Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[O:16])=[O:8])[N:3]=[CH:2]1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CNCCN1C(=O)Cc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Step (b) A flask was charged with (S)-1-(2-(1H-imidazol-4-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (107 mg, 0.252 mmol), benzaldehyde (0.154 mL, 1.51 mmol), methanol (10 mL) and sodium triacetoxyborohydride (534 mg, 2.52 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with deionized water (15 mL). The mixture was washed with ethylene chloride (20 mL) and the aqueous layer was basified with 2N sodium hydroxide (40 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give Compound 175 (S)-1-(2-(1H-imidazol-4-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (41 mg, 32% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.23 (s, 1H), 7.63-7.18 (m, 8H), 7.02-6.82 (m, 7H), 5.42 (s, 1H), 4.02-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.78-3.61 (m, 2H), 3.58-3.34 (m, 2H), 3.08-2.97 (m, 1H), 2.78-2.64 (m 1H), 2.28-2.18 (m, 1H), 2.11-2.00 (m, 1H). MS (EI) for C29H28FN5O3. found 514.3 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1C(OC)=O.CCOCC>C1COCC1>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccccc2Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
230 ml of a 2M solution of NaHMDS in THF are introduced under nitrogen in a 250 ml of THF. The solution is cooled to −60° C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at −60° C., 29.8 g of methyl 2-chlorobenzoate are added and the mixture is stirred at −60° C. for 45 min and then allowed to return to 0° C. The reaction medium is poured on to 500 ml of ice-cold 2N HCl, extraction is carried out with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying and concentrating to dryness, purification is carried out by chromatography on silica (gradient: heptane up to heptane/AcOEt 80/20). 7.3 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.[H][H]>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ncccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ncccc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a suspension of N5-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (2.45 g, 8.5 mmoles) in ethanol (120 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([CH2:40][NH2:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:41][CH2:40][C:30]34[CH2:39][CH:34]5[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]5)[CH2:37]3)[CH2:31]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 1-Adamantanemethylamine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=479
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:17]1([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)C1CCCN(C2CCCC2)C1
Reaction time: 48 h

Procedure:
The crude amine from the above step was dissolved in 1,2-dichloroethane (15 mL) and cyclopentanone (1.0 mL) was added via syringe. The reaction was allowed to stir for 5 min before the addition of HOAc (0.6 mL) and NaBH(OAc)3 (2.3 g, 10.9 mmol) in one portion. The reaction was allowed to stir for 48 h and then quenched with Na2CO3 (10%, 20 mL) and the reaction was allowed to stir for 1 h before being extracted with DCM (3×50 mL). The combined organics were washed with brine (sat, 200 mL), dried with sodium sulfate, filtered, concentrated to provide 1.3 g of crude oil that was purified by a 120 g Isco normal phase column (100% EtOAc) to give benzyl 1-cyclopentylpiperidine-3-carboxylate as a colorless oil. MS m/z: 288 (M+1).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[C:24](I)=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([NH2:29])[CH:28]=1.O>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]1[CH:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][C:24]=1[C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][CH:12]=1
Reactant: Nc1cc(F)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
A mixture of 4-Biphenylboronic acid (737 mg, 2.4 mmol), K2CO3 (995 mg, 7.2 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol), compound 13-1 (700 mg, 2.4 mmol) in 10 mL toluene, 2 mL DMF, and 2 mL H2O was suspended in a microwave reactor vial and heated to 130° C. for 10 min in a microwave reactor. The resulting dark solution was then diluted with EtOAc (150 mL) and washed three times with 50 mL portions of saturated aqueous NH4Cl. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The crude product was purified on ISCO (EtOAc/Hexanes=6/4) to give title compound 13-2.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:38]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[C:44]([N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=2[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])[CH2:40][CH2:39]1)(=[O:46])[CH3:45]
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCOc2cc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)ccc2CS(C)(=O)=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone (15 mg, 0.11 mmol) for 18 hours. The reaction was heated for 2.0 hours at 50° C., then additional potassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone (15 mg, 0.11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 18 mg of 3-(2-(4-acetylpiperazin-1-yl)ethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 543 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: ClCCCCCn1ccc2ccccc21
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCCC(=O)Nc1ccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(5-chloropentyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 432.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Solvent: O
Product: CN1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(4-methylpiperazino)quinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 176° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(C(N)=O)nn2)CC1
Temperature: 130 °C
Yield: 75.3 %

Procedure:
6-Chloropyridazine-3-carboxamide (0.315 g, 2 mmol) and 1-methylpiperazine (0.555 ml, 5.00 mmol) were suspended in 2-propanol (2.000 ml) and sealed into a microwave tube. The reaction was heated to 130° C. for 30 mins in the microwave reactor and cooled to ambient temperature. The resulting precipitate was collected by filtration, washed with 2-propanol (10 mL) and dried under vacuum to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (0.333 g, 75%) as a white solid, which was used without further purification. A sample (100 mg) of the crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (54 mg) as a white solid.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14](=[O:26])[CH2:15][CH2:16][N:17]([CH3:25])C(=O)OC(C)(C)C)=N1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][Mg]Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[O:26][C:14]2([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH3:28])[CH2:15][CH2:16][NH:17][CH3:25]
Reactant: COCCCC[Mg]Cl
Reactant: CN(CCC(=O)c1cc(F)ccc1C1=NC(C)(C)CO1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CNCCC1(CCCCOC)OC(=O)c2ccc(F)cc21
Temperature: -30 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of tert-butyl 3-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluorophenyl)-3-oxopropyl(methyl)carbamate (153 mg, 0.4 mmol) in dry toluene (2 mL) at −30° C. was added 4-methoxybutylmagnesium chloride (2.0 M, 0.6 mL, 1.2 mmol, prepared by refluxing 4-methoxybutylchloride and magnesium in THF for 4 h). The reaction was stirred at −30° C. for 2 h. After warming to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and brine, separated. The aqueous phase was extracted with ethyl acetate once. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g column, EtOAc/Hexanes) to give the Grignard-addition adduct (130 mg, 70%). A portion of the adduct (30 mg, 0.064 mmol) was dissolved in acetonitrile (4 mL), put in a seal tube and added concentrated sulfuric acid (3 drops). The tube was then sealed and heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was purified by preparative HPLC (C-18 column, 2 to 60% CH3CN in H2O containing 0.01% CF3CO2H over 20 min, 20 mL min−1) to afford product as TFA salt (17 mg, 65%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].C([Li])(C)(C)C.CN([CH:20]=[O:21])C>O1CCCC1.CCOCC>[CH3:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)c(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To 4-bromo-3,5-dimethylanisole (20 g, 93.0 mmol) in 500 mL of tetrahydrofuran at -78° C. was added 120 mL of tert-Butyllithium (1.7M in pentane). The reaction mixture was stirred for 30 minutes at -78° C. and then DMF (136.0 g, 186.0 mmol) was added. The reaction mixture was stirred for 1 hour at -78° C. and for 1.5 hours at room temperature, diluted with 300 mL of ether, washed with 300 mL of water, acidified 1N HCl , and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give the crude product, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to yield 2,6-dimethyl-4-methoxybenzaldehyde (6), (9.50 g, 57.8 mmol, 62%) as a white solid; 1HNMR (CDCl3 δ 2.61 (s, 6H), 3.83 (s, 3H), 6.6 (s, 2H), 10.5 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+:30]([O-:38])[C:29]([C:39](O)=[O:40])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:29]5[N+:30]([O-:38])=[C:31]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)[C:26]([CH3:25])=[CH:27][CH:28]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)[n+]([O-])c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.4 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (98.8 mg, 0.303 mmol) and 5-methyl-6-phenylpyridine-2-carboxylic acid 1-oxide (83.1 mg, 0.363 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (150 mg, 0.394 mmol) and N,N-diisopropylethylamine (104 μL, 0.606 mmol), and the mixture was stirred at room temperature for 3.5 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate) to give a white solid. The obtained solid was washed with ethyl acetate to give the title compound (100 mg, 61%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:25](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (5.0 g; 17.7 mmol) was dissolved in dry tetrahydrofuran. Iodomethane (8.8 mL; 141 mmol) was added and the reaction mixture was cooled to 0° C. Sodium hydride (2.1 g; 53.0 mmol) was slowly added and the reaction mixture was stirred for 12 hours at room temperature. Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise to the reaction mixture. The ethyl acetate was removed in vacuo and the residue was diluted with diethyl ether (30 mL) and water (100 mL). The organic phase was extracted with a saturated aqueous solution of sodium hydrogen carbonate (50 mL). Citric acid (5%) was added to the combined aqueous phases until pH 3, which were then extracted with ethyl acetate (2×50 mL) and the phases were separated. The organic phase was washed with water (2×50 mL), an aqueous solution of sodium thiosulfate (5%; 2×50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was dissolved in diethyl ether (10 mL). Dicyclohexylamine (10 mL) was added. Methylene chloride (30 mL) was added and the mixture was heated until the precipitate was dissolved. Diethyl ether (20 mL) and heptane (20 mL) were added and the reaction mixture was left 12 hours without stirring. The reaction mixture was filtered to afford 5.7 g of (R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionic acid as a dicyclohexylammonium salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:13][C:14]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)(Cl)Cl>[N:1]1([C:18]([O:17][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:19])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Yield: 45.4 %

Procedure:
To 4,4′-bipiperidine (5.48 g, 32.6 mmol) in THF (160 mL) and CHCl3 (160 mL) was added BOC-On (4.01 g) in THF (90 mL) dropwise over a 8 h period. The reaction was then concentrated and purified by flash chromatography. The residue was taken up in 1M KHSO4 (250 mL) and washed with diethyl ether (three times). K2CO3 (38.0 g, 275 mmol) was added to the aqueous layer which was subsequently extracted with CHCl3 (3×), dried (MgSO4) and concentrated to provide the title compound of step A (1.98 g, 7.40 mmol, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.18 (m, 5H), 1.42 (s, 9H), 1.58-1.69 (m, 6H), 2.50-2.61 (m, 4H), 3.06 (d, J=12.1 Hz, 2H), 4.08 (br. s., 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:21][C:4]1[N:3]=[C:2]([NH:31][C@H:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:30])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc(Cl)nc(Cl)c2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(-c2cnn(COCC[Si](C)(C)C)c2)cc(Cl)n1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
100 mg of 2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine obtained by Step 2, 44 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 17 mg of 2-(di-t-butylphosphino)biphenyl, 70 mg of sodium t-butoxide and 6 mg of palladium acetate were added in turn to 3 ml of degassed toluene, and then the mixture was stirred at 85° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:12]=[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[O:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:11]1[CH:12]=[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[O:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Solvent: c1ccncc1
Product: CCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 17 h

Procedure:
A mixture of 4-(1-hydroxynonyl)-2-trimethylsilylfuran (1.65 g, 5.9 mmol), acetic anhydride (2 ml) and pyridine (3 ml) was stirred under argon at approximately 20° for 17 hours. After most of the solvent was removed under high vacuum (less than 40° C.), the residue was dissolved in ether (40 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. Fractions with Rf 0.32 on evaporation afforded 4-(1-acetoxynonyl)-2-trimethylsilylfuran as a pale yellow oil.