Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[CH2:26]([NH2:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:28][CH2:26][CH3:27])=[O:21])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCN
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCNC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1

Procedure:
(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5-carboxamide was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethylamine using Amidation Method 1 (HATU). 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.29 (app t, 1H), 7.08 (d, 1H), 6.91 (m, 3H), 4.31 (m, 1H), 4.21 (app d, 1H), 3.85 (m, 5H), 3.25 (m, 2H), 2.08 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H), 1.23 (t, 3H), 1.12 (t, 3H). MS (ES+) 371.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1Br)[CH3:2].C([O-])(=O)C.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[C:6]1/[C:16]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=2[O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]/1=2)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccccc1COc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)/C=C1\c2ccccc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Heat a mixture of 3-[2-(2-bromo-5-fluoro-phenoxymethyl)-phenyl]-acrylic acid ethyl ester (94 g, 0.25 mol), sodium acetate (30 g, 0.37 mol), tetra-n-butylammonium bromide (81 g, 0.25 mol), and palladium (II) acetate (1.7 g, 7 mmol, 3 mol %) in N-methylpyrrolidinone (850 mL) at 100-110° C. for 6 h. Cool to room temperature, dilute with water (1 L), filter through diatomaceous earth, and wash with ethyl acetate (2 L). Transfer the filtrate to a separatory funnel, add water (500 mL) and separate the layers. Wash the organic layer with water (2×1.5 L), dry over anhydrous sodium sulfate, filter through a silica pad, wash with ethyl acetate (1.5 L) and concentrate to dryness. To the residual solid add hexanes (1 L), refrigerate for 2 h, filter, rinse with hexanes (500 mL), and dry at 50° C./20 mm Hg to obtain the title compound (64.3 g, 87%). LC-MS m/z 299.0 [M+H]+.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:17](Br)[CH2:18][CH:19]([CH3:21])[CH3:20]>O1CCCC1>[CH3:20][CH:19]([CH2:18][CH2:17][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:21]
Reactant: CCCCCCCCCC/C=C\CCCl
Reactant: CC(C)CCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC/C=C\CCCCC(C)C
Temperature: 0 °C
Yield: 37.5 %

Procedure:
In a 1-liter reactor, a Grignard reagent was prepared from 5.0 g (0.206 mole) of magnesium and 46 g (0.2 mole) of 1-chloro-cis-3-tetradecene in exactly the same manner as in Example 4. Next, 30 g of tetrahydrofuran, 30 g (0.2 mole) of isoamyl bromide and 0.6 g of cuprous iodide were placed in another 1-liter reactor and cooled to 0° C. Then, the above-described Grignard reagent was added dropwise thereto so that the temperature did not exceed 20° C. After completion of the reaction, the reaction product was distilled in exactly the same manner as in Example 4 to obtain 20 g of 2-methyl-cis-7-octadecene (purity 96.0%, yield 77%, b.p. 155°-158° C./2 mmHg). MS(m/e): 56(100%), 266 (M+, 27%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N:18]#[C:19][NH2:20].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:19](=[NH:18])([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:14][CH:13]=1)[NH2:20]
Reactant: N#CN
Reactant: Cc1cccc(Oc2ccc(CCO)cc2)n1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Temperature: 55 °C
Yield: 49.1 %

Procedure:
To a solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethanol (1.7 g, 7.41 mmol) and cyanamide (0.405 g, 9.64 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (0.856 mL, 9.64 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (1.4 g, 3.64 mmol, 49.1% yield) as a colorless oil. LCMS: rt=1.87 min, [M+H]=272
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.CCOCC.C(N(CC)CC)C>C1COCC1>[NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[O:7][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@H](CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of 29.1 g (1.0 eq) H-D-Glu-OH in 205.6 mL (10.0 eq) benzyl alcohol which was stirred at r.t, 47.7 mL (2.0 eq) boron trifluoride etherate solution was added slowly, and 10 min later, all of the substrate was dissolved. The reaction was completed in 15 h, 616.8 mL (3 times of the volume of benzyl alcohol) THF was added, stirred and 55.1 mL (2.0 eq) triethylamine was added slowly. A large number of white viscous precipitate precipitated. The THF was removed under reduced pressure; the residue was cooled, after adding the proper amount of the AcOEt, the viscous precipitate turned to powder. 36.6 g target compound was obtained with yield of 78% after filtration and drying. m.p.=174˜176° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (95.5 ml) is dissolved in dichloromethane (500 ml), and thereto is added dropwise a suspension of 2-amino-5-chloropyridine (128.6 g) and triethylamine (169 ml) in dichloromethane (1000 ml) under ice-cooling. The reaction solution is warmed to room temperature and stirred for 0.5 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured ice-water, followed by extraction with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and treated with activated charcoal. After filtration to remove insoluble materials, the filtrate is concentrated under reduced pressure and the resulting residue is suspended in diisopropyl ether. The precipitates are collected by filtration, washed with diisopropyl ether and dried to give the title compound (153.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=[O:16])#[N:2]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane is refluxed for 40 hours with I g of 2-hydroxypyridine in 10 ml of dioxane, in the presence of 0.20 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The mixture is taken up with 30 ml of water and the precipitate obtained is-filtered off, washed with isopropyl ether and then recrystallized from 20 ml of absolute ethyl alcohol to give 0.9 g of the expected product.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]2[C:17]=1[N:16]=C(C(O)=O)[CH:14]=[CH:13]2>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:1]([C:2]([Cl:4])=[O:3])[CH:14]=[CH:13]2
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc2cncc(Br)c2n1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.5 equiv.) is added drop wise to a slurry of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv., in 20 mL DMF) at 0° C. (ice bath) and stirred for 30 minutes. The reaction mixture is removed from the ice bath, stirred at room temperature for 3 h and then concentrated in vacuo to give a greenish colored solid, which is used immediately without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].O.NN>C1COCC1.CO>[NH2:23][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(c1ccc(F)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(N)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.2 %

Procedure:
To a solution of 303 (0.0507 g, 0.1072 mmol) and THF/MeOH (1:1) was added hydrazine monohydrate (0.080 mL, 1.072 mmol) and the reaction stirred at RT 3 d. A thick white precipitate formed which was filtered through CELITE. The solution was concentrated and purified by SiO2 chromatography to afford 0.0214 g (58%) of (2R)-tert-butyl 2-(2-amino-2-(3-chloro-4-fluorophenyl)ethyl)pyrrolidine-1-carboxylate (305) as a clear oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH:6]=[CH2:7])(=[O:4])=[O:3].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1.CC([O-])=O.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:7]=[CH:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:14]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=CCS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)CC=Cc1cncc(Br)c1
Yield: 36.2 %

Procedure:
3-Methanesulfonyl-propene (2.4 g, 20 mmol), 3,5-dibromo-pyridine (4.7 g, 20 mmol), NaOAc (1.9 g, 60 mmol), PPh3 (1.6 g, 6.0 mmol) and Pd(OAc)2 (450 mg, 2.0 mmol) are mixed in 1,4-dioxane (350 ml) and heated to reflux for 16 hrs. The reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in DCM and washed with water. The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by flash column chromatography to give 2.0 g of 3-bromo-5-(-3-methanesulfonyl-propenyl)-pyridine with some PPh3O.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:24]([O-])=O)=[C:19]([CH2:20][C:21](O)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO.[OH-].[Na+]>CC1CCCO1.O.C(O)C.[Pt]>[CH2:1]([NH:8][CH2:9][C@@H:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:24][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Agent: [Pt]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC1CCCO1
Solvent: CO
Product: O=C1Cc2c(ccc3c2O[C@@H](CNCc2ccccc2)CO3)N1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A 50 mL two necked flask equipped with a magnetic stir bar, gas inlet adapter and gas outlet adapter is charged with {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid.HCl (1.00 g, 2.53 mmol), methanol (20 mL), 1 N hydrochloric acid (2.53 mL, 2.53 mmol) and platinum (5% on carbon, 62% w/w water, 0.20 g). The flask head space is flushed with hydrogen gas (200 mL), the gas outlet adapter is closed and the slurry is stirred under a hydrogen atmosphere. After ˜1 h, no solid {(3S)-3-[benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid.HCl is visible. The mixture is stirred for an additional 1 h under hydrogen, at which point the reaction is complete by LCMS. The catalyst is removed by vacuum filtration, and the resulting solution is heated to 45° C. (external) in an oil bath for 8 h. The volatiles are removed by rotary evaporation to give a pink solid. The solids are suspended in 2-methyl tetrahydrofuran (18 mL) and water (3 mL). 1 N NaOH is added until the solids dissolved and the pH of the aqueous phase is 10 (pH paper), about 6 mL is required. The aqueous layer is removed, and the organic phase is washed with water (4 mL) and half saturated brine (3 mL). The volatiles are removed by rotary evaporation to give a brown syrup. The syrup is dissolved in absolute ethanol (3 mL) and evaporated to dryness. Absolute ethanol (3 mL) is added to the residue and removed by rotary evaporation to give crude (2S)-2-[(benzylamino)methyl]-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-8-one as a brown syrup.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[C:16]([C:12]1[CH:13]=[CH:14][C:15]([C:5](=[O:7])[CH3:6])=[C:10]([Br:9])[CH:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
Aluminum chloride (8.0 g, 60 mmol) was stirred in CH2Cl2 (200 mL), and acetyl chloride (8.5 mL, 120 mmol) was slowly added, producing a homogeneous solution. A solution of 3-bromo tert-butyl benzene (11 g, 50 mmol) in CH2Cl2 (20 mL) was slowly added, and the reaction was stirred at room temperature 16 h. After being diluted with CH2Cl2, the reaction was washed with water, saturated aqueous NaHCO3, and water. The organic solution was dried over Na2SO4 and concentrated under vacuum. Purification by silica gel chromatography (0%-50% CH2Cl2-hexanes) afforded 1-(4-tert-butyl-2-bromophenyl)ethanone (3.1 g, 24% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=1.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (dd, J=8.1, 1.8 Hz, 1H), 2.63 (s, 3H), 1.32 (s, 9H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:26].[Na+]>CN(C)C(=O)C>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]([NH2:22])=[O:26])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: N#Cc1cccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
463 (48 mg, 0.15 mmol) and NaOH (1M, aqueous, 0.73 mL) were suspended in N,N-dimethylacetamide (2 mL), and stirred for 16 h at 100° C. The reaction mixture was purified directly via prep-LC-MS to provide 473 (24 mg, 47% yield) as a white powder. LC-MS (M+H=345, obsd.=345). 1H NMR (400 MHz, DMSO-D6) δ 8.55 (d, J=7.8, 1H), 8.50 (d, J=4.3, 1H), 8.06 (d, J=8.5, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=7.5, 1H), 7.43 (s, 1H), 7.35 (dd, J=7.2, 14.4, 2H), 6.91 (d, J=8.8, 1H), 5.70 (s, 2H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])[CH:16]([CH3:18])[CH3:17]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)CO
Product: CC(C)COc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as example 160c from 2,6-dinitrobenzonitrile and isobutanol to provide 2-isobutoxy-6-nitrobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6.4 Hz, 6H), 2.11 (sept, J=6.6 Hz, 1H), 4.07 (d, J=6.5 Hz, 2H), 7.75 (dd, J=8.0, 1.9 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.94 (dd, J=8.2, 1.9 Hz, 1H).
Reaction SMILES: O.NN.[Br:4][C:5]1[C:6]([C:24]#[N:25])=[N:7][N:8]([CH3:23])[C:9]=1[CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C>[NH2:12][CH2:11][CH2:10][C:9]1[N:8]([CH3:23])[N:7]=[C:6]([C:24]#[N:25])[C:5]=1[Br:4]
Reactant: Cn1nc(C#N)c(Br)c1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(C#N)c(Br)c1CCN
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of hydrazine hydrate (6.40 g, 127 mmol) and 4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile (9.15 g, 25.5 mmol) in ethanol (200 mL) was heated at reflux for 80 minutes, then was allowed to cool to ambient temperature in a water bath. A precipitate formed and was isolated by filtration and washed with cold ethanol. The filtrate was concentrated under reduced pressure, and the resulting white solid was twice treated with toluene and concentrated under reduced pressure then dried under vacuum to provide 5.74 g of 5-(2-aminoethyl)-4-bromo-1-methyl-1H-pyrazole-3-carbonitrile as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N:9]1[NH:10][N:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(-n2ccnn2)nc1
Reaction time: 24 h

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone was dissolved 1.72 g of 2,5-dibromopyridine, followed by the addition of 500 mg of 2H-(1,2,3)-triazole and 3 g of potassium carbonate at room temperature. Reaction was conducted at 100° C. for 24 hours. After completion of the reaction, the same post-treatment as in Preparation Example 3 was carried out to obtain the title compound. 120 mg.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH:25]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH2:25][NH:6][CH3:5]
Reactant: Cn1cc(C=O)c2cccc(Cl)c21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(Cl)cccc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[N:23]([CH2:26][C:27](O)=[O:28])=[N+:24]=[N-:25].C([O-])(O)=O.[Na+].C(Cl)CCl>CN(C=O)C>[N:23]([CH2:26][C:27](=[O:28])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propylcarbamate (amine, 160 mg, 0.5 mmol), 2-azidoacetic acid (56 mg, 0.55 mmol, in 50% DCM solution), NaHCO3 (168 mg, 2 mmol), and 1 mL DMF was added EDC (115 mg, 0.6 mmol). The mixture was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by silica chromatography (gradient 5% to 90% EtOAc in hexane) to afford compound 141 as a clear oil (130 mg, 65%). MS (ESI) m/z 426 (M+Na+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>CN(C=O)C>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:36][C:35]1=[O:40]
Reactant: O=C1CNCCN1Cc1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1Cc1ccc2ccccc2c1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 1 except that DMF was used in place of methylene chloride as the reaction solvent, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetate salt to give 1-(2-naphthylmethyl)-2-oxo-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine in 18% yield;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+].CO>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:16][CH3:15])=[N:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: Fc1ccc(-c2nccnc2Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccnc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Next, 3.87 g of 2-chloro-3-(4-fluorophenyl)pyrazine, 2.01 g of sodium methoxide, and 30 mL of methanol were put in a three-neck flask equipped with a reflux pipe, and reacted by being heated and refluxed under a nitrogen atmosphere for three hours. After the reaction, the reaction solution was cooled down to room temperature, water was added thereto, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated saline and water, and dried with magnesium sulfate. Then, magnesium sulfate was removed by filtration and the solvent was distilled off, so that 2-(4-fluorophenyl)-3-methoxypyrazine was obtained (milky white powder, yield: 96%). A synthetic scheme of Step 2 is shown in the following (a1-2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:20][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[C:6]([CH3:9])[N:7]=[CH:8][C:3]=1[CH2:2][O:1][C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1
Reactant: Cc1ncc(CO)c(C)c1OCc1ccc(C#N)cc1
Reactant: N#Cc1ccc(O)cc1
Product: Cc1ncc(COc2ccc(C#N)cc2)c(C)c1OCc1ccc(C#N)cc1
Yield: 39.1 %

Procedure:
The coupling of 4-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (22) (800 mg, 3.0 mmol) and 4-cyanophenol (715 mg, 6.0 mmol), as described in Example 9, gave 4-[4,6-dimethyl-5-(4-cyano-benzyloxy)-pyridin-3-ylmethoxy]-benzonitrile (67) (433 mg, 39% yield).