Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10](Cl)=[N:9]2)=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+]>C(#N)C.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.[Cu]I>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([C:28]#[N:29])=[N:9]2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)c(Cl)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)c(C#N)n2)cc1
Yield: 68 %

Procedure:
According to Scheme 13 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-3-chloro-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (75 μmol, 30 mg), KCN (75 μmol, 4.9 mg), Pd(PPh3)4 (7.5 μmol, 8.7 mg) and CuI (75 μmol, 14.4 mg) in acetonitrile (2 mL) was microwaved at 180° C. for 50 minutes under nitrogen. After evaporation of the solvent, the crude residue was dissolved in AcOEt. The organic phase was washed with a saturated aqueous solution of Na2CO3, was dried over MgSO4, was filtered and was concentrated to yield 1-(4-methoxybenzyl)-4-(2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-3-carbonitrile (51 μmol, 20 mg, 68%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+].C(OCC)(=O)C>N1C=CC=CC=1.C(Cl)Cl.CN(C)C=O>[N:22]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])=[N+:23]=[N-:24]
Reactant: OCCCCCCCCO
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCO
Temperature: 10 °C

Procedure:
14.65 g of 1,8-octanediol was dissolved in 80 g of pyridine, and cooled to 10° C. A solution of 19 g p-toluenesulfonyl chloride in 70 ml anhydrous methylene chloride was added dropwise thereto, and the mixture was heated gradually overnight for reaction. After water washing, the solvent was removed by distillation, to produce an oily residue. The residue was dissolved in dimethylformamide to a 200 ml solution, to which was added 20 g of sodium azide, and the resultant mixture was maintained at 80° C. for 2 hours for reaction. The mixture was, after added with ethyl acetate, was washed with water 4 times and the solvent was removed by distillation. The object compound was isolated by silica-gel column-chromatography (CHCl3 -AcOEt 5:1-1:1) The yield was 6.07 g.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[CH:6]=1)([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]2([CH3:15])[O:20][CH2:19][CH2:18][O:16]2)=[C:7]([CH3:17])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(OC(C)C)cc1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(OC(C)C)c([N+](=O)[O-])cc1C1(C)OCCO1

Procedure:
A mixture of 1-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-ethanone (0.788 g, 3.32 mmol), ethyleneglycol (1.8 mL), and p-toluenesulfonic acid monohydrate (6.3 mg) in 60 mL of benzene is heated at reflux with a Dean-Stark trap for 18 hrs. The reaction mixture is diluted with 100 mL of ethyl acetate and successively washed with 100 mL each of aqueous saturated NaHCO3, H2O, and saturated brine. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated in vacuo, affording 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl-[1,3]dioxolane as yellow crystals. MS (ES+): 282.2 (MH+).
Reaction SMILES: [CH3:1]N(C)CCNC.[Li]CCCC.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI>C1COCC1.CCCCCC>[CH3:1][C:23]1[CH:24]=[CH:25][CH:26]=[C:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:20]=1[CH:21]=[O:22]
Reactant: O=Cc1ccccc1N1CCCCC1
Reactant: CNCCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCCCC2)c1C=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N([CH2:12][CH3:13])CC)C>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]1(=[O:6])[O:5][CH:2]1[CH2:12][CH3:13]
Reactant: CCN(CC)CC
Agent: C=C(C)C(=O)O
Product: CCC1OC1=O
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml 3N-RB flask fitted with a gas inlet, thermometer, overhead stirrer and a 125 ml pressure equalizing dropping funnel was added 26.5 g triethylamine. The triethylamine was cooled to 5° C. using a water/ice bath. Once the triethylamine was at 5° C. the methacrylic acid was added dropwise over a 20-25 min period. The mixture exothermed˜10C. After the addition was complete the water/ice bath was removed. While the solution was stirring (20 min) the dropping funnel was removed and replaced with a clean 125 ml pressure equalizing dropping funnel. The bromolactone (41.25 g)/THF (62.5 ml) was added dropwise over a 30 min. The mixture warmed from ˜18° C. to 30° C. with a precipitate forming. The reaction was heated to 55° C. and held at 55° C. for 16 hrs using an oil bath/hot plate. After heating for 16 hrs the mixture was cooled to 20° C. using a water/ice bath. The solid (44.5 g) was removed by vacuum filtration. The filtrates were reduced under partial pressure at 33-34° C. The resulting dark amber/brown oil was diluted with 90 g of methylene chloride. This solution was slowly poured onto a plug of silica gel (180 g, Baker 40 μm flash chromatography packing) which had been pre-conditioned with methylene chloride. The crude mixture was allowed to pass into the silica gel plug by gravity. Once the crude mixture had passed the surface of the silica gel plug a fresh portion of methylene chloride was slowly poured onto the plug. The methylene chloride was pulled through the silica gel plug using reduced pressure. Once the methylene chloride had passed the surface of the silica gel plug the vacuum was removed then the next portion of methylene chloride was slowly poured onto the plug. This procedure was followed until all the product was extracted. The total filtrate was 850 ml. [The product was detected by spotting an aliquot on a TLC plate then illuminating with short UV.] To the orange filtrate was added 36 g of activated charcoal. The mixture was stirred for 1.5 hrs then filtered through a Celite plug (pre-conditioned with methylene chloride). The charcoal/Celite was washed with (2×100 ml, 1×50ml methylene chloride). The filtrate was then washed with 2×200 ml D.I. water. The layers were separated and the organic layer was dried over 100 g of sodium sulfate. The mixture was stirred for 15-30 min. The sodium sulfate was removed and washed with 2×50 ml methylene chloride. The pale yellow filtrate (1.2 L) was stripped under reduced pressure at 33-34° C. leaving 36.4 g of a pale orange oil, Yield 85.6%.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[CH3:10][C:11]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])[CH3:12].C(N(CC)CC)C.C(Cl)Cl.CO>O1CCOCC1.O>[C:11]([O:14][C:15]([N:8]1[CH2:7][CH2:6][NH:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:9]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(C)[C@H]1CNCCN1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
341 mg (2.66 mmol) 2-(S)-Isopropyl-piperazine (84) and 657 mg (2.67 mmol, 1.00 eq.) BOC-ON© (2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile) were dissolved in 20 ml 1,4-dioxane and 20 ml water. After adding 2.04 ml (14.64 mmol, 5.50 eq.) triethylamine the solution was stirred at r.t. for 24 h. Then the mixture was added to water and extracted with EtOAc. The comb. org. fractions were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2/MeOH (3+1)) yielded 454.9 mg (1.99 mmol, 74.90%) 3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester (85) as a clear oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](O)=[O:29])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O.C([O-])(O)=O.[Na+]>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][OH:29])=[CH:23][C:22]=3[F:31])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 40 mg of 9-1 (0.09 mmol) and triethylamine (20 μL, 0.13 mmol) in 1 mL of THF at 0° C., was added ethyl chloroformate (12 μL, 0.13 mmol). The mixture was stirred at room temperature for 4 h then added to a stirred suspension of NaBH4 (15 mg, 0.39 mmol) in water (0.5 mL). After 1 h of stirring, the mixture was diluted with aqueous NaHCO3 (4 mL) and extracted with ethyl acetate (2×4 mL). The combined extracts were dried under a stream of nitrogen and the residue was purified by preparative HPLC to afford 48-1: LC-MS 408.1 (MH+-18).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[C:19]([C:21]([NH:23][CH3:24])=O)[CH:20]=2)=[CH:11][CH:10]=1)=[O:8].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:24][NH:23][CH2:21][C:19]1[CH:20]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:7][OH:8])=[CH:14][CH:13]=2)[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=1
Reactant: CNC(=O)c1cc(-c2ccccc2)cc(-c2ccc(C=O)cc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)cc(-c2ccc(CO)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g (26 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran are introduced into a round-bottomed flask under a stream of nitrogen. The medium is cooled to 0° C. and a solution of 1.4 g (4.4 mmol) of 4″-formyl-N-methyl[1,1′;3′,1″]terphenyl-5′-carboxamide in 30 ml of tetrahydrofuran is added dropwise. The reaction medium is refluxed for 48 hours. It is then allowed to cool to room temperature and aqueous sodium sulfate solution is added dropwise. After 30 minutes, the medium is acidified to pH 5 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue is purified by chromatography on a column of silica eluted with a dichloromethane/ethanol mixture (9/1) and 660 mg (49%) of the expected product are obtained in the form of a white solid.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]=[C:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[CH:14][C:13]1=2.B(F)(F)F.C(=O)=O.CC(C)=O>C1COCC1.CO>[OH:11][C:12]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[CH:14][C:13]1=2
Reactant: c1cscn1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: FB(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCC2(O)c1nccs1

Procedure:
A solution of n-butyllithium (2.3 M in hexanes) is pumped (push-pull syringe-pump) to a ⅛″ tee with a pressure gauge and 2 feet of ⅛″ stainless steel tubing (for pre-cooling). This tubing is connected to a ¼ inch T-mixer. Thiazole (0.5 M in THF) is pumped using a pump, 100 μL head (Fluid Metering, Inc., Syosset, N.Y. USA) to 2 feet of ⅛″ stainless steel tubing (for pre-cooling) connected to the same T-mixer. The T-mixer is connected to a static mixer ¼-34 (5.3 mL) (Koflo Corporation, Cary, Ill. USA) connected to a ¼″ elbow and ¼″ stainless steel tubing of 6 inches in length (3.3 mL). This 6-inch length tubing is connected to another ¼″ T-mixer which is also connected to a feed of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate and BF3 (0.5 M in THF, pumped with a FMI pump, 100 μL head), and to a second static mixer Koflo ¼-34 (5.3 mL) followed by a “loop” of ¼″ stainless steel (2.5 ft length, 16.8 mL). The reactor has a total volume of 30.7 mL, and is placed into a cold bath at −45° C. (±5° C., dry ice/acetone). The outlet stream is then connected to a ⅛″ T-mixer (outside of the cold bath) fed with methanol (FMI pump, 100 μL head) for in situ quenching, and is finally collected into an extractor containing MTBE and aqueous phosphoric acid (1.5 M). A flow diagram of the assembly is shown in FIG. 1.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[O:10][C@@H:11]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:13][OH:14])[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:19]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][C@@H:11]([C:15]([F:16])([F:18])[F:17])[CH2:12][CH2:13][OH:14])[N:8]=1)=[O:20])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: O=C(O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 313a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:21][C:15]=3[N:14]=2)[CH:4]=1.Cl[O-].[Na+].S([O-])([O-])(=[O:33])=S.[Na+].[Na+]>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:21][C:15]=3[N:14]=2)=[O:33])[CH:4]=1
Reactant: O=S([O-])([O-])=S
Reactant: COc1cnc(CSc2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1OC
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc(CS(=O)c2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1OC

Procedure:
0.8 g of 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole is dissolved in 15 ml of dioxane and 2.5 ml of 1N sodium hydroxide solution. A mixture of 3 ml of 8% strength sodium hypochlorite solution and 3.5 ml of 1N sodium hydroxide solution are added dropwise in the course of 2 hours, while cooling to 0°-5° C. After addition of 5 ml of 5% strength sodium thiosulfate solution, the mixture is concentrated to dryness, the residue is taken up in water and the mixture is brought to pH 7 with phosphate buffer. The solid which has precipitated out is filtered off with suction, dried and recrystallized from ethyl acetate/diisopropyl ether. 0.45 g (55% of theory) of the title compound is obtained as colorless crystals of m.p. 142°-143° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionic acid tert.-butyl ester (Example K12) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (360 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C([BH3-])#N.[Na+]>C(O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:1][NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])=[CH:4][CH:5]=1)=[O:8]
Reactant: CCOC(=O)CN
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)CNCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To an ethanol solution (50 ml) of methyl 4-formylbenzoate (6.4 g, 40 mmol.) and glycine ethyl ester hydrochloride (5.6 g, 40 mmol.) was added potassium carbonate (5.6 g, 40 mmol.), and the mixture was stirred at room temperature for one hour. To the reaction solution was added sodium cyanoborohydride (2 g, 50 mmol.), and the mixture was stirred for further 18 hours. The reaction solution was subjected to filtration, and the filtrate was concentrated under reduced pressure. To the concentrate was added water (50 ml), and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (developing solvent: IPE:ethyl acetate=1:1) to afford ethyl N-(4-methoxycarbonylbenzyl)aminoacetate (2-g, 5 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([CH3:23])[C:18]([CH:19]=O)=[C:17]([CH3:24])[CH:16]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([CH3:23])[C:18]([CH2:19][NH:1][C:2]2[C:3]3[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[C:17]([CH3:24])[CH:16]=1
Reactant: COc1cc(C)c(C=O)c(C)c1
Reactant: Cc1nc2c(N)cccn2c1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c(CNc2cccn3c(C)c(C)nc23)c(C)c1
Temperature: 2.5 °C
Yield: 60.5 %

Procedure:
8-amino-2,3-dimethylimidazo[1,2-a]pyridine (0.5 g, 3.1 mmol), 4-methoxy-2.6-dimethylbenzaldehyd (0.51 g, 3.11 mmol) were dissolved in methanol (10 ml) whereupon zinc chloride (0.51 g, 3.82 mmol) dissolved in methanol (5 ml) was added. Sodium cyanoborohydride was added in portions and the mixture was refluxed for 3 h under under nitrogen. The mixture was stirred at 0-5° C. and 1 M sodium hydroxide (20 ml) was added. After extraction with 2×50 ml of methylene chloride the combined organic layer was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica (dichloromethane: ethyl acetate, 1:1) yielding 0.58 g 60% of the title compound.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:12][C@@H:13]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:15][C@H:14]1[C:44]1[CH:49]=[C:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][NH:59]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:53][CH:52]=2)[C:47]([CH3:79])=[CH:46][C:45]=1[O:80][CH2:81][C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C([O-])=O>C(O)C>[CH2:5]([O:12][C@@H:13]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:15][C@H:14]1[C:44]1[CH:49]=[C:48]([CH2:50][C:51]2[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][NH2:59])=[CH:55][CH:56]=2)[C:47]([CH3:79])=[CH:46][C:45]=1[O:80][CH2:81][C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCN)cc1
Reaction time: 3 h
Yield: 103.1 %

Procedure:
To a chloroform solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-4-methyl-5-[4-[2-(tritylamino)ethyl]benzyl]phenyl]-D-glucitol (0.402 g, 0.336 mmol) was added at room temperature trifluoroacetate (0.5 mL), and the mixture was stirred for 3 hours at the same temperature. To the reaction solution was added ethanol and then the solvent was evaporated under reduced pressure. Thus obtained residue was purified with NH type silica gel column chromatography (hexane:ethyl acetate=4:6, chloroform:methanol=20:1) to obtain the title compound (0.296 g, quant.) as a colorless oily compound.