Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH:17]([CH2:27][CH3:28])[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[Na+]>C(O)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH:17]([CH2:27][CH3:28])[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=NOC(CC)CNC(=O)OC(C)(C)C)c1csc(NC=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CNC(=O)OC(C)(C)C)ON=C(C(=O)O)c1csc(NC=O)n1
Reaction time: 2 h

Procedure:
1.65 g of ethyl 2-(2-formamidothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer) is dissolved in 30 ml of dimethylformamide. To this solution, 165 mg of sodium hydride is added, and this is followed by 10 minutes of agitation at room temperature. 2.5 g of the product obtained in (1) is then added, and this is followed by 15 hours of agitation at the same temperature. 200 ml of ethyl acetate is added, and this mixture is washed with 200 ml of a sodium chloride solution and dried with anhydrous Glauber's salt. The dried solution is concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate, whereafter the desired fraciton is concentrated to give 1.3 g of ethyl 2-(2-formamidothiazol-4-yl)-2-(2-t-butoxycarbonylamino-1-ethylethoxyimino)acetate) (syn isomer). This ester is dissolved in 13 ml of ethanol. To this solution, 3.1 ml of an aqueous solution of 2N sodium hydroxide is added, and this is followed by 2 hours of agitation at room temperature. This mixture is concentrated under reduced pressure. To this concentrate, 200 ml of ethyl acetate is added, and this mixture is washed with 100 ml of 10% citric acid and 100 ml of a sodium chloride solution, and dried with anhydrous Glauber's salt. The dried solution is concentrated under reduced pressure to give 1.1 g of 2-(2-formamidothiazol-4-yl)-2-(2-t-butoxycarbonylamino-1-ethylethoxyimino)acetic acid (syn isomer).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)(=[O:31])=[O:30])[CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 2, methyl 2-(1-benzylpiperazin-3-yl)acetate (J. Chem. Soc. Perkin I, 1992, 1035) was reacted with 2-naphthylsulphonyl chloride to give methyl 2-[4-benzyl-1-(2-naphthylsulphonyl)piperazin-2-yl]acetate in 90% yield.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[N:6][N:5]=2)[CH2:3][CH2:2]1.[O:9]=[S:10]1(=[O:36])[CH2:15][CH:14]=[C:13]([C:16]2[C:21]([F:22])=[CH:20][C:19]([N:23]3[CH2:27][C@H:26]([CH2:28]OS(C)(=O)=O)[O:25][C:24]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:12][CH2:11]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[O:36]=[S:10]1(=[O:9])[CH2:11][CH:12]=[C:13]([C:16]2[C:21]([F:22])=[CH:20][C:19]([N:23]3[CH2:27][CH:26]([CH2:28][N:6]4[N:7]=[N:8][C:4]([CH:1]5[CH2:3][CH2:2]5)=[N:5]4)[O:25][C:24]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: C1CC1c1nnn[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Product: O=C1OC(Cn2nnc(C3CC3)n2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Yield: 73.8 %

Procedure:
Cyclopropylcarbonitrile (2 ml, 27 mmol) was added to a solution of trimethylsilylazide (4.3 ml, 32.5 mmol) and trimethylaluminum (16 ml of a 2M toluene solution, 32 mmol) at 0° C. The cold bath was removed, the mixture was stirred at room temperature for 15 minutes, then warmed to 80° C. for 16 hours. The solution was carefully added to a slurry of ice and 1N HCl, followed by acidification with concentrated HCl and extraction twice with ethyl acetate. The combined organic phases were washed with saturated NaCl, dried over sodium sulfate, and evaporated to yield a solid residue. Trituration with 1:1 hexane:ethyl acetate gave 5-cyclopropyl-1H-tetrazole (CAS# 27943–07–3) as a white crystalline solid (1.5 g, 51%). 5-cyclopropyl-1H-tetrazole (0.183 g, 1.66 mmol), (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol), polystyrene-triphenylphosphine (1.73 mmol/g loading: Argonaut Technologies, Inc. Foster City, Calif. USA, 1.46 g, 2.53 mmol) and diisopropylazodicarboxylate (0.33 ml, 1.68 mmol) were reacted as described for Example 58. Purification was carried out by chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane solution with ether to yield the title compound as a white powder (0.28 g, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:13]([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[N:24]=4)[CH:3]=3)[N:8]=2)[CH2:14]1
Reactant: Brc1ccc2nc(NC3COc4ccccc43)ccc2c1
Reactant: Nc1cccc(C(F)(F)F)n1
Product: FC(F)(F)c1cccc(Nc2ccc3nc(NC4COc5ccccc54)ccc3c2)n1

Procedure:
The title compound, light yellow foam, MS: m/e=423.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(2,3-dihydro-benzofuran-3-yl)-amine (see example 96, step A) and commercially available 2-amino-6-trifluoromethyl-pyridine.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:30])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(F)cc2Cl)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [3-(2-chloro-4-fluorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.45 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue diluted with water. The pH of mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and the resulting precipitate collected by filtration and dried to afford title compound as a white solid, 0.18 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([Br:17])[CH:10]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:18][NH:19][C:20]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([Br:17])[CH:10]=1)=[O:21]
Reactant: CN=C=O
Reactant: NCc1ccccc1-c1ccc(CO)c(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)NCc1ccccc1-c1ccc(CO)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 68 mg (0.23 mmol) of 2'-aminomethyl-3-bromo-1,1'-biphenyl-4-methanol (Step H) in 3 mL of dry methylene chloride and 1 mL of dry dimethylformamide under nitrogen atmosphere at 0° C. was added 0.015 mL (0.25 mmol) of methyl isocyanate. The reaction mixture was stirred for 30 minutes at 0° C. then diluted with 100 mL of ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give 71 mg (88%) of the product as a white solid which was used in the next step without further purification. 1H NMR (200 MHz, CD3OD): δ 2.64 (s, 3H), 4.20 (s, 2H), 4.69 (s, 2H), 7.16 (m, 1H), 7.22-7.43 (m, 4H), 7.50 (d, 2 Hz, 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated for C16H17BrN2O2 349; found 349, 351 (80%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Nc2cc(I)ccn2)c1
Temperature: 130 °C
Yield: 16 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (500 mg, 2.24 mmol), 3-nitroaniline (620 mg, 4.49 mmol), and Cs2CO3 (1460 mg, 4.48 mmol) in dry DMF (12.5 mL) was heated for 1 h at 130° C. in a microwave oven. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (DCM/MeOH 100:0 to 95:5) to yield the desired product A5 as a white solid (122 mg, 16%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 7.21 (d, J=5.4 Hz, 1H), 7.29 (s, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.93 (m, 2H), 8.74 (t, J=2.1 Hz, 1H), 9.62 (s, 1H). MS (ES) C11H8IN3O2 requires: 341. found: 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:27]([O:29]CC)=[O:28])[O:26][CH2:25][C:11]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18][C:17]4[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:27]([OH:29])=[O:28])[O:9][CH2:10][C:11]3([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[O:18][C:19]4[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:25][O:26]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)OCC2(CO1)c1ccccc1Oc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(c2ccc(Cl)cc2)OCC2(CO1)c1ccccc1Oc1ccccc12
Yield: 73.4 %

Procedure:
A mixture of 0.09 g (0.2 mmol) of the ester prepared in Example 77, Example [sic], 0.5 g (9 mmol) of KOH, 20 ml of ethanol and 10 ml of water is stirred at reflux for 3 h. After cooling, the reaction medium is acidified with concentrated HCl solution to pH=5 and extracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and then evaporated. The residual oil is crystallized from a suitable solvent. 0.06 g of white solid is isolated (yield=64%). m.p.=244-246° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[N:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:28]3[CH2:29][CH2:30][CH:25]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:26][CH2:27]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CCN(C2CCNCC2)CC1
Product: Clc1nc(N2CCOCC2)c2cc(CN3CCC(N4CCCCC4)CC3)sc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde was reacted with 4-piperidinopiperidine using the general reductive amination General Procedure to yield 1′-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-[1,4]bipiperidinyl, which was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester in General Procedure A. Purification on silica yielded 390. NMR: (CDCl3): 1.45-1.48 (2H, m), 1.52-1.56 (6H, m), 1.79-1.81 (2H, m), 2.02-2.05 (2H, m), 2.25-2.27 (1H, m), 2.53-2.56 (4H, m), (3.06 (2H, d), 3.72 (2H, s), 3.86-3.90 (4H, m), 3.95-3.99 (4H, m), 5.25 (2H, s, br.), 7.10 (1H, s), 9.30 (1H, s). MS ESI m/z 495 (MH+, 100%)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].C[O-].[Na+].[C:13](=O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5](=[NH:6])[O:14][CH3:13])[CH3:2]
Reactant: CCOC(C#N)OCC
Reactant: O=C=O
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Yield: 95 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH2:7][OH:8])[N:6]=1.[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: Cc1nc(CO)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: Cc1nc(C=O)c(C)[nH]1

Procedure:
A 42.2 gm. portion of 2,5-dimethyl-4-imidazolemethanol and 44.8 ml. of concentrated nitric acid are mixed. When the initial reaction subsides, the solution is heated on a steam bath for one hour. The reaction mixture is neutralized with concentrated aqueous sodium carbonate, then concentrated under vacuum. After leaching the residue with 150 ml. of hot ethanol several times, the combined organic solutions are concentrated under vacuum. Chromatographing the residual oil on silica gel gives a solid which is recrystallized from iso-propanol-ethyl acetate to give the desired product, m.p. 164.5°-166° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[N:11]([CH3:15])[N:12]=[CH:13][N:14]=2)=[N:6][N:5]2[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:17][N:18]=[C:4]2[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:26][C:27]1[CH:32]=[C:31]([C:2]2[C:7]([O:8][CH2:9][C:10]3[N:11]([CH3:15])[N:12]=[CH:13][N:14]=3)=[N:6][N:5]3[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[N:17][N:18]=[C:4]3[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1-c1cccc(F)c1
Temperature: 100 °C
Yield: 34.8 %

Procedure:
A stirred mixture of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine (50.2 mg, 0.124 mmol), 3-fluorobenzeneboronic acid (24.7 mg, 0.177 mmol), potassium phosphate (74.1 mg, 0.339 mmol), and tetrakis(triphenylphosphine)-palladium(0) (11.5 mg, 0.00995 mmol) in anhydrous DMF (3 ml) was degassed by evaporating and refilling the flask with nitrogen four times, then heated at 100° C. under nitrogen for 14.5 h. The mixture was partitioned between ethyl acetate (20 ml) and brine (15 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml) and the combined organic extracts were evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to afford 18.1 mg (35%) of the title compound as a white solid: m.p. 204-206° C. (CH2Cl2-EtOAc-hexane); 1H NMR (360 MHz, CDCl3) δ 3.70 (3H, s), 5.54 (2H, s), 7.18 (1H, m), 7.28-7.40 (4H, m), 7.46 (1H, m), 7.58 (1H, m), 7.86 (1H, s), 7.88 (1H, td, J=7.5 and 1.8 Hz), 8.08 (1H, s); MS (ES+) m/e 420 [MH]+.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 17 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (17%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH:2]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:27])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCN
Product: NCCCCCCCCCCCCCCC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 18 g of galactose and 20 g of tetradecylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]CBr)=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:20]2[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][CH2:19]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(CN2CCN(CC)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).