask were charged 250 g of the copolymer of 2-ethyl-2-adamantyl methacrylate and p-acetoxystyrene (30:70) obtained in Reference Example 7, 10.8 g (0.088 mol) of 4-dimethylaminopyridine and 239 g of methanol and the mixture was aged for 20 hours under reflux. After cooling, the reaction solution was neutralized with 8.0 g (0.133 mol) of glacial acetic acid, and precipitated by pouring into a large amount of water. The precipitated polymer was dissolved in acetone, then, poured into a large amount of water to cause precipitation. This operation was repeated three times in total, to effect purification. The amount of the resulted copolymer of 2-ethyl-2-adamentyl methacrylate and p-hydroxystyrene was 102.8 g. The weight-average molecular weight was about 8200, the degree of dispersion was 1.68 (GPC method: reduced by polystyrene), and the copolymerization ratio was determined to be about 30:70 by a nuclear magnetic resonance (13C-NMR) spectrometer. This resin is called resin A6.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>>[CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:15](=[O:17])/[CH:16]=[C:21](/[N:23]([CH3:25])[CH3:24])\[CH3:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(SCc2ccccc2)ccc1F
Reactant: COC(C)(OC)N(C)C
Product: C/C(=C\C(=O)c1cc(SCc2ccccc2)ccc1F)N(C)C
Yield: 63.6 %

Procedure:
A solution of 1-(5-(benzylthio)-2-fluorophenyl)ethanone (3.6 g, 13.83 mmol) in N,N-dimethylacetamide dimethyl acetal (12.13 mL, 83 mmol) was irradiated at 130° C. for 10 minutes in a microwave reactor (Biotage Initiator). The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude product was purified by column chromatography, eluting with 20-100% ethyl acetate in heptane, to provide (E)-1-(5-(benzylthio)-2-fluorophenyl)-3-(dimethylamino)but-2-en-1-one (2.9 g, 8.80 mmol, 63.7% yield) as a tan solid. m/z (ESI) 330.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20]C(=O)C)=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:47]([C:50]1[N:51]=[CH:52][NH:53][CH:54]=1)([O-:49])=[O:48]>CN1CCCC1=O.C(OCC)(=O)C>[C:35]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][NH:26][C:4]2[N:3]=[C:2]([N:53]3[CH:54]=[C:50]([N+:47]([O-:49])=[O:48])[N:51]=[CH:52]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH2:19][OH:20])[C@@H:13]([OH:24])[C@H:12]2[OH:25])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O
Temperature: 150 °C

Procedure:
The title compound is prepared by dissolving acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in N-methyl-2-pyrrolidinone, followed by potassium carbonate (5 equivalents) and 4-nitro-1H-imidazole (10 equivalents). The mixture is heated by microwave irradiation to 150° C. for two hours, then diluted with ethyl acetate and washed consecutively with water (×2) and brine, before drying over magnesium sulfate. Filtration, removal of the volatile components under reduced pressure and purification by flash column chromatography/crystallisation affords the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(Cl)CCl.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH2:3]1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexane carboxylic acid (1.5 g, 10.6 mmol) in CH2Cl2 (35 mL) were added DMAP (0.129 g, 1.06 mmol), EDC (4.05 g, 21.1 mmol), and BnOH (1.2 mL, 11.6 mmol). The reaction was maintained at ambient temperature for 1 h. The reaction was further diluted with CH2Cl2, and then washed with saturated aqueous NaHCO3, followed by brine. The organic layer was separated, dried with MgSO4, filtered, and concentrated. The resulting crude product was used in the next step without further purification. LCMS: calculated for C14H16O3 232.28, observed m/e 233.1 (M+H)+ 255.0 (M+Na) (Rt 1.74/4 min).