Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl.[H][H]>[Pd].CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](/C=C\c2cccnc2)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1cccnc1
Yield: 93.5 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (4.13 g), conc. hydrochloric acid (1.71 ml), 10% palladium on carbon (50% wet) (2.0 g) in methanol (80 ml) was stirred for 4 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (40 ml) and water (40 ml). To the solution was added dropwise a solution of allyl chloroformate (1.52 ml) in tetrahydrofuran (5 ml) with stirring, while keeping the pH to 8~10 with 4N aqueous sodium hydroxide under ice-cooling. The mixture was stirred at the same condition for 1 hour. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (200 ml). The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.40 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].I[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: ICC1CCOCC1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl(4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25-1.45 (3H, m), 1.55-1.65 (2H, m), 1.70-1.80 (1H, m), 2.05-2.15 (1H, m), 3.25-3.35 (2H, m), 3.79 (1H, t), 3.90-3.95 (2H, m), 4.10-4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP-HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH:20](I)([CH3:22])[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: CC(C)I
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 18 mg of 60% sodium hydride was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.05 ml of isopropyl iodide was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 17 mg of the above compound.
Reaction SMILES: C(OC(=O)N[C:8]1[C:13]([I:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])(C)(C)C.N([O-])=O.[Na+].[BrH:21]>C(O)C.O.[Cu]Br>[Br:21][C:8]1[C:13]([I:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: Br
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1I
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1cccc(I)c1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F).
Reaction SMILES: [CH2:1]([CH:4]([C:8]([O:10]CC)=[O:9])[C:5]([NH2:7])=[O:6])[CH2:2][CH3:3].[OH-].[K+]>CC(C)=O.C(O)C>[CH2:1]([CH:4]([C:8]([OH:10])=[O:9])[C:5]([NH2:7])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(C(N)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCC(C(N)=O)C(=O)O
Reaction time: 4 h
Yield: 61.5 %

Procedure:
A solution of 3.8 g of ethyl 2-propylmalonamidate in 30 ml of acetone was treated with 22 ml of 1N KOH in ethanol and stirred for 4 hours, then concentrated, taken up in sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase was acidified to pH 2 at 0° C. with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried, concentrated and the residue was recrystallized from ethyl acetate/ether. There were obtained 1.96 g of 2-propylmalonic acid monoamide, m.p. 137° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>C1COCC1>[CH2:14]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-phenylethanol (9.09 g; 72.9 mmol) dissolved in THF (75 ml) and cooled to 0° C. is added NaH (60%; 3.5 g; 87 mmol) in portions over 10 minutes. The mixture is allowed to warm to room temperature, stirred for 45 minutes and cooled. Allyl bromide (6.3 ml; 73 mmol) is added and the mixture is brought to room temperature and stirred vigorously. The reaction mixture is heated at 45° C. for 3 hours, quenched with MeOH, diluted with Et2O, washed with H2O 3× and brine, dried (MgSO4) and concentrated to dryness. The resultant yellow oil is purified by column chromatography using 10% ether/petroleum ether to give 2-allyloxyethylbenzene as a clear oil which is used directly in Step B.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11].O1CCOCC1>[Pd].C(O)C>[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1CC[C@@H]2CCCC[C@@H]2N1
Yield: 50.3 %

Procedure:
A suspension of 1 g of 3,4,5,6,7,8-hexahydro-2(1H)-quinolinone in 1:1 mixture of dioxane and ethanol was hydrogenated in presence of 250 mg of 10% palladium on carbon at 60 psi and room temperature for 4 hours. The catalyst was filtered on a bed of filter cell and washed with dioxane-ethanol mixture. The filtrate was concentrated to give a residue which was purified on silica gel using ethyl acetate as solvent to give 510 mg of the desired product containing about 10% trans-isomer. Recrystallization from hexane did not improve the isomer ratio.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[C:11]3([O:13][CH2:12]3)[C:10]([CH3:15])([CH3:14])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([CH3:15])([CH3:14])[C:11]2([CH2:12][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[OH:13])=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=Cc2ccc(F)cc2)C12CO2
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C=CC(=Cc2ccc(F)cc2)C1(O)Cn1ccnc1

Procedure:
A mixture of 7-(4-fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene (5.5 g), produced according to the previous example, with imidazole (2 g) and potassium carbonate (6.6 g) is heated in N,N-dimethylformamide (50 cc) for 4 hours. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed, dried and recrystallized to obtain the product indicated, m.p. 172° C., compound no. 32.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]([C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[CH3:23][NH:24][CH3:25]>C(O)C>[CH3:23][N:24]([CH3:25])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]([C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1N(C/C=C/CBr)c1nccnc1Cl
Reactant: CNC
Solvent: CCO
Product: CN(C)C/C=C/CN(c1ccccc1[N+](=O)[O-])c1nccnc1Cl

Procedure:
Similar to Example 1094, 0.34 g of (E)-2-[N-(4-bromo-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazine was treated with 20 ml of a 0.86 M ethanol solution of dimethylamine in 5 ml of ethanol to thereby give 0.17 g of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([C:13]#[N:14])[CH:11]=1
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a 35° C. magnetically stirred solution of 2.40 g (11.8 mmol, 1.00 equivalent) of 2-(p-chlorophenyl)pyrrole-3-carbonitrile, and 65 mL of glacial acetic acid is added dropwise by syringe 0.75 mL (1.26 g, 9.34 mmol., 0.79 equivalent) of sulfuryl chloride over a period of 5 minutes. Approximately 5 minutes after the completion of the addition, a solid precipitated out of the reaction solution. After stirring at room temperature for 45 minutes, the reaction mixture is filtered and the collected solid is washed well with cold acetic acid to give 2.08 g (74% crude yield) of an off-white solid. This solid is recrystallized from 75 mL of hot acetic acid to give 1.63 g (58% yield) of 97 wt % pure. Product mp 258.5°-261° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:27]([NH2:29])[CH3:28])[CH:23]=[C:24]([F:26])[CH:25]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:29][CH:27]([C:22]2[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=2)[CH3:28])=[CH:13][CH:14]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Yield: 94.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 2.0 g of 4-chlorophenyl 3-nitrophenyl ketone, 2.40 g of 1-(3,5-difluorophenyl)ethylamine, 4.26 ml of triethylamine, 1.01 ml of titanium tetrachloride, 3.02 g of sodium cyanoborohydride and 0.66 ml of acetic acid were reacted, to obtain 2.92 g of the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N1CCCC1COCc1ccccc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 13 (4.75 g, 12.16 mmol) in CH2Cl2 (10 mL) is added TFA (10 mL). The solution is stirred for 1 h and then quenched with a saturated solution of NaHCO3 (50 mL). The mixture is extracted with CH2Cl2 (50 mL×2). The combined organic layers are washed with 50 mL portions of sat. NaHCO3, water, and brine. It is then dried over Na2SO4 and concentrated to give pure 14 as a yellow oil (3.07 g, 10.56 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=6.8 Hz, 3H), 0.91 (d, J=6.8, 3H), 1.65-1.79 (m, 2H), 1.79-1.96 (m, 2H), 1.99-2.17 (m, 1H); 3.27-3.45 (m 1H), 3.46-3.54 (m, 1H), 3.59-3.62 (m, 1H), 4.33-4.38 (m, 1H), 4.46-4.54 (m, 2H), 7.27-7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 16.9, 19.8, 24.4, 27.2, 47.2, 56.6, 58.3, 70.1, 73.1, 127.3, 127.4, 128.2, 138.4, 173.8. HRMS calcd for C17H27N2O2 (MH+): 291.2072. Found (DCI): 291.2088 (Δ=−5.3 ppm).
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5](N)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.C(N(CC)CC)C>[CH2:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: Nc1c2c(cc3c1CCC3)CCC2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Yield: 113.8 %

Procedure:
To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (77 grams) in tetrahydrofuran (1.5 L) and triethylamine (68.3 mL) was added triphosgene (43.9 grams) in one portion. The mixture was heated to reflux for ½ hour, then cooled to room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was taken up in pentane and filtered through a plug of silica gel. Removal of the pentane in vacuo afforded 80 grams of a white solid, m.p. 35.0-36.2° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[NH2:12])=[CH:2]1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C(O)CCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:12][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[CH:2]1
Reactant: Brc1ncccn1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Solvent: CCCCO
Product: c1ccc(-c2c[nH]c([C@@H](Cc3c[nH]c4ccccc34)Nc3ncccn3)n2)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine (2 g; 0.0066 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 10 ml n-butanol. 2-bromopyrimidine (1 g; 0.0066 mol) and then diisoethylamine (1.15 ml; 0.0066 mol) were added dropwise. The mixture was then heated to around 80° C. for about 16 hours. The n-butanol was evaporated and the residue taken up in water and ethyl acetate. The organic phase was washed with water and then with a saturated solution of sodium chloride before being dried over magnesium sulfate and concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/7-3, followed by CH2 Cl2—MeOH—NH4OH/95-4.5-0.5 and ethyl acetate). A white powder was obtained (yield of 20%). Free base. Melting point: 138-140° C. MH+=381.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then benzylamine (56.4 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to afford the title compound (210 mg) as a yellow solid. LC-MS (ES) m/z=445 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH:13]=O)[N:5]=[CH:4][CH:3]=1.[C:15]([NH:18][NH2:19])(=[O:17])[CH3:16]>C(O)C>[C:15]([NH:18]/[N:19]=[CH:13]/[C:6]1[N:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:17])[CH3:16]
Reactant: CCOC(=O)c1c(Cl)ccnc1C=O
Reactant: CC(=O)NN
Solvent: CCO
Product: CCOC(=O)c1c(Cl)ccnc1/C=N/NC(C)=O
Yield: 73.6 %

Procedure:
To 2.1 g (9.83 mmol) of ethyl 4-chloro-2-formylnicotinate in 60 mL of ethanol was added 0.874 g (11.80 mmol) of acetohydrazide at room temperature. Then, the reaction mixture was heated under reflux for 2 h. The reaction mixture was extracted with water/DCM. The organic phase was washed with brine, dried, filtrated and concentrated to give 1.95 g (73.6%) of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:57])[C:5](=[N:55]O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C@H:16]1[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[Al]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:57])[CH:5]([NH2:55])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C@H:16]1[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)=NO
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(N)Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
First, 1.73 g (2.25 mmol) of 2-hydroxyimino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (IX) wherein R1 to R4 are benzyl and R6 is ethyl] was dissolved in tetrahydrofuran (225 ml)-water (25 ml). Then, aluminum amalgam prepared from 8.50 g (0.32 mmol) of aluminum was added to the mixture and stirred at 55° C. for about 0.5 hour. Then, the reacted solution was filtrated on Celite which was then washed with 10% ethanol-dichloromethane. The filtrate was then concentrated and the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: 3% methanol-dichloromethane] to give 1.54 g (yield 90%) of 2-amino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (x) wherein R1 to R4 are benzyl and R6 is ethyl].
Reaction SMILES: C([O:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH2:15][CH2:16][O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][CH2:16][CH2:15][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:4])[C:14]=3[O:13][CH2:12][CH2:11]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
8-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine (482 mg) was dissolved in THF (2 ml) and a methanol (10 ml), and anhydrous potassium carbonate (250 mg) was added to the resultant solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was poured into 5% citric acid, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated to obtain the colorless oily object compound (429 mg, yield 99%).