Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 88 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl (3R)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl (3R)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 88% yield: 1H NMR (DMSO-d6) (rotamers) δ 8.11 and 8.00 (2d, J=8.1, 8.2 Hz, 1H), 7.89 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=8.0, 7.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.69 (m, 10H), 3.02-2.80 (m, 2H), 1.97-1.93 (m, 1H), 1.76 (m, 1H), 1.59-1.20 (m, 2H), 1.35 (s, 9H). Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.9; H, 6.1; N, 20.1%.
Reaction SMILES: [CH3:1][C:2]1([CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:7][CH2:6][C:5]([CH2:14]OC(=O)CC)([CH2:8][O:9]C(=O)CC)[CH2:4][O:3]1.[C:26]([O:30][CH2:31][C:32](=[O:34])[CH3:33])(=[O:29])[CH2:27][CH3:28]>>[CH3:1][C:2]1([CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:7][CH2:6][C:5]2([CH2:8][O:9][C:32]([CH3:33])([CH2:31][O:30][C:26](=[O:29])[CH2:27][CH3:28])[O:34][CH2:14]2)[CH2:4][O:3]1
Reactant: CCC(=O)OCC(C)=O
Reactant: CCC(=O)OCC1(COC(=O)CC)COC(C)(COC(=O)CC)OC1
Product: CCC(=O)OCC1(C)OCC2(CO1)COC(C)(COC(=O)CC)OC2
Yield: 53 %

Procedure:
A solution of propionyloxyacetone (10 g, 76.8 mmol), pentaerythritol (5.22 g, 38.4 mmol), and pyridinium p-toluenesulfonate (1.0 g, 4 mmol) in toluene (200 ml) was stirred under reflux for 6 hours, while water was removed using a Dean-Stark water separator. After cooling to room temperature, the reaction liquid was poured into ethyl acetate (300 ml)/an aqueous sodium hydrogencarbonate solution (350 ml). After phase separation, the organic layer was washed twice with water (200 ml), and once with saturated brine (200 ml), and then dried over sodium sulfate. After the sodium sulfate was filtered out, the solvent was distilled off under reduced pressure, to obtain 11.0 g of a concentrate residue. As a result of measurement of NMR spectra of the concentrate residue, it was found that the by-product of Comparative Example 1 (2-methyl-2,5,5-tris(propionyloxymethyl)-[1,3]dioxane) was hardly detected, while other by-products were formed, and that the starting material propionyloxyacetone remained at a similar level to that in Comparative Example 1. The concentrate residue was purified by column chromatography (eluent: ethyl acetate/hexane=1/2), to give 3,9-dimethyl-3,9-bis(propionyloxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (7.3 g, 20.3 mmol, yield 53%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][CH3:33])[CH:20]=[C:19]1[C:34](=[O:36])[NH2:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][N:5]([C@@H:18]1[C:19]([C:34]([NH2:35])=[O:36])=[CH:20][C@@H:21]([CH2:31][O:32][CH3:33])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](COC)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCON([C@H]1CN[C@H](COC)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
To a solution of Intermediate 112 (729 mg, 1.38 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2133 μl, 27.69 mmol). This solution was slightly darker after addition. The reaction was placed under a nitrogen atmosphere and stirred until LCMS analysis indicated consumption of starting material (˜45 minutes). At that time, solvent was removed in vacuo. The residue was taken up in toluene and sonicated, and then toluene was removed in vacuo. This was repeated twice, affording an orange solid of high purity by proton NMR. The product was taken forward without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.035 g), and the mixture was stirred at room temperature overnight. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl ]-5-methyl-1H-pyrazole (0.043 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.Cl[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>O1CCOCC1>[OH:9][CH2:8][C:6]1[N:7]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:1]=[C:2]2[CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cccc(CO)n1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cccc(CO)n12

Procedure:
The title product is prepared by the reaction of the title compound from Example 3 with ethyl a-chloroformylacetate by the method of Example 4 or in dioxane by the procedure of W. W. Paudley; R. A. VanDahm; Y. N. Park, J. Heterocyclic Chem., 1972, (9), 81-85.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[S:4][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1>O1CCCC1>[Cl:2][C:3]1[S:4][C:5]([S:9]([NH2:1])(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: N
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1S(N)(=O)=O

Procedure:
117.7 g (1.8 mol) of 26% strength aqueous ammonia solution are added dropwise to a solution of 208 g (95% pure, 0.9 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 1000 ml of tetrahydrofuran at −10° C. The reaction mixture is left to stirr without further cooling for 2 h and is then concentrated in a rotary evaporator. The crude product is employed without further purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:22]2[C:18](=[N:19][O:20][N:21]=2)[C:17]([S:23](Cl)(=[O:25])=[O:24])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[C:22]2=[N:21][O:20][N:19]=[C:18]2[C:17]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c2nonc12
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c3nonc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole as described in the synthetic METHOD B to give a yellow solid (2.5 mg) with purity >90%. MS (pos) m/z 403.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
According to Scheme 13 Step 1: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.38 mmol, 1.43 g), 1-(chloromethyl)-4-methoxybenzene (7.38 mmol, 1.00 mL) and K2CO3 (7.38 mmol, 1.02 g) in acetonitrile (10 mL) was heated at 80° C. for 5 hours. Water was added and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.68 mmol, 2.10 g, 91%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][CH2:17][C:18]2[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:21][CH:22]=2)=[CH:14][CH:13]=1.[NH:37]1[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:39]=[N:38]1.O>CN(C)C=O>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:16][C:15]3[CH:35]=[CH:36][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:37]4[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:39]=[N:38]4)=[CH:13][CH:14]=3)[N:19]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Reactant: CCOC(=O)c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CCCCc2ccc(OCc3coc(/C=C/c4ccc(C(F)(F)F)cc4)n3)cc2)nn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
Potassium carbonate (2.4 g) was added to a solution of 4-[[4-(4-iodobutyl)phenoxy]methyl]-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (7.5 g) and ethyl 1H-1,2,3-triazole-4-carboxylate (2.1 g) in dimethylformamide (100 ml), and the mixture was stirred at 70° C. for 5 hr. After the reaction was completed, the reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=3:1), and recrystallized from ethyl acetate-hexane to give the titled compound (1.85 g) as a colorless crystal powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0 g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min at ambient temperature. After this time methyl iodide (17.1 g, 0.124 mol) was added, and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with water (750 mL) and extracted with ethyl acetate (3×1.0 L). The organic extracts were combined, washed with brine (500 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by flash chromatography on silica to afford an 85% yield (21.7 g) of 41 as a yellow solid: mp 122-423° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:37]=3)=[N:30][CH:31]=2)=[C:22]([F:45])[C:21]=1[F:46])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:45][C:22]1[C:21]([F:46])=[C:20]([OH:19])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:31]=[N:30][C:29]([C:32]2[CH:33]=[N:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:37]=2)=[N:28][CH:27]=1
Reactant: CCCCCCOc1ccc(-c2ncc(-c3ccc(OCc4ccccc4)c(F)c3F)cn2)cn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Yield: 74.1 %

Procedure:
1.5 g of 10 percent palladium/charcoal and 0.1 g of 4-toluenesulfonic acid are added to a solution of 14 mmol of 5-(4-benzyloxy-2,3-difluorophenyl)-2-(6-hexyloxypyridin-3-yl)pyrimidine in 200 ml of THF. The mixture is stirred at 50° C. under hydrogen in a suitable apparatus until the take-up of hydrogen is complete, the catalyst is filtered off, and the solvent is removed in vacuo. Purification by recrystallization from acetonitrile gives 4.0 g (73%) of a colorless solid, m.p. 150-155° C.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:5])[CH3:2].Cl.C(NC(C1(C2C=CC(Cl)=C(Cl)C=2)CCC1)C)C.[OH-].[Na+].C(O[C:42](=[O:44])[CH3:43])(=O)C>>[C:42]([N:3]([CH:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:5])[CH2:1][CH3:2])(=[O:44])[CH3:43]
Reactant: CCNC(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(C(C)=O)C(C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A mixture of N-ethyl-1-[1(3,4-dichlorophenyl)cyclobutyl]ethylamine (0.5 g prepared by treating the product of Example 21 with aqueous sodium hydroxide) and acetic anhydride (1 ml) was heated at 40°-45° C. for thirty minutes. The reaction mixture was basified and extracted with ether. The ether extract was washed, dried and evaporated to give N-acetyl-N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12][C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.C(N(CC)CC)C>CO>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1c(Cl)ccc(C)c1N

Procedure:
110 g (0.52 mol) of 6-chloro-3-methylisatoic anhydride were introduced into a mixture of 750 ml of methanol and 47.6 g (0.47 mol) of triethylamine at 22° C. with stirring and the mixture was then stirred at 65° C. for 2 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in methylene chloride and extracted 3× with 0.5 N sodium hydroxide solution. After drying over magnesium sulfate, filtering through silica gel and concentrating in vacuo, 45.5 g (43.8% of theory) of the title compound were obtained as a colorless oil of nD23=1.5765.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:50][C:51]1([CH3:57])[CH2:53][C@@H:52]1[C:54](O)=[O:55].CN(C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:54]([C@H:52]6[CH2:53][C:51]6([CH3:57])[CH3:50])=[O:55])[CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC1(C)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of the hydrochloride salt of ((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (60.0 mg, 0.0775 mmol) and (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine (54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight, and then concentrated. The residue was redissolved in 1:1 acetic acid:water (6 mL), filtered and purified by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid 34.1 mg). (m/z): [M+H]+ calcd for C43H52N8O5 761.42 found 761.7. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H), 7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t, 1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H), 3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H), 2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H), 1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s, 3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:28]3[CH2:27][CH2:26][N:25]([CH2:24][C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[C:21]([F:35])([F:36])[F:20])[CH2:30][CH2:29]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)cc1OC
Yield: 62.8 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benzyl]piperazine (8.0, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.5 hr and followed the same processes as in Example 1 to obtain 12.3 mg (65.6%) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@@H:19]([CH3:30])[CH2:20][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:15]1.N1CCCC1>CO>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][CH:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][C@@H:19]([N:16]3[CH2:17][CH2:18][C@@H:14]([CH3:13])[CH2:15]3)[CH3:30])=[CH:23][CH:24]=1)[CH2:11][C:10]2=[O:12]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: C[C@@H]1CCN([C@@H](C)COc2ccc(C=O)cc2)C1
Solvent: CO
Solvent: C1CCNC1
Product: COc1ccc2c(c1)C(=O)CC(c1ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc1)O2
Temperature: 50 °C
Yield: 18 %

Procedure:
A mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (1 g, 6 mmol), 4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)benzaldehyde (1.5 g, 6.08 mmol), and pyrrolidine (0.12 mL, 1.5 mmol) in methanol (12 mL) was heated at 50° C. for two days. After cooling, the solvent was removed and the residue was purified by silica gel chromatography to afford 427 mg of 6-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)chroman-4-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (d, 2H), 7.22-7.18 (m, 2H), 7.03 (d, 1H), 6.98 (d, 2H), 5.52 (dd, 1H), 4.04 (m, 1H), 3.83 (m, 1H), 3.80 (s, 3H), 3.24 (dd, 1H), 2.87 (m, 1H), 2.76 (dd, 1H), 2.67 (m, 2H), 2.58 (m, 1H), 2.11 (m, 2H), 1.91 (m, 1H), 1.22 (m, 1H), 1.13 (d, 3H), 0.97 (d, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 66.4 %

Procedure:
40 mg (1 mmol) of sodium hydroxide are added to a solution of 483 mg (1 mmol) of ethyl 2-[1-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 48 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 310 mg (83%) of 2-[1-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a white powder with a melting point of 98-100° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
L-threonine 21.2 g (178 mmol) was dissolved in toluene (100 mL), and benzyl alcohol (100 mL, 966 mmol) and p-toluenesulfonic acid monohydrate (35.0 g, 194 mmol) were added, followed by heating to reflux for 17 hours under nitrogen atmosphere. After cooling to room temperature, water (200 mL) was added, followed by washing three times with ethyl acetate (100 mL). To the aqueous layer, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out three times with ethyl acetate (100 mL). After the organic layer was washed with saturated brine, drying was carried out over anhydrous magnesium sulfate, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-15%) to afford the desired product (10.6 g, yield 28%) as a white solid.