Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[CH:17]=O)[CH:9]=2)[N:3]=1.[CH3:19][NH:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.CC(O)=O.N>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:20]([CH3:19])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:27]=3)[CH:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)cnn2)n1
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)cnn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarbaldehyde (23-6, 70 mg, 0.29 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (42 mg, 0.35 mmol, 1.2 eq.) in ethanol (1.5 mL) was added anhydrous CuSO4 (56 mg, 0.35 mmol, 1.2 eq.) and AcOH (21 mg, 0.35 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours then basified with 2 M NH3 in ethanol (1.0 mL). The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (70% acetone in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (23-7) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.07 (d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=2.1 Hz), 7.75-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 2.96 (s, 3H), 2.86 (m, 1H), 2.52 (m, 1H), 2.44 (s, 3H), 2.18 (m, 1H), 1.83 (m, 1H). LRMS m/z (M+H) 346.0 found, 346.4 required.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH:25]=[CH:26][CH:27]([CH3:29])[CH3:28])C1C=CC=CC=1>CO.[Pd]>[C:21]([O:20][C:18](=[O:19])[NH:17][C@@H:14]1[CH2:15][CH2:16][C@H:11]([NH2:10])[C@H:12]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:13]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C=C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 14 h

Procedure:
A sample of [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(3-methyl-but-1-enyl)-cyclohexyl]-carbamic acid benzyl ester (0.24 g, 0.57 mmol) was dissolved in methanol (8 mL) and the resultant solution was charged with 5% Pd/C, Degussa (47 mg). The flask was evacuated and back-filled with hydrogen; this was repeated three times. The reaction was stirred under 1 atm of hydrogen for 14 h before being filtered and concentrated in vacuo to afford (1R,3R,4S)-[4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester. MS found: (M+H)+=285.3.
Reaction SMILES: F[B-](F)(F)F.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=2[F:29])[C:16]([NH2:18])=[S:17])=[CH:10][CH:9]=1)#[N:7].[C:30](OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:30][S:17][C:16](=[NH:18])[CH:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29]
Reactant: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Reactant: CCOC(C)=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
After adding 0.904 g of Me3O+BF4− to a solution of 2.01 g of 2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetamide in 150 ml of acetonitrile under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. Next, 400 ml of ethyl acetate and 300 ml of saturated aqueous sodium hydrogencarbonate were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The mixture was dried over anhydrous magnesium sulfate and the desiccating agent was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (2.05 g) as a light yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:28][CH2:27]2)=[O:25])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 6.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 4-(4-chlorobenzoyl)piperidine (300 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (37 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[CH3:21]B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Reactant: CB(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2ccccc2)nc2c1CCC(=O)N2
Temperature: 140 °C
Yield: 79.2 %

Procedure:
4-Chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.434 g, 2.05 mmol) was dissolved in DMF (5 mL) and added to a microwave vial. MeB(OH)2 (0.273 g, 4.56 mmol), Pd(Ph3P)2Cl2 (0.107 g, 0.152 mmol) and K2CO3 (1.05 g, 7.61 mmol) were added and the vial was capped. The reaction was heated at 140° C. in the microwave for 10 minutes. The reaction was concentrated onto silica gel and purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off-white solid (0.431 g, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH:10]=1)[O:17][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Benzyloxy)-2-hydroxybenzaldehyde (5.8 g), ethyl 4-bromobutyrate (7.1 mL), potassium carbonate (10.5 g) and sodium iodide (3.8 g) were added to N,N-dimethylformamide (50 mL), and the mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the title compound (8.2 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CC(C)=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=1[F:24]
Reactant: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.20 g, 0.67) and K2CO3 (0.27 g, 1.34 mmol) in acetone (10 mL) was added 2,4-difluorobenzyl bromide (0.16 g, 0.8 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H), 6.14 (d, J=8 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ES HRMS m/z 424.0159 (M+H C19H14BrF3NO2 requires 424.0155).
Reaction SMILES: [CH2:1]([C@H:8]([NH:19]C(=O)OC(C)(C)C)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:19][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)ONC[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
A mixture of tert-butyl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (3.285 g, 8.98 mmol) and trifluoroacetic acid (25 mL) was stirred at ambient temperature under Argon for approximately 30 minutes. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydroxide (1N). The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filter, evaporated in vacuo and dried under high vacuum to provide (2R,3S)-3-amino-1-[(1-ethylpropoxy)amino]-4-phenyl-2-butanol (2.455 g, 100%) as a solid. H1-NMR (chloroform-D3): 0.94 (m, 6H), 1.56 (m, 4H), 2.55 (m, 1H), 3.01 (m, 2H), 3.22 (m, 2H), 3.51 (m, 1H), 3.81 (m, 1H), 7.30 (m, 5H). MS(ESI): 267(M+H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(O)[CH2:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[CH:13]=3)[C:8]([CH2:30][CH3:31])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O.[OH-].[Na+]>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:16][C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[CH:13]=3)[C:8]([CH2:30][CH3:31])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2cc(C(O)(Cc3ccncc3)c3ccccc3)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(C(=Cc3ccncc3)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.2 %

Procedure:
1.00 g (2.43 mmol, 1.0 equiv) (±)-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1-phenyl-2-pyridin-4-yl-ethanol, 578 mg (3.04 mmol, 1.25 equiv) p-toluenesulfonic acid and 25 mL anhydrous toluene were placed in a flask fitted with a Dean-Stark trap and heated to reflux under nitrogen atmosphere. After 7 hours, the reaction mixture was cooled to room temperature and allowed to stir for 72 hours. The reaction mixture was diluted with 200 mL H2O and 100 mL 1N NaOH, and extracted 2×100 mL ethyl acetate. The organic extracts were combined, washed 1×50 mL each H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (2.5% CH3OH/CH2Cl2) to give 0.92 g (95%) of a white amorphous solid. A small sample was crystallized from ethyl acetate/hexanes to give 27 mg white needles: mp 134-1 36° C.; Anal. calcd for C27H27N3 : C, 82.41; H, 6.92; N, 10.68; Found: C, 82.31; H, 7.17; N, 10.80.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[H-].[Na+].[Br:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[CH:39][C:38]=1[CH2:47]Cl.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][N:7]([CH2:47][C:38]1[CH:39]=[C:40]([O:45][CH3:46])[C:41]([O:43][CH3:44])=[CH:42][C:37]=1[Br:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: COc1cc(Br)c(CCl)cc1OC
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)cc1OC
Yield: 78.5 %

Procedure:
Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzyl-amino)-pyrimidin-5-yloxy]-butyrate (100 mg) is dissolved in DMF (1 ml) and thereto is added sodium hydride (60%) (10.8 mg) under ice-cooling, and the mixture is stirred under ice-cooling for 15 minutes. Thereto is added 1-bromo-2-chloromethyl-4,5-dimethoxybenzene (83.1 mg) and the mixture is stirred under ice-cooling for 1 hour. To the reaction solution are added aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→14:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (116 mg). MS (m/z): 708/710 [M+H]+
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:10]1[CH:52]=[CH:51][C:13]([CH2:14][C@@:15]2([CH3:50])[N:19]3[C:20]([C:23]([NH:25][C:26]4([C:29]([NH:31][C@@H:32]5[CH2:36][CH2:35][C@H:34]([C:37]([O:39]C)=[O:38])[CH2:33]5)=[O:30])[CH2:28][CH2:27]4)=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:41]3[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[CH:42]=3)[C:16]2=[O:49])=[CH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[CH:52]=[CH:51][C:13]([CH2:14][C@@:15]2([CH3:50])[N:19]3[C:20]([C:23]([NH:25][C:26]4([C:29]([NH:31][C@@H:32]5[CH2:36][CH2:35][C@H:34]([C:37]([OH:39])=[O:38])[CH2:33]5)=[O:30])[CH2:27][CH2:28]4)=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:41]3[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[CH:42]=3)[C:16]2=[O:49])=[CH:12][CH:11]=1)#[N:9]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N[C@@H]4CC[C@H](C(=O)O)C4)CC3)n21
Temperature: 100 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
1N HCl in 1,4-dioxane (1 mL, 1 mmol) and 1N HCl (aq.) (0.5 mL, 0.5 mmol) were added to methyl (1S,3R)-3-({[1-({[(3R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-5-yl]carbonyl}amino)cyclopropyl]-carbonyl}amino)cyclopentanecarboxylate (35 mg, 0.054 mmol). The reaction tube was sealed and the reaction solution was stirred at 100° C. for 1 h. The reaction solution was then cooled to room temperature, filtered and purified via reverse phase HPLC. The title compound (23.1 mg) was isolated as a white solid, m/z 635.1 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:15])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:2]=[CH2:3].[CH3:16][O:17][CH2:18][C:19](=O)[CH3:20].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]2[C:5]=1[O:15][C:19]([CH2:18][O:17][CH3:16])([CH3:20])[CH2:13][C:12]2=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)ccc(C(C)=O)c1O
Reactant: COCC(C)=O
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)ccc2c1OC(C)(COC)CC2=O
Temperature: 25 °C
Yield: 32.5 %

Procedure:
445 mg of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone and 0.57 g of methoxyacetone were dissolved in 10 ml of toluene. Thereafter, 0.19 g of pyrrolidine and 0.19 ml of acetic acid were added to the reaction solution. Thereafter, the reaction solution was heated to reflux using Dean-Stark for 1 hour. Thereafter, the reaction solution was cooled to a room temperature. 1.14 g of methoxyacetone, 0.38 g of pyrrolidine, and 0.38 ml of acetic acid were added to the reaction solution, and the obtained mixture was further heated to reflux overnight. The reaction solution was cooled to a room temperature and then concentrated under a reduced pressure. The residue was diluted with ethyl acetate, and then successively washed with 2 N hydrochloric acid, a 1 N sodium hydroxide aqueous solution, water, and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 194 mg of the subject compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([O:16][C@@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C>ClCCl>[CH2:25]([O:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[CH:12][C:11]([C:14]([O:16][C@@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:15])=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[O:45])=[CH:47][CH:48]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCC[C@H](C)OC(=O)c1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ncc(C(=O)O[C@@H](C)CCCCCC)cn3)cc2)cc1
Yield: 28.5 %

Procedure:
--The hydroxy ester 60 (410 mg, 1.25 mol), 4-tetradecyloxybenzoic acid (417 mg, 1.25 mmol), DCC (257 mg, 1.25 mmol) and dimethylaminopyridine (cat.) in dry dichloromethane (15 ml) were stirred for 48 h at room temperature. Flash silica was added and the solvent was removed in vacuo and the residue was purified by flash chromatography (10% ethyl acetate-light petroleum) to give the ester 61 (230 mg, 28%) (from EtOH/MeOH), transitions/° C. I TGB(fog) TGB(C or A) SC 88 SCferri1 81.4 SCferri2SCanti 69 K (m.p. 85.4° C.); [α]D19 +20.2° (c 1.9 in CHCl3); νmax /cm-1 (KBr) 2880, 1705 (CO), 1690 (CO), 1610, 1460, 1290, 1240, 1195, 1110 and 830; δ 0.88 (6H, m), 1.20-1.60 (33H, m), 1.60-1.90 (4H, m), 4.05 (2H, t, J 6, OCH2), 5.22 (1H, sext, J 6, OCHMe), 6.98 (2H, J 8, 3'- and 5'-H), 7.37 (2H, d, J 8, ArH), 8.16 (2H, d, J 8, ArH), 8.60(2H, d, J8, 2'- and 6'-H) and 9.31 (2H,s,); m/z 642 (M+ -2), 419,317,265 and 121.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:23])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[F:22])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC>[BH4-].[Zn+2].[BH4-].O>[Si:1]([O:8][C@@H:9]([CH3:23])[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:13]=1[F:22])[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)c1cccc(C(F)(F)F)c1F
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](O)c1cccc(C(F)(F)F)c1F
Reaction time: 2 h

Procedure:
To a solution of 112 (1.374 g, 3.921 mmol) and Et2O (20 mL) cooled to 0° C. was added a solution of zinc borohydride (8.46 mL, 1.176 mmol) was added and the reaction was stirred for 2 h. Water was added slowly and the mixture was extracted with ether. The organic layer was washed with water and brine then dried, filtered, and concentrated to afford (1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(2-fluoro-3-(trifluoromethyl)phenyl)propan-1-ol (114) which was used without additional purification.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][C:23]([OH:25])=[O:24])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].S(=O)(=O)(O)O>O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][C:23]([OH:25])=[O:24])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)CC(N)C(=O)O
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 60 °C

Procedure:
Ten grams of DL-leucine, 12.2 g of N-carbobenzoxy-L-aspartic acid and 1.9 g of sulfuric acid were added to 500 ml of water and the resulting solution was heated to 60° C. This solution was cooled to 10° C. at a rate of 2° C. per hour while stirring, and was stirred for another two hours. The resulting crystal was separated, washed with 30 ml of water and dried to give 9.1 g of an L-leucine/N-carbobenzoxy-L-aspartic acid. Analysis showed that the optical purity of the L-leucine was 95%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([F:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH:20]=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[C:6](/[CH:21]=[CH:20]/[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[F:12])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: C=Cc1cc(F)ccc1F
Reactant: OB(O)c1cc(Br)ncc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(/C=C/c2cc(Br)ncc2F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 2-bromo-5-fluoropyridin-4-ylboronic acid (1.569 g, 7.14 mmol) and 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol) in dimethylformamide (20 mL) was flushed with a balloon of oxygen. To this was added sodium carbonate (1.51 g, 14.3 mmol) and palladium(II) acetate (0.16 g, 0.71 mmol) as solids in one portion. The flask was flushed with another balloon of oxygen and fitted with a balloon of oxygen. The reaction was warmed to 50° C. After 1 h, the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g). This process was repeated twice more (total boronic acid addition=6.3 g). The reaction was cooled to room temperature, diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid. 1H NMR (CDCl3) Shift: 8.28 (d, J=1.8 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.49 (d, J=16.5 Hz, 1H), 7.33 (ddd, J=8.9, 5.8, 3.1 Hz, 1H), 7.17 (d, J=16.8 Hz, 1H), 6.98-7.14 (m, 2H). 19F NMR (CDCl3) Shift: −118.54 (d, J=13.0 Hz, 1F), −122.71 (br. s., 1F), −135.71 (br. s., 1F). Mass spec.: 314.0 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:15]=1[C:16](O)=[O:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:16](=[O:17])[C:15]1[C:14]([OH:13])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:23])[CH3:2]
Reactant: O=C(O)c1c(O)cccc1O
Reactant: CCNCc1ccc(OC)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)C(=O)c1c(O)cccc1O
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a stirred solution of N-ethyl-4-methoxybenzyl amine (1.07 g, 6.49 mmol) in DMF (10 mL) was added 2,6-dihydroxybenzoic acid (1.0 g, 6.49 mmol) followed by HOAt (0.97 g, 7.14 mmol) and EDC (1.31 g, 6.81 mmol). After stirring overnight, the reaction was diluted with EtOAc prior to washing 3× with H2O. The combined aqueous layers were extracted once with EtOAc. The organic fractions were combined, washed once with brine, and dried over Na2SO4 prior to concentrating using a rotary evaporator. The residue was chromatographed on silica gel using 75% EtOAc/hexane as the eluent. The resulting promising impure fractions were further purified by silica gel chromatography. A total of 631 mg of the desired N-ethyl-N-4-methoxybenzyl 2,6-dihydroxybenzamide was obtained.