Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1N)([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].[BrH:16]>O.[Cu]>[Br:16][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Br
Reactant: CC(C)(C)c1ccccc1N
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccccc1Br
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 2-tert-butylaniline (7.46 g, 50 mmol 15.6 mL) in hydrobromic acid (40% w/w, 15 mL) cooled at <5° C. (ice/salt bath), a solution of 7.55 g (0.11 mol) of sodium nitrite in 10 mL of water was added at a rate that the temperature did not exceed 10° C. (ca two hour addition time). When the diazotization was completed, 0.20 g of copper powder was added. (CAUTION: the solution was refluxed very cautiously because of vigorous gas evolution!). When the vigorous evolution of nitrogen subsided, the system was kept at 50° C. for 30 minutes and was then diluted with 80 mL of water and extracted three times with diethyl ether (100 mL each). The organic layer was washed with 10% solution of KOH; dried over Na2SO4, concentrated in vacuo, and purified by chromatography on silica gel chromatography. The product obtained was further distilled at 85° C. (3 mm Hg) to yield 1-bromo-2-tert-butylbenzene (2.88 g, 27%). 1H NMR (400 MHz, CDCl3): δ 7.58 (m, 1 H, Ph-H), 7.45 (m, 1 H, Ph-H), 7.24 (m, 1 H, Ph-H), 7.02 (m, 1 H, Ph-H), 1.51 (s, 9 H, C(CH3)3).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:11]=3[O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([S:20]([N:23](CC4C=CC(OC)=CC=4OC)[C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[C:15]([F:40])[CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:11]=3[O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:21])=[O:22])=[C:15]([F:40])[CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4[nH]cnc4c3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccc3[nH]cnc3c2)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.149 g, 0.22 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at 0° C. The reaction mixture was stirred for 2 h at 0° C. The mixture was concentrated in vacuo and the residue was suspended in methanol (20 mL) and filtered. The filtrate was concentrated in vacuo and the residue triturated in diethyl ether (5 mL) and suspended in water (2 mL). Lyophilization affored 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzene-sulfonamide as the corresponding beige trifluoroacetate salt in 75% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ9.11 (s, 1H), 8.37 (s, 1H), 7.84 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.64 (dd, J=10.2, 6.5 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.49 (dd, J=8.7, 2.5 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 7.11 (dd, J=10.4, 6.5 Hz, 1H), (NH not observed); 19F NMR (282 MHz, DMSO-d6) δ−76.6 (s, 3F), −113.0 (d, J=15.8 Hz, 1F), −139.0 (d, J=15.9 Hz, 1F); MS (ES+) m/z 519.7 (M+1), 521.7 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][NH:13][C:14](=O)[CH:15]=2)[CH:5]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][CH:14]1[NH:13][N:12]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH:2][CH3:1])=[O:17])=[CH:15]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNC(=O)c1cccc(-c2cn[nH]c(=O)c2)c1
Product: CNC(=O)c1cccc(C2=CC(Cl)NN=C2)c1
Temperature: 110 °C

Procedure:
N-Methyl-3-(6-oxo-1,6-dihydro-pyridazin-4-yl)-benzamide (1 eq, 3.14 mmol, 720 mg) is suspended in POCl3 (10 ml) and the reaction mixture is heated at 110° C. for 2 h. After cooling to room temperature, the solvent is removed in vacuo and then ice water is added. The pH is adjusted to pH8 with portionwise addition of sat. aqueous Na2CO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over MgSO4, filtered and evaporated to dryness to yield 3-(6-Chloro-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide as a yellow solid which did not require further purification; [M+H]+=248
Reaction SMILES: [H-].[Na+].[Cl:3][CH:4]([C:9]([CH3:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[Li]CCCC.[CH:17]1([C:22](=[O:35])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([F:33])[F:32])=[C:27]([F:34])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[Cl:3][CH:4]([C:9](=[O:10])[CH2:11][C:22]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([OH:35])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([F:32])[F:33])=[C:27]([F:34])[CH:26]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: O=C(CCc1ccc(C(F)F)c(F)c1)C1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(C(F)F)c(F)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a slurry of NaH (450 mg, 18.65 mmol) in dry THF (6 mL) at −40° C. under nitrogen was added a cold solution of methyl 2-chloroacetoacetate (2.67 g, 17.76 mmol) in 20 mL dry THF (20 mL) at such a rate that the temperature was maintained within 5° C. of −40° C. When the addition was complete, the mixture was stirred at this temperature for an additional 30 min, then cooled to −70° C. with a dry ice/acetone bath. Cold n-BuLi (9 mL, 2.08 M, 18.65 mmol) was slowly added via syringe, maintaining the temperature at −70° C. The mixture was stirred for an additional 45 min at this temperature. A solution of 1-cyclopentyl-3-[4-(difluoromethyl)-3-fluorophenyl]propan-1-one (4 g, 14.8 mmol) in dry THF (20 mL) was added slowly via an addition funnel. The reaction was allowed to stir at −70° C. for 45 min, then warmed to room temperature. After stirring for 2 h, the mixture was quenched with 4M aqueous NH4Cl (9.35 mL, 37.3 mmol), stirred for 5 min, then concentrated in vacuo. The oily residue was treated with water and extracted with CH2Cl2 (3×50 mL). The extract was dried over Na2SO4, filtered and concentrated to a orange resin. Purification by column chromatography on silica gel and a gradient of 10% ethyl acetate/hexanes to 100% ethyl acetate afforded 3.5 g (8.32 mmol, 56%) of methyl 2-chloro-5-cyclopentyl-7-[4-(difluoromethyl)-3-fluorophenyl]-5-hydroxy-3-oxoheptanoate. This hydroxyester intermediate was dissolved in toluene (20 mL), treated with bis(dibutylchlorotin)oxide (2.07 g, 3.75 mmol, 0.45 equiv), and the mixture refluxed for 1 h. The solution was cooled to room temperature, the solvent removed in vacuo, and the resin filtered through a plug of silica gel, eluting with 5% MeOH/ethyl acetate. The fractions containing the product were evaporated and recrystallized from ethyl ether, affording 437 mg (13.5% yield) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:12][CH:13]([CH2:18][CH:19]=[CH2:20])[C:14]([F:17])([F:16])[F:15])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([O:12][CH:13]([CH2:18][CH:19]=[CH2:20])[C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: C=CCC(Oc1cc(F)ccc1C(=O)OC)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(Oc1cc(F)ccc1CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 4-fluoro-2-[(1,1,1-trifluoropent-4-en-2-yl)oxy]benzoate (2.92 g, 10 mmol) was dissolved in 20 mL of THF and cooled to 0° C. 1M (THF) LiAlH4 (10 mL, 10 mmol) was added and the mixture stirred for 3 hours. Ethyl acetate (10 mL) was added and the mixture stirred 5 min, after which sat'd NaHCO3 was added and stirring continued for 15 min. The mixture was transferred to a separatory funnel and extracted with ethylacetate. The organic layers were combined and dried over Na2SO4, filtered and the solvent removed under vacuum. The crude product was purified by column chromatography on a Biotage instrument using hexanes/ethyl acetate as eluent. 1H NMR (400 MHz, CDCl3) δ 2.70 (m, 2H), 4.64 (overlapping m, 3H), 5.23 (d, 1H), 5.27 (d, 1H), 5.84 (m, 1H), 6.68 (dd, 1H), 6.77 (td, 1H), 7.35 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1COc2ccc(CO)cc2N1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6.9 g of methyl 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylate in 230 ml of tetrahydrofuran is cooled to −40° C. 88.9 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −40° C. over the course of 30 minutes. The reaction mixture is stirred at −40° C. to −20° C. for 1.5 hours and then cautiously poured into 150 ml of 2N HCl (cold). The organic phase is separated off, and the aqueous phase is extracted with tetrahydrofuran (5×100 ml). The organic phases are washed with brine (1×100 ml), filtered through cotton wool and evaporated. The title compound is obtained as beige crystals from the residue by crystallization (from ethanol). Rf=0.16 (EtOAc/heptane 2.1); Rt=2.23; m.p.: 186-187° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>O>[CH3:26][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:23]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4])=[O:24]
Reactant: N[C@@H](CCCc1ccccc1)C(=O)O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C(=O)N[C@@H](CCCc2ccccc2)C(=O)O)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and the reaction vessel was flushed with nitrogen. Catalytic amount of palladium (10% on carbon) was added and the reaction vessel was placed under a hydrogen atmosphere. The mixture was stirred for 2 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-amino-5-phenyl-pentanoic acid 2 (51 mg, quant.) as a white powder: 1H-NMR (400 MHz, CD3OD) δ=7.42–7.25 (m, 5H), 3.71 (t, J=6.0, 1H), 2.69 (t, J=6.4, 2H), 1.85 (m, 2H), 1.70 (m, 2H). MS calcd. for C11H16NO2 (M+H+) 194.12. found 194.4. Step B: (S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.83–7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01–1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16. found 312.4. Step C: (S)-2-(3-Methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 0.07 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{1-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-4-phenyl-butyl}-3-methyl-benzamide 4 (18 mg, 0.04 mmol, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.56–7.48 (m, 2H), 7.36–7.16 (m, 7H), 6.96–6.87 (m, 4H), 4.48 (dd, J=6.2, J=13.7, 1H), 3.82 (s, 3H), 3.78–3.64 (m, 2H), 3.58–3.50 (m, 2H), 2.71–2.64 (m, 2H), 2.35 (s, 3H), 2.06–1.70 (m, 4H). MS calcd. for C28H34N3O3 (M+H+) 460.26. found 460.5.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([O:20][CH3:21])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:26][CH2:18][C:16]1[CH:15]=[C:14]([O:20][CH3:21])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:2]([F:1])[CH:17]=1
Reactant: COc1cc(C=O)cc(F)c1Oc1ccc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(CNCCC(C)(C)C)cc(F)c1Oc1ccc(C(N)=O)cn1
Yield: 80.1 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinamide (250 mg, 0.861 mmol), 3,3-dimethyl-butylamine (104 mg, 1.03 mmol), and NaBH4 (49 mg, 1.29 mmol) gave the title compound (259 mg) as a white solid. Mass spectrum (ion spray): m/z=376 (M+1); 1HNMR (DMSO-d6): 8.50 (s, 1H), 8.23 (d, 1 μl), 7.98 (s, 1H), 7.44 (s, 1H), 7.13 (d, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 3.71 (s, 3H), 3.68 (s, 2H), 2.51 (t, 2H), 1.37 (t, 2H), 0.86 (s, 9H).
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:22]=[C:23]([C:24]([O:26]C)=[O:25])[C:5]=2[N:4]=1.[Li+].[OH-]>C1COCC1>[F:34][CH:2]([F:1])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:22]=[C:23]([C:24]([OH:26])=[O:25])[C:5]=2[N:4]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C(F)F)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 45 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate (700 mg, 1.45 mmol) and 2 N LiOH (5 mL) in THF (10 mL) was stirred at 45° C. for 4 h. It was filtered, the filter cake was dissolved in water (10 mL) and formic acid was added to adjust pH=3-4. Then a filtration was performed and the filter cake was dried under vacuum to give the desired product (400 mg, 59%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.53 (s, 3H), 3.13 (s, 4H), 3.73 (s, 4H), 5.75 (s, 2H), 6.29 (d, 1H, J=7.5 Hz), 7.19-7.61 (m, 5H), 12.97 (br s, 1H); LC-MS: m/e=470 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[O:15][CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].C([Li])(C)(C)C.[CH2:26]([Si:29](Cl)([CH3:31])[CH3:30])[CH:27]=[CH2:28].C(OC(=O)NC1C=CC([Si](CC=C)(C)C)=CC=1OC)(C)(C)C>CCCCCC>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Si:29]([CH2:26][CH:27]=[CH2:28])([CH3:31])[CH3:30])=[CH:10][C:9]=1[O:15][CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(Br)ccc1NC(=O)OC(C)(C)C
Reactant: C=CC[Si](C)(C)Cl
Agent: C=CC[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)c(OC)c1
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Product: C=CC[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)c(OCC)c1
Yield: 58.5 %

Procedure:
The reaction between 5.3 g (16.8 mmol) of tert-butyl-N-(4-bromo-2-ethoxyphenyl)carbamate 5, 2.4 g (20.16 mmol, 1.2 eq) of 35% potassium hydride, 20.2 ml (34.4 mmol, 2.05 eq) of 1.5 M tert-butyllithium in hexane and 6 ml (40.3 mmol, 2.4 eq) of allyl(chloro)dimethylsilane according to the procedure described for compound 6, followed by two successive purifications by column chromatography (eluant petroleum ether/AcOEt 9:1), lead to 3.3 g of a colorless oil (yield: 58%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])[CH:20]=2)[NH:15][CH:14]=1)=[O:4]>[Pd].CO>[CH3:27][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[CH:20]=2)[NH:15][CH:14]=1)=[O:4]
Reactant: CC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3CCC(=O)N(C)C)c2c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCC(=O)N(C)C)c2c1

Procedure:
Obtained from the title compound of Example 69 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a gum. Rf 0.35 (SS 7). [α]D25 +82° (c=0.1, CH3OH). LRMS: m/z 370.6 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=[CH:9][N:8]=1.P(Cl)(Cl)(Cl)=O>O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:13]=1
Reactant: CN(C)CCCN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2F)=Nc2cccnc21
Yield: 38.8 %

Procedure:
A solution of 8.5 g (0.022 mole) of N-[2-[[3-(dimethylamino)propyl]phenylamino]-3-pyridinyl]-2-fluorobenzamide in 26 g (0.173 mole) of phosphorus oxychloride was refluxed under nitrogen atmosphere for 16 hr. The cooled reaction mixture was poured over ice, diluted with water, and extracted twice with diethyl ether. The acidic portion was made basic with sodium hydroxide pellets, cooled with ice and extracted twice with methylene chloride. The combined methylene chloride layers were washed in sequence with water and saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl alcohol-isopropyl ether using charcoal treatment to yield 3.2 g (39%) of a bright-yellow solid, m.p. 92°-94° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[CH2:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: NCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(CNCc1ccc(F)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.3 %

Procedure:
Diisobutylaluminum hydride (39.6 mL of a 1.0 M solution in toluene, 39.6 mmol) was added over 5 min to a solution of 2-propyl-malonic acid diethyl ester (4.00 g, 19.8 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (1.18 g, 7.46 mmol, 38%). This material was dissolved in ethanol (20 mL) at 25° C. and 4-fluorobenzylamine (0.852 mL, 7.46 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (0.937 g, 14.9 mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-pentanoic acid ethyl ester (0.703 g, 2.63 mmol, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.1 Hz), 1.29-1.38 (2H, m), 1.44-1.51 (1H, m), 1.57-1.64 (1H, m), 2.57-2.64 (1H, m), 2.68 (1H, dd, J1=4.7 Hz, J2=11.7 Hz), 2.86 (1H, dd, J1=9.2 Hz, J2=11.7 Hz), 3.74 (1H, d, J=14.0 Hz), 3.79 (1H, d, J=13.2 Hz), 4.13-4.18 (2H, m), 6.96-7.01 (2H, m), 7.25-7.29 (2H, m).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH2:10]([O:17][C:18]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:19]=1[CH2:20][OH:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of DIBAL-H (179 mL, 1M) was added to a solution of the product from step (i) (26.4 g) in THF (400 ml) at rt. The mixture was stirred for 3 h then a further 0 ml of DIBAL-H was added and stirred for a further 1 h. The mixture was quenched carefully with EtOAc and then with 2M aq HCl. The mixture was partitioned between ether/2M HCl, the organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with isohexane and filtered to give the subtitle compound as a solid, 21 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Li+].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 50 °C
Reaction time: 14.5 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (2.00 g) in N,N-dimethylformamide (40 ml) were added lithium carbonate (2.44 g) and benzyl bromide (4.0 ml), and the mixture was stirred for 14.5 hours at 50° C. To the reaction mixture was added 1N hydrochloric acid, and the resulting mixture was extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g). To a stirred solution of the obtained 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (2.2 ml) under ice-cooling, and the mixture was stirred for 10 minutes. Chloromethylmethyl ether (1.2 ml) was added to the mixture, and the resulting mixture was stirred for 5.5 hours at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) gave 4′-benzyloxy-3′-methoxymethoxyacetophenone (2.28 g).