Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.C(OCC)(=O)C>CS(C)=O>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
That is, to a solution of 27.27 g of 1-benzhydrylazetan-3-ol dissolved in 225 ml of dimethylsulfoxide was added 135.5 ml of triethylamine, 59.80 g of sulfur trioxide-pyridine complex was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer was washed with a saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain 21.35 g of 1-benzhydrylazetidin-3-one.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>C(O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)CC1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 43.9 %

Procedure:
261 mg of 4-(4-trifluoromethoxyphenoxy)piperidine and 224 mg of 1,4-cyclohexanedione were heated under reflux in 5 ml of ethanol and reacted for 7 hours. After concentrating the reaction mixture under reduced pressure, the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 154.9 mg of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine was obtained (yield 43.8%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:7]([OH:8])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]>[Ag]=O.CCOCC>[C:1]([C:5]1[C:6](=[O:16])[C:7](=[O:8])[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Agent: O=[Ag]
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reaction time: 0.5 h

Procedure:
To a solution of 5 g. (22.5 mmol.) of 3,5-di-t-butylcatechol in 75 ml. of ether at 0° was added 25 g. of silver oxide. The reaction mixture was stirred at 0° for 30 minutes then at ambient temperature for an additional 30 minutes. The mixture was filtered and the filtrate was evaporated to dryness. Benzene was added to the residue and the resulting precipitate was collected by filtration and air dried to give 3,5-di-t-butyl-1,2-dioxobenzene, m.p. 110°-112°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)[CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=3)[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(C(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (688 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:43][N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH:47]([NH2:52])[CH2:46][C:45]1([CH3:54])[CH3:53]>C1COCC1>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:52][CH:47]4[CH2:46][C:45]([CH3:53])([CH3:54])[N:44]([CH3:43])[C:49]([CH3:51])([CH3:50])[CH2:48]4)=[O:16])=[CH:13][CH:14]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: O=C(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc2)CC1(C)C
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of 5,6-dichloro-2-(4-carboxyphenyl)benzimidazole (0.3 g, 0.9 mmol) prepared as described in Preparation 8, 1-hydroxybenzotriazole (0.145 g, 1.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.207 g, 1.08 mmol) in THF (10 ml) was heated at 35–40° C. for 1 h. 1,2,2,6,6,-Pentamethyl-4-aminopiperidine in THF (2 ml) was added dropwise and the reaction was refluxed for 1 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was treated with 2N NaOH (5 ml). The solid was filtered, washed with water and dried at 50° C. under vacuum. The solid was suspended in isopropyl alcohol and stirred for half an hour, filtered and dried to give 91 mg of the title compound (yield 22%) as an yellow powder, mp>280° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:24][C:23]4([CH3:26])[CH2:25][CH:19]3[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22]4)=[O:17])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:29][CH3:30])C.[OH-].[Na+]>C(O)C>[CH2:29]([C:8]1[N:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:24][C:23]4([CH3:26])[CH2:25][CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[CH2:22]4)=[O:17])=[CH:15][C:10]=2[N:9]=1)[CH3:30]
Reactant: CCOC(=O)CCn1c(CC)nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2n1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a solution of 3-[2-ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)benzimidazol-1-yl]-propionic acid ethyl ester (104 mg, 0.244 mmol) in 96% ethanol (5 mL) at room temperature under an inert atmosphere of nitrogen was added 1N NaOH (aq) (0.3 mL, 0.3 mmol). The mixture was stirred for 2 hrs at room temperature. The reaction was quenched by the addition of water (5 mL) and acidified to pH 2 with 1N HCl followed by extraction with diethyl ether (2×10 mL). The combined organic phases were washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo affording 11 mg (11%) of the title compound as yellow oil. MS-ESI m/z 398; 1H NMR (400 MHz, CDCl3) δ 0.83-1.06 (m, 6H), 1.12-1.22 (m, 7H), 1.24-1.28 (m) and 1.46-1.54 (m, 1H), 1.30-1.39 (m, 2H), 1.33 (t, 3H), 1.63-1.74 (m, 1H), 2.22-2.32 (m) and 3.15-3.27 (m, 1H), 2.26 (t, 2H), 2.85 (t, 2H), 3.51 (q, 2H), 7.25-7.35 (m, 2H), 7.56 (d) and 7.74 (d, 1H).
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][F:31])[CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][F:31])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCF)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FCC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M HCl (anhydrous)/ether (2.0 mL) was added to a stirred solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-2-(2-fluoroethyl)cyclopropyl]pyridine (160 mg, 0.45 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated and purified by HPLC to give the title compound (97 mg). 1H NMR (CD3OD, 400 MHz) δ 8.38 (s, 1H), 8.28 (s, 1H), 7.71 (s, 1H), 4.92-4.86 (m, 1H), 4.61-4.48 (m, 4H), 4.18-4.04 (m, 2H), 2.75-2.61 (m, 2H), 2.03-1.97 (m, 1H), 1.91-1.77 (m, 2H), 1.46-1.35 (m, 1H), 1.25-1.19 (m, 1H), 1.16-1.09 (m, 1H). MS (ESI) m/z 273 (M+Na+).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[N:16][OH:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O.C(#N)C>[CH3:28][O:27][C:25]([O:17][N:16]=[C:12]1[C:13](=[O:15])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:26]
Reactant: COC(=O)Cl
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)ON=C1C(=O)c2ccccc2-c2ccccc21
Yield: 81.5 %

Procedure:
22.3 g (0.1 mole) of 9,10-phenanthrene-dione-9-oxime are dissolved in 200 ml of 1:1 mixture of dimethyl formamide and acetonitrile under stirring, whereupon 16 ml of pyridine are added. To the reaction mixture a solution of methyl chloroformate and 30 ml of acetonitrile is added dropwise under stirring. The reaction mixture is stirred first at room temperature for an hour and thereafter at boiling point for 15 minutes. The reaction mixture is cooled and poured into 700 ml of icecold water. On cooling the precipitated oily product solidifies. Thus 22.9 g of 9,10-phenanthrene-dione-9-methoxycarbonyl-oxime are obtained in the form of an orchre-yellow product. Yield 81.5%, mp.: 142°-143° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC#N>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(NCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile (from step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treated with triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90 minutes before being concentrated in vacuo. Water (200 mL) was added to the residue, and the aqueous solution was extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by crystallisation from iso-propanol to yield 24.6 g (77%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([OH:26])=O)[N:21]=1)=[CH:5]2.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([NH:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:21]=1)=[CH:5]2
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)NCCN1CCOCC1
Yield: 26 %

Procedure:
The compound (150 mg, 0.38 mmol) prepared in Example 149 and 4-(2-aminoethyl)morpholine instead of morpholine were reacted according to the same procedure as Example 70 to give the title compound (50 mg, Yield 26%).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.P(OCC)(OCC)[O:14]CC.C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)[N+](CC3C=CC(C(F)(F)F)=CC=3)(CC2)C1.[Br-].[OH-].[Na+].O=O>C1(C)C=CC=CC=1>[OH:14][C:2]1([CH3:1])[C:11](=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: CC1C=CC2=C(CCCC2)C1=O
Reactant: CCOP(OCC)OCC
Agent: C=C[C@H]1C[N+]2(Cc3ccc(C(F)(F)F)cc3)CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: O=O
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC1(O)C=CC2=C(CCCC2)C1=O

Procedure:
2-Hydroxy-2-methyl-benzocyclohexan-1-one (compound Id) was prepared by dissolving 2-methyl-benzocyclohexan-1-one (19.7 g, 0.123 mol) in toluene (750 mL) in a 2000 mL three neck flask. Triethyl phosphite (98%, 25 mL, 0.2 mol) and N-[4-(trifluoromethyl)benzyl]-cinchoninium bromide (CPTC, 3.3 g, 6.25 mmol, 5 mol %) and 50% aqueous sodium hydroxide (375 mL) were added into the flask. A Pasteur pipet was installed in one neck and immersed in the solution to serve as an inlet for oxygen. One of the other necks was attached to a condenser which was topped with an outlet opening to air. A mechanical stirrer was used to keep the two phase solution stirring vigorously. Molecular oxygen was bubbled through the reaction mixture and the solution was kept stirring for 24 hours at room temperature. After the reaction, water (400 mL) was added to the mixture. The water layer and toluene layer were separated using a separatory funnel. The aqueous layer was extracted with benzene (100 mL×3). The benzene portion and the toluene portion were combined. The organic layer was washed with 10% hydrochloric acid (350 mL), water and finally with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate. The organic solvent was removed by a rotary evaporator to give a yellow liquid. The yellow liquid was purified by vacuum distillation. Two fractions corresponding to a boiling range of 110-113° C. at 17 mm Hg (triethyl phosphite) and 135-140° C. at 17 mm Hg (the desired compound) were collected separately. The fraction containing 2-hydroxy-2-methyl-benzocyclohexan-1-one (14.5 g) was obtained in 67% isolated yield. The purity of the product was 100% by GC.
Reaction SMILES: O1CCCC1.[Si]([O:23][CH2:24][CH2:25][C@H:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[C:58]4[C:53](=[N:54][CH:55]=[C:56]([Cl:59])[CH:57]=4)[CH2:52][C:51]([CH3:61])([CH3:60])[C:50]3=[O:62])[CH2:45][CH2:44]2)=[O:42])=[C:37]([F:63])[CH:36]=1)[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Cl:59][C:56]1[CH:57]=[C:58]2[C:53]([CH2:52][C:51]([CH3:60])([CH3:61])[C:50](=[O:62])[N:49]2[CH:46]2[CH2:45][CH2:44][N:43]([C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C@H:26]([CH3:27])[CH2:25][CH2:24][OH:23])=[CH:36][C:37]=3[F:63])=[O:42])[CH2:48][CH2:47]2)=[N:54][CH:55]=1
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a tetrahydrofuran solution (11 ml) of 1-{1-[(2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}-7-chloro-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (525 mg) was added at room temperature a tetrahydrofuran solution (1 M, 1.28 ml) of tetrabutylammonium fluoride, followed by stirring for 3 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with a saturated aqueous ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 7-chloro-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (301 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1.[C:34]([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:37][C@@H:38]([CH3:42])[C:39]([NH:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([C:21](=[O:22])[NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:10]2)[CH2:5][O:4]1)=[O:40])(=[O:36])[CH3:35]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CN)CO4)C3)nc(C)n2)ccc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(=O)[C@H](C)OC(C)=O)CO4)C3)nc(C)n2)ccc1F
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 6-((S)-5-((2R,5R)-5-(aminomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.15 g, 0.326 mmol, Preparation #J.1) in DCM (3 mL) at 0° C., was added TEA (0.100 mL, 0.718 mmol) followed by (S)-(−)-2-acetoxypropionylchloride (0.045 mL, 0.359 mmol, Spectrochem). The reaction mixture was stirred for 30 min. at the same temperature and was quenched with water (10 mL). The product was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified using silica gel column chromatography by eluting with 70% EtOAc in hexane. The relevant fractions containing compound were combined and concentrated to afford (S)-1-(((2R,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methylamino)-1-oxopropan-2-yl acetate 0.11 g (58%); 1H NMR (400 MHz, DMSO): δ 9.48 (t, J=6.4 Hz, 1H), 8.13 (s, 1H), 7.17-7.11 (m, 2H), 6.89-6.86 (m, 1H), 4.87-4.85 (m, 1H), 4.79-4.78 (m, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.88-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.63 (m, 2H), 3.49-3.37 (m, 4H), 3.26-3.21 (m, 2H), 3.09-3.07 (m, 2H), 2.75 (s, 3H), 2.04 (s, 3H), 1.30 (d, J=6.8 Hz, 3H); LC/MS) (Table 1, method c) Rt=3.12 min; MS: m/z 574 (m+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=O)N[C:9]2[CH:13]=[CH:14][CH:15]=C[C:8]=2[O:7]1)=[O:5])[CH3:2].[H-].[Na+].IC.C(OCC)(=O)C.[CH3:27][N:28]([CH3:31])[CH:29]=[O:30]>>[CH3:11][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:15]=[CH:14][CH:13]=[CH:9][C:8]=2[O:7]1
Reactant: CCOC(=O)C1Oc2ccccc2NC1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)Oc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.5 mmol (1.2 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (described in C.R. Acad. Sci. Paris Series C, 1969, 269, 154) in 5 ml of dimethylformamide are added at 0° C. to a suspension of 11 mmol (0.44 g) of 60% sodium hydride in 5 ml of dimethyformamide. The reaction mixture is stirred at 0° C. for 30 minutes. 22.2 mmol (1.38 ml) of iodomethane are then added, and the reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with ethyl acetate, the organic phase is dried, concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CCCCNc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: CCCCNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
8.5 g of 2-amino-4-butylamino-6-chloropyrimidine are dissolved in 150 ml of ethanol. 19.95 g of meta-chloroperbenzoic acid are added dropwise as solution in 150 ml of ethanol. The reaction mixture is stirred at room temperature for 2 hours. 250 ml of water are added and ethanol is then evaporated off. The pH is adjusted to 1 with concentrated hydrochloric acid. After 1 hour's stirring, the precipitate is filtered off on sintered glass, rinsed with 50 ml of water and discarded. The pH of the solution is adjusted to 8 by adding sodium hydroxide. The mixture is extracted with 3×100 ml of dichloromethane. The organic phase is dried over sodium sulfate and then evaporated to dryness. The precipitate obtained is recrystallized from 50 ml of acetonitrile. 2.35 g of 2-amino-4-butylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[O:4][C@@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:36][C@H:37]([C:39](O)=[O:40])[CH3:38])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:36][C@H:37]([C:39]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[O:4][C@@H:3]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:40])[CH3:38])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: COC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To a stirred solution of methyl [(2R,3S)-3-amino-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70b) (130 mg, 0.398 mmol) in dichloromethane (4 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (125 mg, 0.514 mmol), HOBt (71 mg, 0.525 mmol), NMM (53 mg, 0.525 mmol) and EDAC-HCl (100 mg, 0.522 mmol). After stirring at ambient temperature under nitrogen for 48 h the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexane:ethyl acetate to afford the title compound (185 mg, 82%) as a white solid. TLC Rf=0.13 (1:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.21 (d, 3H, J=7.0 Hz), 3.46 (s, 2H), 3.80 (s, 3H), 4.23 (m, 1H), 4.55 and 4.68 (AB quartet, 2H, J=17.1 Hz), 5.16 (t, 1H, J=7.2 Hz), 5.72 (d, 1H, J=7.4 Hz), 5.87 (br d, 1H, J=7.0 Hz), 6.17 (br d, 1H, J=6.6 Hz), 6.66-6.87 (m, 3H), 7.19-7.33 (m, 4H), 7.37 (s, 5H). MS APCI, m/z=552 (M+1). LC/MS: 2.52 min.