Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH2:41][CH3:42])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCBr
Agent: Cl
Product: CCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 1-bromobutane (0.322 mL) as starting materials, 5-benzyloxy-N-[(1-butylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.41 g) was obtained. MS (ESI) m/z: 447 [MH]+
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:3]1.[N+:23](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:24].CC(C)([O-])C.[K+].O>COCCOC>[C:24]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:3]1)#[N:23]
Reactant: COC(=O)N1CCC(=O)CC1Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)N1CCC(C#N)CC1Cc1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of methyl 4-oxo-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (8.75 g, 27.75 mmol) (Syngene) in DME (100 mL) under nitrogen was added simultaneously 1-(isocyanomethylsulfonyl)-4-methylbenzene (8.13 g, 41.63 mmol) in 100 mL DME and potassium tert-butoxide (83 mL, 83.26 mmol) (1 M) over 30 min at −20 to −10° C. The solution was stirred at −20° C. for 2 h and then allowed to warm to room temperature overnight. To the orange reaction mixture was added water (200 mL), the solution was stirred for 20 min and then extracted with diethyl ether (3×) and EtOAc (3×). The combined organic phases were washed once with brine and then dried over Na2SO4 and evaporated to yield a brown oil. The oil was purified by flash chromatography on silica gel using a gradient of 20-60% EtOAc in heptane as eluent. Methyl 4-cyano-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (7.96 g, 87.9%) was isolated as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=1>>[C:26]1([C:23]2[CH:22]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[O:25][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1cc(-c2ccccc2)no1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccccc2)no1

Procedure:
Synthesized in a manner similar to Example 23 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: MS (ES) m/z 410 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Br:26][C:24]1[CH:23]=[CH:22][C:18]([CH2:19][OH:20])=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12][CH2:13]2)[CH:25]=1
Reactant: O=C(O)c1ccc(Br)cc1N1CCN(C(=O)OCc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN(c2cc(Br)ccc2CO)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-((benzyloxy) carbonyl)piperazin-1-yl)-4-bromobenzoic acid (2 g, 9.1 mmol) in THF (20 mL) was added dropwise BH3/THF (1.0 M, 40 mL) at 0° C. The mixture was refluxed for 2 h, then cooled to RT, quenched with H2O, and extracted with ethyl acetate, 3 N HCl, brine, then dried over Na2SO4, filtered and concentrated. Purification by normal phase silica gel (ethyl acetate/hexanes) provided benzyl 4-(5-bromo-2-(hydroxymethyl)phenyl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([CH:14]([CH:20]([CH2:26][CH2:27][CH3:28])[C:21](OCC)=[O:22])[C:15]([O:17]CC)=[O:16])(=O)[CH2:11][CH3:12].C[O-].[Na+]>CO>[CH2:27]([C:26]1[N:9]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[NH:8][C:21](=[O:22])[C:20]=1[CH:14]([CH2:10][CH2:11][CH3:12])[C:15]([OH:17])=[O:16])[CH3:28]
Reactant: CCCC(C(=O)OCC)C(C(=O)CC)C(=O)OCC
Reactant: N=C(N)N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(CC)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (1 g; 7.86 mmol) and diethyl 2-propionyl-3-propylsuccinate (2.14 g; 7.86 mmol) in methanol (8 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (3.60 mL; 15.72 mmol) and the reaction was heated under reflux for 18 h. The mixture was concentrated under reduced pressure and the curde residue was used as such in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(F)c(F)c3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 3,4-difluorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(3,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].O.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2nccn2C)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 88.7 %

Procedure:
2-(4-Bromo-3-methylphenyl)-1-methylimidazole (D89, 600 mg, 2.39 mmol) was dissolved in dimethoxyethane (15 ml) and H2O (15 ml) and treated with 4-boronobenzoic acid (397 mg, 2.39 mmol), sodium carbonate (1.01 g, 9.56 mmol), tetrakis (triphenylphosphine)palladium (O) (60 mg) and heated at reflux for 36 hours. The dimethoxyethane was removed in vacuo, the aqueous residue treated with 10% Na2CO3 (approx. 10 ml) and washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that formed collected by filtration and dried in vacuo to yield the title compound as an off-white solid (620 mg, 89%).
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.[CH:14]1([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:16][CH2:15]1.[H-].[Na+]>CS(C)=O.C(OCC)C>[CH:14]1([C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][NH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)C=CC1CCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1C1CCC1
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
Toluenesulfonylmethyl isocyanide (3.04 g, 15.59 mmol) was added to the stirred solution of ethyl 3-cyclobutylprop-2-enoate (2.00 g, 12.99 mmol) in a mixture of dimethylsulfoxide (2 mL) and diethyl ether (30 mL) and stirred for 45 min. The resulting mixture was added to a slurry of sodium hydride (675 mg, 38.14 mmol, 60% in mineral oil) in diethyl ether (10 mL) over a period of 30 min then stirred for a further 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, the organics were separated and the aqueous layer was extracted with diethyl ether (4×10 mL). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was subjected to column chromatography over silica gel (100-200 mesh) using 0% to 15% of ethyl acetate in pet-ether as eluent, concentrated and dried under reduced pressure to afford ethyl 4-cyclobutyl-1H-pyrrole-3-carboxylate (1.70 g, 67%) as a liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=O)=[N:9][N:8]=2)[CH:2]=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH3:14])=[N:9][N:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccccc1-c1nnc(-c2cccnc2)o1
Solvent: CCO
Product: Cc1ccccc1-c1nnc(-c2cccnc2)o1

Procedure:
2-[5-(3-Pyridyl)-1,3,4-oxadiazole-2-yl] benzoic acid, M.P. 213°-5° (ethanol) wt., 5g (36%). (Found: C, 62.83, 62.71; H, 3.64, 3.47; N, 16.17, 16.05. C14H9N3O3 requires, C, 62.92; H, 3.39; N, 15.73.)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]CC2C=CC=CC=2)[N:8]=1)=[O:5]>C(OCC)(=O)C.[Pd].CCOCC>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccccc2OCc2ccccc2)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(Nc1ccn(Cc2ccccc2O)n1)c1c(F)cccc1F

Procedure:
A solution of 2,6-difluoro-N-[1-({2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide (for a preparation see Example 59)(2.34 g, 5.58 mmol) in ethyl acetate (20 ml) was stirred overnight with 10% palladium on carbon (wet) (0.594 g, 0.279 mmol) under an atmosphere of hydrogen. The reaction mixture was filtered and the filtrate evaporated in vacuo to give a colourless oil. The oil was dissolved in ether and the solution evaporated in vacuo to give the title compound as a white foam (1.82 g); LCMS: (System 3) MH+=330, tRET=0.92 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCCC3)c2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCCC2)n1
Yield: 99.5 %

Procedure:
A solution of 160 mg (0.258 mmol) 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 200 μL MeOH and 3 mL TFA at RT for 3.5 h. Solvents were evaporated in vacuo. The residue was taken up in CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 100 mg (100%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C23H27N5O, 390.2 (M+H), found 390.3.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[C:20]([F:23])(F)[F:21].C1COCC1>C(Cl)Cl>[F:21][C:20]1([F:23])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), Nat (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL). The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:13][OH:14].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[N:13][OH:14]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(C=NO)c1
Yield: 82.3 %

Procedure:
To 16.6 g (99.9 mmol) of 2,5-dimethoxybenzaldehyde in ethanol (100 mL) is added a mixture of 7.64 g (169 mmol) of H2NOH—HCl and 13.9 g (169 mmol) of sodium acetate in 50 mL of H2O. This reaction mixture is heated to reflux for 2.5 h. After adding H2O to dissolve the precipitated inorganic salt, ethanol is removed by evaporation in vacuo. The resulting white solid is filtered off and washed with H2O. 14.9 g of white solid are obtained (82%). 1H-NMR (CDCl3). δ [ppm]: 3.79 (s, 3H), 3.82 (s, 3H), 6.85 (d, 1H), 6.92 (d, 1H), 7.25 (d, 1H), 8.00 (broad s, 1H), 8.47 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(O)C.[Pd]>[NH2:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1

Procedure:
A solution of 3-tertiary-butoxycarbonyl-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (2.1 g) was stirred under a hydrogen atmosphere (50 p.s.i. equivalent to 344.7 kPa) in ethanol (20 ml) and methanol (20 ml) solution containing 5% Pd/C (0.21 g) for 3 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound as an oil, yield 2.0 g.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8](Cl)(Cl)=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[N:21]=[CH:22][N:23]([C:25]([N:27]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH3:28])=[O:26])[CH:24]=2)[CH:16]=[CH:17][C:18]=1[OH:19].O>ClCCl.ClCCl.C(O)(C)C>[CH:29]1([N:27]([CH3:28])[C:25]([N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]4[O:19][C:8](=[O:9])[NH:12][C:13]=4[CH:14]=3)[N:21]=[CH:22]2)=[O:26])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(Cl)Cl
Reactant: CN(C(=O)n1cnc(-c2ccc(O)c(N)c2)c1)C1CCCC1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CN(C(=O)n1cnc(-c2ccc3oc(=O)[nH]c3c2)c1)C1CCCC1
Reaction time: 5 h
Yield: 32 %

Procedure:
A 20% toluene solution of phosgene (0.590 mL, 1.121 mmol) was added dropwise at room temperature to a stirred solution of 4-(3-amino-4-hydroxyphenyl)-N-cyclopentyl-N-methyl-1H-imidazole-1-carboxamide (0.259 g, 0.862 mmol) in dichloromethane (5 mL) and the off-white suspension was allowed to stir for 5 h. Water was added and the organic layer was diluted with a mixture of dichloromethane/isopropanol (7:3). The organic layer was separated, dried (MgSO4), filtered and evaporated to give an off-white solid that was triturated with hot methanol. Filtration and drying gave the product as an off-white solid (90 mg, 30%).
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:9]([CH3:19])[N:8]=1>[Pd].[Pt](=O)=O.C(O)(=O)C>[NH2:14][CH2:13][C:12]1[C:7](=[O:6])[NH:8][C:9]([CH3:19])=[CH:10][C:11]=1[C:15]([F:16])([F:17])[F:18]
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(O)n1
Agent: O=[Pt]=O
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Yield: 46.6 %

Procedure:
To a dried 500 mL Parr bottle equipped with nitrogen inlet were added sodium acetate (1.502 g, 18.30 mmol), 10% palladium on carbon (1.579 g, 0.742 mmol), platinum(IV) oxide (0.011 g, 0.049 mmol) and a small amount of acetic acid to wet the catalysts, under nitrogen stream. Next was added 2-hydroxy-6-methyl-4-(trifluoromethyl)-3-pyridinecarbonitrile (2.0 g, 9.89 mmol) followed by acetic acid (175 mL) while under nitrogen atmosphere. The contents were sealed, placed on a Parr shaker, and reacted at 40 psi of H2 for ca. 6 hr, keeping the H2 psi between 20 and 40 psi (vessel was refilled twice). The vessel was purged with nitrogen and the reaction mixture filtered through Celite, and the filter pad was further washed with a small amount of acetic acid. The volatiles were removed in vacuo to afford a residue, which was dried under high vacuum for 45 min. The solid was suspended in conc. HCl (12 mL), stirred, and filtered. The clear filtrate was concentrated in vacuo and the residue dried under high vacuum. The collected solid was suspended in conc. HCl (2 mL) and diluted with EtOH (13 mL). The contents were agitated and stored at ca. 0° C. (freezer) for 30 min to give a white solid. The solid was filtered and washed with cold ethanol (5 mL). The solid was filtered and dried in vacuum oven for 1 h to give 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone (0.95 g, 40%). LCMS E-S(M+H)=206.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.40-3.62 (m, 2H), 3.87 (d, J=5.05 Hz, 2H), 8.12-8.37 (m, 3H).
Reaction SMILES: OC([C@@]1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)[O:5][C@H:6]1[C@@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[O:21][C@@H:8]([O:9][C@H:10]2[C@@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][CH:12]([OH:13])[C@@H:11]2[NH2:20])[C@@H:7]1[OH:27])=O.CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+]>>[O:9]([C@H:10]1[C@@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][CH:12]([OH:13])[C@@H:11]1[NH2:20])[C@@H:8]1[O:21][C@H:22]([CH2:25][OH:26])[C@H:23]([OH:24])[C@H:6]([OH:5])[C@H:7]1[OH:27]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]3[C@@H](O)[C@@H](CO)OC(O)[C@@H]3N)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: [Na+]
Product: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Synthesis of NeuAcα2-3Galβ1-3GalNH2 βSEt. Galβ1-3GalNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a α2-3-sialyltransferase (e.g. EC 2.4.99.4) reaction with a suitable glycosyl donor such as CMP-NeuAc.
Reaction SMILES: CS[C:3]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:14][NH2:15]>CCO>[N+:5]([CH:4]=[C:3]([NH:14][NH2:15])[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:7])=[O:6]
Reactant: NN
Reactant: CSC(=C[N+](=O)[O-])N1CCCCC1
Solvent: CCO
Product: NNC(=C[N+](=O)[O-])N1CCCCC1

Procedure:
1-(1-Methylsulfanyl-2-nitro-vinyl)-piperidine (WO 2000016766, 202 mg, 1.00 mmol) was reacted with hydrazine (30 μL, 1.0 mmol) in EtOH to afford (2-nitro-1-piperidin-1-yl-vinyl)-hydrazine and which was converted to 4-nitro-3-piperidin-1-yl-pyridazine following procedures analogous to literature methods (Tett. Lett. 41, 3619, (1977)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCC>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.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH:3]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:23])([F:24])[F:25])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Reactant: OB(O)c1ccc(F)nc1
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: [Na+]
Solvent: CCO
Solvent: CCCC
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(-c3ccc(F)nc3)c2)c(F)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (35.0 mg, 0.08 mmol) prepared in Step 2 of Preparation 5, 2-fluoro-5-pyridineboronic acid (16.3 mg, 0.11 mmol), Pd(PPh3)4 (8.9 mg, cat.) and a 2N sodium carbonate solution (385.0 uL) were added to a mixed solvent of ethanol (400.0 uL) and 1,2-dimethylethane (1.5 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:31])[C:10]=1[C:11](=[O:30])[NH:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[N:21]=[C:15]2[CH:14]=1)=[O:5])C.CO.O.[Li+].[OH-]>C1COCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:15]3[CH:14]=[C:13]([NH:12][C:11]([C:10]4[N:9]([CH3:31])[N:8]=[CH:7][C:6]=4[C:4]([OH:5])=[O:3])=[O:30])[CH:18]=[CH:17][N:16]3[N:19]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(OC)c3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.5 g, 8.33 mmol) in a mixture of THF (20 ml), MeOH (14 ml) and water (7 ml) was added LiOH×H2O (1.0 g, 25.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 4 h. Solvents were removed in vacuum and the resultant crude material was diluted with water (150 ml). The aqueous layer was washed with ether (2×100 ml), cooled to 0° C., and slowly acidified (pH 5) with aqueous 1N HCl solution under stirring. The resultant precipitated solid was filtered and dried under vacuum to give 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid as white solid (5.9 g; crude, quant). LC-MS: m/z=393.0 [M+H]+.