Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22](OS(C(F)(F)F)(=O)=O)=[N:21]2)=[CH:17][CH:16]=1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:40]=[CH:41][C:15]([O:14][CH2:13][C:3]4[N:4]=[C:5]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[O:6][C:2]=4[CH3:1])=[CH:16][CH:17]=3)[N:21]=2)=[CH:46][CH:45]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(OC)cc1
Yield: 24.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (790 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (2.00 g), 4-methoxyphenylboronic acid (0.77 g), 2N aqueous sodium carbonate solution (5.0 ml), ethanol (5 ml), and toluene (100 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (450 mg, yield: 24%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][CH:15]([F:27])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[OH:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[N+:11]([C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([C@@H:16]([OH:17])[CH:15]([F:27])[F:14])=[CH:23][CH:22]=2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Reactant: OB(O)c1ccc([C@@H](O)C(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2ccc([C@@H](O)C(F)F)cc2)cc([N+](=O)[O-])c1
Temperature: 85 °C

Procedure:
A mixture of 1-bromo-3,5-dinitrobenzene (5 g, 19.6 mmol), PdCl2(dppf)-dichloromethane adduct (0.802 g, 0.982 mmol), {4-[(1R)-2,2-difluoro-1-hydroxyethyl]phenyl}boronic acid (4.36 g, 21.6 mmol), and aqueous sodium carbonate (2 M, 29.5 mL, 58.9 mmol) in dioxane (65.6 mL) was degassed by sparging with nitrogen. The mixture was heated to 85° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to give (1R)-1-(3′,5′-dinitrobiphenyl-4-yl)-2,2-difluoroethanol as an off-white solid. MS ESI calc'd. for C14H9F2N2O4[M+H−H2O]+ 307, found 307.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH2:22]([NH:26][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Reactant: CC(C)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
A THF solution of crude ˜0.12M intermediate 15, 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (160 mL, 19.3 mmol) was combined with isobutylamine (3.8 mL, 38.2 mmol) and T3P (50% wt in EtOAc, 13.8 mL, 23.2 mmol) and stirred at room temperature for 20 h. The mixture was made basic with saturated aqueous NaHCO3 and EtOAc (50 mL) was added. The phases were separated and the aqueous phase was extracted again with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated to yield an orange oil. Flash chromatography on a 2″×4″ silica gel column flushing first with EtOAc (1 L) and 10% MeOH/EtOAc (500 mL) to remove higher Rf impurities followed by elution with an additional 500 mL of 10% MeOH/EtOAc and 500 mL 20% MeOH/EtOAc afforded 4.22 g (63%) of the title compound as an waxy, orange solid: Rf=0.3 (30% MeOH/EtOAc); 1H NMR (CDCl3) δ 7.34 (t, J=7.9 Hz, 1H), 7.20-7.13 (m, 2H), 5.84 (br s, 1H), 3.66 (d, JH-F=1.3 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.84-2.76 (m, 3H), 2.55-2.45 (m, 6H), 1.81-1.72 (m, 4H), 0.91-0.87 (d @ 0.90 (J=6.6 Hz, 6H) overlapping m (1H)); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:54][CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([N:55]([CH3:57])[CH3:56])[CH:51]=3)[C:46]2=[O:58])[C:35]=1[CH2:36][O:37]C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>>[CH3:56][N:55]([CH3:57])[C:50]1[CH:51]=[C:52]2[C:47](=[CH:48][CH:49]=1)[C:46](=[O:58])[N:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH2:36][OH:37])[CH2:54][CH2:53]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(Nc4ccc(C(=O)N5CCOCC5)cn4)c(=O)n(C)c3)c1CO)C2=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (60 mg, 0.14 mmol), Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (46 mg, 0.1 mmol), potassium phosphate (47 mg, 0.22 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.1 mg, 0.0065 mmol), and bis(dibenzylidineacetone)palladium(0) (1.9 mg, 0033 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 2 mL tetrahydrofuran, 1 mL methanol, and 1 mL water. 1M aq. lithium hydroxide solution (0.33 mL, 0.33 mmol) was added. After stirring for 18 hours, the resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (36 mg, 0.059 mmol). MS (ESI) 609.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Cl:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].ClC1C=C(F)C=CC=1C=O.CNC>>[Cl:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[CH:17]([N:18]([CH3:20])[CH3:19])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: C[N+](C)=Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: CNC
Agent: O=Cc1ccc(F)cc1Cl
Agent: [Cl-]
Product: CN(C)C(c1ccc(F)cc1Cl)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (2-chloro-4-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.C(OCC)(=O)C.O.O1CCOCC1>[CH3:18][C:16]1[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:14]=[C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:3][CH:4]=3)[N:12]=2)[CH:17]=1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CCCC5=O)cc4)no3)cc2C)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 200 mg, 0.44 mmol), pyrrolidinone (67 μl, 0.88 mmol), potassium phosphate (186 mg, 0.88 mmol), copper(I) iodide (25 mg, 0.13 mmol), N,N′-dimethylethylenediamine (28 μl, 0.26 mmol) and 1,4-dioxane (4 ml) was stirred at 70° C. for 15 h. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified using preparative HPLC, to afford the title compound as a white solid (73 mg, 40%): 1H NMR (400 MHz, CDCl3) 8.21 (d, 2H), 7.79 (d, 2H), 7.13 (d, 2H), 7.08 (d, 2H), 6.79 (s, 1H), 5.41 (s, 2H), 3.93 (t, 2H), 2.65 (t, 2H), 2.33 (s, 3H), 2.26 (s, 3H), 2.20 (quint, 2H); ES-MS m/z 414 (MH)+, HPLC RT (Method E) 4.82 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][C:4]=1[OH:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:18][C:4]1[CH:5]=[C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:31]
Reactant: COc1ccc(-c2cc3nccnc3[nH]2)cc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-c2cc3nccnc3[nH]2)ccc1OC
Temperature: 50 °C

Procedure:
To a solution of 2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol [0.5 g, Example 28]in dimethylformamide (10 mL) and cesium carbonate (0.67 g) was added ethyl chloroacetate (0.025 g). The reaction mixture was heated at 50° C. overnight. After cooling, the dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic fraction was dried over sodium sulfate, evaporated and subjected to flash column chromatography on silica eluting with 2.5% methanol in dichloromethane. This product was further triturated with a mixture of ethyl acetate and pentane to give the title compound as a white solid, m.p. 183-184° C. MS: 328 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([O:12][C@@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][CH2:31]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cc(O[C@H]2CC[C@@H](Nc3ncccn3)CC2)c2nccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C1=C(c2cc(O[C@H]3CC[C@@H](Nc4ncccn4)CC3)c3nccnc3c2)CCOC1

Procedure:
As shown in step 8-ii of Scheme 8, a mixture of N-((cis)-4-((7-bromoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1025, 52 mg, 0.1299 mmol), Pd(dppf)Cl2 (10.61 mg, 0.01299 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 1026, 27.3 mg, 0.13 mmol), Na2CO3 (195 μL of 2M (aq) solution, 0.39 mmol) in DMF (1 mL) was flushed with nitrogen gas for 10 minutes. The mixture was subjected to microwave radiation for 20 min at 150° C. After cooling, the mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to provide N-[(cis)-4-[7-(3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl]oxycyclohexyl]pyrimidin-2-amine (compound 36) as an off-white solid: 1H-NMR (300 MHz, CDCl3) δ 8.94-8.76 (m, 2H), 8.29 (d, J=4.8 Hz, 2H), 7.67 (d, J=1.7 Hz, 1H), 6.53 (t, J=4.8 Hz, 1H), 6.37 (tt, J=3.1, 1.5 Hz, 1H), 5.30 (d, J=7.9 Hz, 1H), 4.87 (dt, J=7.5, 3.6 Hz, 1H), 4.43 (q, J=2.8 Hz, 2H), 4.02 (t, J=5.5 Hz, 3H), 2.68 (dqd, J=6.0, 3.4, 3.0, 1.8 Hz, 2H), 2.35-2.11 (m, 2H), 2.07-1.84 (m, 6H); ESMS (M+H+)=404.2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:58])[C@H:55]([CH3:57])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:58])[CH3:57])[CH2:30][CH2:29]1)=[O:27]
Reactant: C[C@H](N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](C)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-alanine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.34 (1H, s), 5.34 (1H, m), 4.17 (2H, m), 4.07 (1H, m), 3.19 (3H, m), 2.98 (2H, t, J=12 Hz), 1.96 (2H, m), 1.93 (11H, m), 1.56 (3H, d, J=7.2 Hz), 1.29 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity >98%, m/z 447.25 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:11])[C:6]=2[C:5]([OH:12])=[C:4]([CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])\[CH3:16])[C:3]=1[O:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:35][CH2:36][CH:37]=[CH:38][CH2:39]Br>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]([CH2:39][CH:38]=[CH:37][CH2:36][Br:35])[CH2:17][C:15]([CH3:16])=[CH:14][CH2:13][C:4]1[C:5]([OH:12])=[C:6]2[C:7](=[C:2]([CH3:1])[C:3]=1[O:23][CH3:24])[CH2:8][O:9][C:10]2=[O:11]
Reactant: BrCC=CCBr
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a cooled (−78° C.) solution of mycophenolic acid methyl ester 159A (138 mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodium bis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes, a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL) was added and stirring was continued for 10 minutes. The resulting mixture was warmed to −30° C. and stored at this temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate to give, after evaporation of the solvent, a residue which was purified by chromatography on silica gel eluting with ethyl acetate (0% to 40%)/hexanes, affording 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 159B (150 mg, 78%) as an oil; 1H NMR (300 MHz, CDCl3) δ 1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H), 7.67 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CO[CH:24](OC)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:20][CH:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[N:6]([C:7]([NH:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C@H:5]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:21]
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Reactant: COC(=O)C(O)C(NC(=O)NC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1

Procedure:
N-(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester (PREPARATION 1, 68 mg, 0.23 mM) is dissolved in dry TBF (5 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (70 mg, 0.33 mM) and pyridinium p-toluenesulfonate (6 mg, 0.02 mM) and the mixture warmed to reflux. Approximately 2 mL solvent is boiled away 3 times in a 45 minute period replenishing with 2 mL of fresh THF at which time TLC shows no starting material. The solvent is concentrated under reduced pressure and chromatographed (7 g of silica gel packed in ethyl acetate/1hexane, 1/3; elution with 80 mL ethyl acetate/hexane, 1/3; 45 mL ethyl acetate/hexane, 1/2; 30 mL ethyl acetate/hexane, 2/3 and 30 mL ethyl acetate/hexane, 1/1) to give the title compound: less polar isomer found in fractions 21-31—NMR (CDCl3, TMS) 1.19, 3.82, 3.85, 3.89, 4.68, 4.88, 5.52, 6.46, 6.70 and 7.25-7.50 δ, MS (FAB-High Res.) theory for C24H31N2O6+H=443.2182, found=443.2172; more polar isomer in fractions 33-42—NMR (CDCl3, TMS) 0.99, 3.53, 3.81, 3.88, 4.05, 4.55, 5.45, 6.48, 6.79 and 7.25-7.50 δ; MS (FAB-High Res.) theory for C24H31N2O6+H=443.2182, found=443.2180.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1cccc(Sc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-methoxy-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 363 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[N+:10]([CH3:13])([O-:12])=[O:11].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([CH2:13][N+:10]([O-:12])=[O:11])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccsc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 21 h
Yield: 19.3 %

Procedure:
A solution composed of 10 g (70 mmol) of 3-methyl-2-thiophenecarboxylic acid, 3.4 g (56 mmol) of nitromethane and 115 ml of DMF is cooled to 0° C. 11.9 g (72.8 mmol) of diethyl cyanophosphonate in 56 ml of DMF, and then 18.2 g (180 mmol) of triethylamine in 56 ml of DMF are added thereto successively. The medium is then stirred for 2 hours at 0° C. and for 21 hours at room temperature. The reaction medium is poured over 1 litre of a toluene/ethyl acetate (1:1) mixture, and extracted with water. This aqueous phase, acidified with 40 ml of acetic acid, is extracted with a toluene/ethyl acetate (1:1) mixture. The organic extracts are washed with water and then with a saturated NaCl solution in water, before being dried over Na2SO4 and concentrated. The residue, purified by chromatography on a silica column in dichloromethane and then by recrystallization from an ethyl acetate-hexane mixture, gives 2 g of a pale yellow solid (Yield=19%).
Reaction SMILES: [C:1]1([SH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[S:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[C:1]1([S:11][C:13]2[S:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1cccc2ccccc12
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cccc3ccccc23)s1
Yield: 29.1 %

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-naphthalenethiol (320 mg, 2 mmol) and 1-(5-Chloro-4-nitro-2-thienyl)ethanone (412 mg, 2 mmol) to afforded the title compound as a yellow solid (192 mg, 29% yield). 1H NMR (300 MHz, CDCl3) δ: 8.33 (1H, m), 8.11 (1H, m), 8.08 (1H, s), 7.98 (2H, m), 7.59 (3H, m), 2.43 (3H, s).