Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][OH:40].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (45 mg) was suspended in N,N-dimethylformamide (4 ml). Potassium carbonate (50 mg) and 4-bromo-1-butanol (55 mg) were added to the suspension, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (26 mg, yield 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[C:20]([F:23])([F:22])[F:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:26][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
Crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butanedione (Example 3, Step 2) (1.0 g) was reacted with anhydrous hydrazine (0.13 g) in glacial acetic acid. The mixture was held at 80°-110° C. for 18 hours and poured into water. The resulting solid precipitate was filtered, purified by HPLC and recrystallized from methylene chloride-hexane to give 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole as a solid (0.88 g, 89%): mp 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.C(N(CC)CC)C.S(Cl)([Cl:22])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][Cl:22])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 5-chloro-2-nitrobenzyl alcohol (80 g, 0.42 mol) and triethylamine (64 ml, 0.46 mol) in dichloromethane (840 ml) was added drop wise thionyl chloride (34 ml, 0.46 mol) during a period of 30 min while the internal temperature was kept below 32° C. by cooling with a water bath. The reaction mixture was stirred for 3 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether (970 ml). The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (85 g, 99%) as brown oil which was used in the next step without purification. MS m/e: 205 (M+).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:16][CH2:15]1)=O)C1C=CC=CC=1>O1CCCC1.O.[Pd]>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH2:11])[CH2:15][CH2:16]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(CCNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCN(CCN)CC1
Reaction time: 48 h
Yield: 28.9 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-2-[4-(t-butyldimethyl siloxy)-1-piperidyl] ethylamine (1.47 g) in tetrahydrofuran (37 ml), there was added 20% palladium hydroxide-on-carbon (100 mg). The resulting mixture was stirred over 2 days under a hydrogen gas atmosphere. The mixture was filtered through celite to remove the palladium hydroxide-on-carbon and the resulting filtrate was concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to thus give the title compound (Reference Compound 5-1, 0.28 g).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C1COCC1>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of 4-(1,1-dimethylpropyl)aniline (Preparation 100, 12.5 g, 0.076 mol) in THF (100 mL) was added acetic anhydride slowly at 0° C. The reaction was stirred at room temperature for 8 hours. The reaction was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (12 g, 76%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2
Reactant: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)nc(-n3cncn3)c12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2.53 g (1.54 ml, 16.51 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.57 g (5.50 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 8A in 10 ml of dry pyridine at 0° C., and the mixture is stirred for 30 min at 20° C. Subsequently, 3.42 g (49.53 mmol) of 1,2,4-triazole are added, and the mixture is stirred overnight at RT. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution, and the mixture is extracted using dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].C(OCC)(=O)CC(OCC)=O.Cl[C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([NH2:25])[CH:24]=1.[OH-].[K+].Cl>CS(C)=O.O>[CH3:1][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([NH2:25])[CH:24]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20-30° C. under ice bath cooling. To the thick white suspension was the added solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60° C. and stirred for 20 h at 60° C. The mixture was cooled to 23° C. and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100° C. and stirred for further 4 h. The mixture was cooled to 23° C., diluted with water (ca. 1000 mL), acidified with 37% HCl 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M−H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=[N:10][CH:11]=2)[S:21][CH:22]=1
Reactant: O=C(O)c1cncc(Oc2cccnc2)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)c2cncc(Oc3cccnc3)c2)n1
Yield: 38.9 %

Procedure:
Compound 6 (30 mg, 0.14 mmol, 1.0 eq), 4-methylthiazol-2-amine (19 mg, 0.17 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.289 mmol, 2.10 eq), and N,N-Diisopropylethylamine (38 mg, 0.29 mmol, 2.1 eq) were dissolved in CH2Cl2 (1.5 mL) and DMF (0.30 mL) and stirred at rt for 72 h. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by reverse-phase preparatory HPLC to afford 17 mg (38%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J=1.7 Hz, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.49 (dd, J=4.7, 1.2 Hz, 1H), 8.04 (t, J=2.2 Hz, 1H), 7.68 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 7.23 (d, J=1.2 Hz, 1H), 2.36 (d, J=1.0, 3H); ES-MS [M+1]+:313.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]2=[O:18])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>CN(C=O)C>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])=[CH:5][CH:4]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: O=c1cc(O)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(O)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (1.62 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-hydroxy-1H-pyridin-2-one (preparation 4) in 2.5 mL DMF is added at RT 482 mg (1.79) piperidine-4-carboxylic acid dimethylamide and 0.46 mL (3.25 mmol) triethylamine. The mixture is stirred overnight at RT and after filtration is purified via HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([OH:18])[CH2:17][CH2:16][CH2:15]3)=[C:10]([O:19][CH3:20])[CH:9]=2)OC1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[Cl:32])[NH:28][N:27]=[C:26]2[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].OS([O-])(=O)=O.[Na+]>C(OCC)(=O)C.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1COCC1.C1(C)C=CC=CC=1>[Cl:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26]([C:33]([OH:35])=[O:34])=[N:27][NH:28]2)=[CH:24][C:23]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:18])[CH2:15][CH2:16][CH2:17]2)=[C:10]([O:19][CH3:20])[CH:9]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: COc1cc(B2OCC(C)(C)CO2)ccc1C1(O)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)ccc1C1(O)CCC1
Temperature: 115 °C
Yield: 12.6 %

Procedure:
A sealed tube was charged with 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]cyclobutanol (50 mg, 0.17 mmol), 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (47.4 mg, 0.172 mmol), toluene (0.80 mL), THF (0.40 mL), EtOH (0.40 mL), and 2M potassium carbonate (0.40 mL, 0.80 mmol). Nitrogen was then bubbled through the mixture for 5 minutes. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.6 mg, 0.017 mmol) was added and the tube sealed and heated to 115° C. for 2 hours. The reaction was cooled to room temperature, opened, neutralized with 1M NaHSO4, and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude material (80 mg). 40 mg was dissolved in DMSO and subjected to reverse phase chromatography to provide 8 mg (10% yield) of title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH2:5].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.[I-].ClC1C=CC=C[N+]=1C.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH:5][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCNC(=O)c1cccnc1
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A mixture of 2 mmol of N-(3,7,11-trimethyl-2,6,10-dodecatrienyl)amine (hereinafter abbreviated as farnesylamine), 2.2 mmol of nicotinic acid, 562 mg (2.2 mmol) of 2-chloro-1-methylpyridinium iodide, and 444 mg (4.4 mmol) of Et3N in 20 ml of CH2Cl2 is heated with stirring for 3 hours. The reaction mixture is washed twice with 20 ml of saturated aqueous NaHCO3 and twice with 20 ml of water. The mixture is dried and evaporated under reduced pressure. The residual oil is purified by silica-gel column chromatography and eluted with AcOEt to give 426 mg of the titled compound I-85. Yield: 65.2%.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]=[N+]=[N-])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].Cl.[CH2:28]([O:30][CH2:31][CH3:32])C>C(O)C.[Pd]>[C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([NH:24][C:17](=[O:18])[C:12]2[CH:32]=[C:31]([O:30][CH3:28])[CH:5]=[C:6]([O:7][CH3:8])[CH:11]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Reactant: CCOCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-D-galactopyranose 1 (167 mg, 0.45 mmol) was suspended in ethanol (5 ml), and palladium (10% on carbon, 17 mg) and HCl (1 ml of a 1M solution in diethyl ether) were added. The mixture was degassed and stirred at room temperature under a hydrogen atmosphere. After 1 h, dichloromethane was added, and the mixture was filtered through Celite and concentrated in vacuo. Half of the residue was dissolved in dichloromethane (2 ml) and pyridine (0.5 ml). 3,5-Dimethoxybenzoyl chloride (168 mg) was added, and the mixture was stirred at room temperature. After 18 h, TLC (1:1, heptane:ethyl acetate) showed the presence of a single carbohydrate product (Rf 0.2). The reaction mixture was diluted with diethyl ether (30 ml) and washed with H2SO4 (30 ml of a 10% aqueous solution), NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-D-galactopyranose 4 (50 mg, 44%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(O)(C)(C)C>[CH3:14][O:13][C:11]([CH:10]1[CH2:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[N:3]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:4](=[O:15])[N:5]12)=[O:12]
Reactant: COC(=O)C1CCCn2c(=O)[nH]c(=O)n21
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C1CCCn2c(=O)n(CC(=O)OCc3ccccc3)c(=O)n21
Reaction time: 4 h
Yield: 52.2 %

Procedure:
1.50 g (0.007 mol) of methyl hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate were dissolved in 40 ml of dry tert.butanol. A solution of 0.87 g (0.008 mol) of potassium tert.butoxide in 50 ml of dry tert.butanol was added and the mixture was stirred under reflux and under a nitrogen atmosphere for 4 hours. 1.61 g (0.007 mol) of benzyl bromoacetate were added and the heating was continued for a further 4 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel using chloroform for the elution to give 1.32 g (52%) of benzyl 5-methoxycarbonyl-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-acetate of melting point 103°-106° C. (from dichloromethane/hexane).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[CH2:3]([O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCOCc1ccccc1
Yield: 100.9 %

Procedure:
60% Sodium hydride (1.33 g) was suspended in dimethylformamide (40 ml), and benzyl alcohol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1,5-dibromopentane (6.4 g) was added, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 7.2 g of 5-benzyloxypentyl bromide.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[1-(4-fluorophenyl)ethyl]-3-nitropyridine-2,6-diamine (Method 12; 0.26 g, 0.68 mmol) and zinc dust (0.223 g, 3.41 mmol) in MeOH:THF (1:1, 12 ml) was slowly added saturated ammonium chloride solution (1.5 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was then added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, and concentrated. The title compound was used directly for the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1)[CH:6]=[O:7]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 91.1 %

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzaldehyde (0.355 mL, 2.60 mmol), 3-(trifluoromethyl)phenol (0.289 mL, 2.60 mmol) and K2CO3 (1079 mg, 7.81 mmol) were in DMSO (10 mL) was heated at 100° C. overnight. Purification via reverse phase flash chromatography afforded the title compound (989 mg, 2.368 mmol, 91.0% yield). LCMS: rt=3.84 min, [M+H+]=335
Reaction SMILES: [C:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH:1]1([C:6]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=2[O:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a solution of 3-cyclopent-1-enyl-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1b) (600 mg, 2.08 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (554 mg, 0.52 mmol) under argon atmosphere. The reaction mixture was stirred under hydrogen balloon pressure for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The crude thus obtained was purified by column chromatography (Combi-Flash, 40 g, 25% ethyl acetate/hexane) to get the title compound (375 mg, 69.16%) as colorless liquid; MS (ESI): 259 [M−H]−.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:20]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=425.99.
Reaction SMILES: Br.C(OC([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([NH:24][CH2:25][C:26]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=3[O:34][CH3:35])=[NH:23])[S:20][C:14]=2[CH2:13]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-]>C(O)(=O)C.CO>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=1[CH2:25][NH:24][C:22]([NH:21][C:19]1[S:20][C:14]2[CH2:13][NH:12][CH2:17][CH2:16][C:15]=2[N:18]=1)=[NH:23]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.2 ml HBr (33% in glacial acetic acid) were added to 150 mg benzyl-2-{[[(2,6-dimethoxybenzyl)amino](imino)methyl]amino}-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylat (0.28 mmol) in 2 ml glacial acetic acid, and the mixture was stirred for 2 hours at room temperature. After reaction completion, the mixture was evaporation-concentrated, was filtered over C18 Chromabond (water/CH3CN+0.1% glacial acetic acid; 0-30%), and the free base was obtained by stirring with polymer-bound carbonate in methanol. 60 mg; ESI-MS [M+H+]=348.15.