Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1)#[N:2].[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:39][CH2:40][N:41]([C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)[CH:17]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:28][CH:27]=3)[CH:10]=2)[CH2:42][CH2:43]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(OCc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.16 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.16 mmol) were used to afford 0.92 g of the required product. 1H NMR (DMSO-d6): δ 1.10 (2H, m), 1.30 (2H, m), 1.4 (9H, s), 1.50 (2H, m), 1.75 (1H, m), 2.70 (1H, m), 2.8 (3H, m), 3.5 (1H, m), 4.4 (1H, m), 5.2 (2H, s), 6.65 (1H, s), 6.78 (1H, m), 6.88 (2H, m), 7.16 (2H, s), 7.64 (2H, d), 7.88 (4H, m).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[N:6][C:5]=1[NH:11]C(=O)C(C)(C)C)[CH3:3].Cl>>[NH2:11][C:5]1[N:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH:2]([CH3:1])[CH3:3]
Reactant: Cc1cc(C(C)C)c(NC(=O)C(C)(C)C)nn1
Agent: Cl
Product: Cc1cc(C(C)C)c(N)nn1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
N-[4-(1-methylethyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide (1.38 g, 5.87 mmol) is treated with HCl 0 (10 mL), and refluxed for 3 h. It is cooled to rt, poured into ice-H2O (30 mL); extracted with EtOAc (2×30 mL). The aqueous layer is treated with 5 M NaOH to adjust the pH to 8-9. It is then extracted with EtOAc (3×50 mL); dried with Na2SO4, filtered and concentrated gives the title compound (0.59 g, 3.91 mmol, 67%). %). 1H NMR (CDCl3): δ 1.28 (d, J=7.0 Hz, 6H), 2.51 (s, 3H), 2.72-2.83 (m, 1H), 5.95 (bs, 2H), 7.02 (s, 1H) ppm. ES-MS (m/z): calcd for C8H13N3 (M+H)+: 152.2. found: 152.1.
Reaction SMILES: C(O[C:6]([NH:8][N:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])C(O)=O>C(Cl)Cl>[CH3:22][O:21][C:19]([C:18]1[N:9]([NH:8][C:6](=[O:7])[C:37]([F:42])([F:41])[F:36])[C:10](=[O:35])[C:11]2[C:16]([C:17]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:20]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of the compound obtained in Example 67 (5.60 g) in methylene chloride (15 ml) is added trifluoroacetic acid (15 ml), and the mixture is allowed to stand at room temperature for three hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and extracted. The extract is washed, dried, and concentrated under reduced pressure. The resulting residue is crystallized from ethyl acetate to give 3-methoxycarbonyl-2-(trifluoroacetyl-amino)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 24.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4C([CH:20]=3)=CC=CC=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:22]2)[C:3]=1[Br:31].[NH2:32]C1N2N=CC(C3C=NN(C)C=3)=C2N=C(C2CCN(CC(OC(C)(C)C)=O)CC2)C=1.NC1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN(CC(OC(C)(C)C)=O)CC2)C=1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:20]=[N:32][N:13]([CH3:14])[CH:12]=3)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:22]2)[C:3]=1[Br:31]
Reactant: Nc1c(Br)c(C2CCN(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: Cn1cc(-c2cnn3c(N)cc(C4CCN(CC(=O)OC(C)(C)C)CC4)nc23)cn1
Agent: CC(C)(C)OC(=O)CN1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Product: Cn1cc(-c2cnn3c(N)c(Br)c(C4CCN(CC(=O)O)CC4)nc23)cn1

Procedure:
2-(4-(7-amino-6-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetic acid was synthesized in a manner similar to the synthesis of 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetic acid, but with tert-butyl 2-(4-(7-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate substituted for tert-butyl 2-(4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate. The reaction mixture was reduced in vacuo and purified via reverse-phase preparatory HPLC to yield 2-(4-(7-amino-6-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetic acid as off-yellow solid. (m+H=434.19, retention time=2.25 min)
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.P([O-])([O-])([O-])=O>[C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(C=O)cnc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C=O)cnc21
Reaction time: 1 h
Yield: 21.1 %

Procedure:
To a stirred solution of the alcohol 13 (54 mg, 0.20 mmol) in a mixture of CH2Cl2 (15 mL) and 0.2 M pH 7 phosphate buffer (0.15 mL) was added DDQ (53 mg, 0.23 mmol) in three equal portions. When TLC analysis showed complete consumption of the starting material, the mixture was diluted with saturated aqueous NaHCO3 (16 mL) and stirred vigorously for 1 h. The mixture was then extracted with AcOEt (2×). The combined organic solutions were washed with saturated brine (1×), dried (MgSO4) and concentrated. The residue was purified by PTLC with benzene as eluent to afford aldehyde 16 (11 mg, 21%). 1H NMR (400 MHz; CDCl3) δ 0.66 (s, 6H), 0.94 (s, 9H), 6.67 (d, J=3.5 Hz, 1H), 7.34 (d, J=3.5 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H), 10.11 (s, 1H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[N:16]=1)=[O:10]>C(Cl)Cl>[Br:1][C:14]1[S:13][C:12]([NH:11][C:9]([NH:8][CH2:7][C:6]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:4]([Cl:3])[CH:5]=2)=[O:10])=[N:16][C:15]=1[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: BrBr
Reactant: COCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Solvent: ClCCl
Product: COCCOCc1nc(NC(=O)NCc2ccc(Cl)c(Cl)c2)sc1Br

Procedure:
Bromine (120 μL, 0.12 mmol, IM in CH2Cl2) was added dropwise to a CH2Cl2 (5 mL) solution of 1-(3,4-dichlorobenzyl)-3-(4-((2-methoxyethoxy)methyl)thiazol-2-yl)urea (39 mg, 0.1 mmol). The bromination was instantaneous. The mixture was washed with dilute Na2SO3 solution, dried and evaporated to afford the title compound. 1H NMR (400 MHz, CDCl3): 11.38 (1H, br), 7.70 (1H, br), 7.45 (d, 1H), 7.39 (d, 1H), 7.19 (dd, 1H), 4.50 (s, 2H), 4.39 (d, 2H), 3.53 (m, 2H), 3.38 (m, 2H), 3.20 (s, 3H). MS (ES+): M/Z 470 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>ClCCl.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccccc1C
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccccc1OC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
The title compound, mp 142°-3° C. (dichloromethane-hexane), was prepared from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methylphenoxy)propanoate by a method analogous to that described for Example 2.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([O:32][Si](C)(C)C)[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH3:2].B(F)(F)F.CCOCC.CCCCCC.C(OCC)(=O)C.ClCCl.CO>C(#N)C>[CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([OH:32])[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: CCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (11β,16β)-21-(acetyloxy)-9-fluoro-16-methyl-3,20-dioxo-11-[(trimethylsilyl)-oxy]pregna-1,4-dien-17-yl ethylcarbamate (138 mg, 0.239 mmol) in 2.5 mL of acetonitrile was added boron trifluoride etherate (0.12 mL, 0.96 mmol). After stirring at room temperature for 5 hours, additional boron trifluoride etherate (0.060 mL, 0.47 mmol) was added. The solution was stirred at room temperature for 15 hours more and was then partitioned between ethyl acetate and water. The organic layer was washed with water (twice) and brine and dried over Na2SO4. Filtration and evaporation under vacuum gave a pale yellow oil. Chromatography on silica gel eluting with hexane/ethyl acetate/dichloromethane/methanol (5:2:2:1) gave (11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl ethylcarbamate as a white film.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].Cl.[H][H]>CO.[Pd]>[CH2:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[CH3:11]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc(OC)cc1F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 1-(2-fluoro-4-methoxyphenyl)ethanone (FMAP) (13.46 g, 80 mmol) in MeOH (100 mL), 37% HCl (7.0 mL, 85 mmol) diluted with MeOH (5 mL) was added, followed by 5% Pd/C (340 mg, 0.4 mol %). The mixture was placed under 3 bar hydrogen at rt until the reaction was complete based on HPLC analysis. The mixture was cooled to room temperature and the catalyst was removed by filtration. The solvent was removed under reduced pressure, and water (100 mL) and petroleum ether were added. The organic layer was cut and washed with water (50 mL) and dried over Na2SO4. The solvent was removed under the reduced pressure. The oily residue was distilled using 8×1 cm distillation column with Raschig rings at 95-97° C. and 45 mbar to yield 1-ethyl-2-fluoro-4-methoxybenzene (MET) as a colorless oil (8.15 g, 66%). 1H NMR (CDCl3) δ 1.19 (t, J=7.6, 3H), 2.60 (q, J=7.6, 2H), 3.77 (s, 3H), 6.52-6.68 (m, 2H), 7.08 (t, J=8.6, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[BH3-][C:19]#N.[Na+].Cl>CO>[CH3:19][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: O=C(O)c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.8 %

Procedure:
4-piperidin-4yl-benzoic acid (110 mg, 0.54 mmol, reference example 109) was added to paraformaldehyde (180 mg, 6 mmol) in MeOH (10 mL) and NaCNBH3 (120 mg, 1.94 mmol). The reaction was stirred at room temperature for 4 days, at which time HPLC shows no remaining starting material. The solution was acidified to pH 2 with concentrated HCl, evaporated, dissolved in water (20 mL), and extracted with ether (3×20 mL). Then the solution was brought to pH 12 with KOH pellets, extracted with dichloromethane (3×20 mL) and finally brought to pH5 with acetic acid. The mixture was lyophilized and the solid was extracted with MeOH (3×15 mL). The combined methanol extracts were evaporated and the residue chromatographed (reverse-phase HPLC, C18 column, 10-100% CH3CN/water) to yield, after lyophilization, 72 mg of the desired product (61%). 1H NMR (CD3OD): δ 7.98 (d, 2H), 7.38 (d, 2H), 3.60 (m, 2H), 3.18 (t, 2H), 2.94 (s, 3H), 2.85-2.95 (m, 2H), 2.08-2.18 (m, 2H), 1.90-2.02 (m, 2H). MS (ion spray) m/z 220 (M+H+). >98% pure by analytical HPLC.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:18][O:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1cc2c(cc1O)OCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cc1OC)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.7 %

Procedure:
A mixture of methyl 6-hydroxy-1,3-benzodioxole-5-carboxylate (2.7 g, 14 mmol), sodium hydride (456 mg, 19 mmol, 760 mg of a 60% dispersion in mineral oil), iodomethane (1.9 g, 13 mmol) and DMF (approximately 35 mL) was stirred 2 hours. The mixture was poured into ice-water and the mixture was extracted with diethyl ether (2×). The combined extracts were washed with water (3×) and brine (1×) and concentrated to give methyl 6-methoxy-1,3-benzodioxole-5-carboxylate (3 g, 14 mmol), m.p. 74°-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH:3]=1.NC1C(OC)=C2C(C3C=C(C)C=NC=3N2)=C(C2C=C(N[C:54]([CH:56]3[CH2:58][CH2:57]3)=[O:55])C=CC=2)C=1>>[CH:56]1([C:54]([NH:1][C:2]2[C:10]([O:11][CH3:12])=[C:9]3[C:5]([C:6]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=4[NH:8]3)=[C:4]([C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])[CH:3]=2)=[O:55])[CH2:58][CH2:57]1
Reactant: COc1c(N)cc(-c2cccc(C(=O)NC3CC3)c2)c2c1[nH]c1ncc(C)cc12
Reactant: COc1c(N)cc(-c2cccc(NC(=O)C3CC3)c2)c2c1[nH]c1ncc(C)cc12
Product: COc1c(NC(=O)C2CC2)cc(-c2cccc(C(=O)NC3CC3)c2)c2c1[nH]c1ncc(C)cc12

Procedure:
The title compound was prepared from Compound 244 by using an analogous procedure to that outlined in the preparation of Compound 241. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.55 (m, 2 H) 0.68 (m, 2 H) 0.81 (br. m, 4 H) 2.17 (m, 1 H) 2.23 (s, 3 H) 2.87 (m, 1 H) 3.94 (s, 3 H) 7.40 (s, 1 H) 7.63 (t, J=7.71 Hz, 1 H) 7.72-7.71 (m, 2H) 7.94 (d, J=7.58 Hz, 1 H) 8.01 (s, 1 H) 8.21 (d, J=1.77 Hz, 1 H) 8.54 (d, J=4.04 Hz, 1 H) 9.84 (s, 1 H) 12.00 (s, 1 H); [M+H] calc'd for C27H27N4O3, 455.2; found, 455.4.
Reaction SMILES: [OH:1][CH:2]([C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)[C@@H:3]([NH:6][C:7](=[O:26])[CH:8]([CH2:18][S:19]([CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:25][CH:23]([CH3:24])[CH2:22][S:19]([CH2:18][CH:8]([CH2:9][C:10]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:11])[C:7]([NH:6][C@H:3]([C:2]([C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)=[O:1])[CH2:4][CH3:5])=[O:26])(=[O:20])=[O:21]
Reactant: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(O)c1noc(-c2ccccc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(=O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide (41 mg, 0.076 mmol) in methylene chloride (6 mL) was treated with Dess-Martin periodinane (39 mg, 0.092 mmol) and stirred at room temperature for 90 minutes. The reaction mixture was washed with a solution of Na2S2O3 in water (0.26M), saturated aqueous bicarbonate solution and water, dried over Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of ethyl acetate and heptane to give 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide as an off white solid (18 mg) (mixture of diastereoisomers).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].C(=O)(OC(C)(C)C)[O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.N1C=CN=C1.C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9]
Reactant: O=C1COCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Morpholin-3-one (35 g, 346.2 mmol) was slurried in dry THF (350 ml). Tert-butoxycarbonyl tert-butyl carbonate (105.8 g, 111.4 mmol) was added, followed by DMAP (4.2 g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24 hrs. The mixture was then cooled in an ice bath and imidazole (23.57 g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500 ml) was added. The organic phase was separated and washed with 1% (v/v) HCl (500 ml), then sat NaHCO3 (500 ml), then brine (200 ml), dried (MgSO4), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200 ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4-carboxylate was obtained as a white solid which was dried under vacuum (52.7 g, 76%); 1H-NMR (CDCl3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+-tBu).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[N:3]=1.[CH3:32]B1OB(C)OB(C)O1.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:32][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[N:3]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4ccccc4)c(Cl)n3)CC2)cc1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4ccccc4)c(C)n3)CC2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 43.5 mg (0.10 mmol) (S)—N-(1-{4-[1-(4-chloro-5-phenyl-pyrimidin-2-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (5.50 mmol) in 1 mL MeOH and 2 mL dioxane is added under an argon atmosphere 0.042 mL (0.30 mmol) trimethylboroxine, 0.1 mL NaHCO3 solution (2 mmol/mL) and 2.9 mg (0.0042 mmol) bis(triphenylphosphin)palladium(II)chloride and the mixture is stirred for 3 h at 80° C. After that time, another 100 μL (0.7 mmol) trimethylboroxine and 2.9 mg (0.0042 mmol) bis(triphenylphosphin)-palladium(11)chloride are added and stirring is continued for 12 h at 80° C. The mixture is diluted with DMF, filtered and purified by HPLC (C18 RP Sunfire; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:21][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(C)(C)C)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(C)(C)C)cc1CBr
Yield: 104.5 %

Procedure:
N-Bromosuccinimide (5.66 g) and 2,2′-azobis(isobutyronitrile) (71 mg) were added to a solution of 4-tert-butyl-1-methoxy-2-methylbenzene (5.16 g) in carbon tetrachloride (25 mL), and the mixture was heated under reflux for 1.5 hours. The reaction solution was ice-cooled and then the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 7.78 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3](Cl)[CH3:4].[C:17]([O-:21])(=[O:20])[CH:18]=[CH2:19].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3]([O:21][C:17](=[O:20])[CH:18]=[CH2:19])[CH3:4]
Reactant: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reactant: C=CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OC(C)OC(=O)C=C
Yield: 89.4 %

Procedure:
1-Chloroethyl 4-acryloyloxybutyl carbonate (1.253 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.28 g (89%) of the title product. 1H NMR (60 MHz, CDCl3): δ1.58 (3H, d, J=5 Hz, CH3 --CH), 1.80 (4H, m, CH2 --CH2), 4.24 (4H, m, 2×CH2 --O), 5.7-6.7 (6H, m, 2×CH=CH2), 6.87 (1H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH2:3][OH:4].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH2:3][OH:4].[F:29][C:30]([C:31]([OH:33])=[O:32])([F:35])[F:34]
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
65.7 g of BOC-Ser-Thr-OBzl are dissolved in 100 ml of 90% strength trifluoroacetic acid and the solution is left for one hour at 20° C. It is then added dropwise to 1000 ml of dry either whilst stirring and the mixture is stirred for one hour and left to stand overnight at -10° C. The resulting precipitate is filtered off and washed three times with dry ether and dried in vacuo over sodium hydroxide; melting point 128°-129° C.; Rf7 = 0.65; Rf4 = 0.50 (on silica gel).