Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22].[Br:23]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:23][C:22]#[C:21][C:3]1[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[Cl:13])[C:2]=1[Cl:1]
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-ethynylpyrazole (0.499 g) in acetone (5 ml) was added N-bromosuccinimide (0.244 g) followed by silver nitrate (0.023 g). Stirring was continued for one hour then the reaction mixture was evaporated to dryness. The residue was partitioned between ether and water. The aqueous layer was separated and extracted with ether. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from hexane provided the title compound as a white solid m.p. 152.9-153.4° C.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22](OC(C)(C)C)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>FC(F)(F)C(O)=O.ClCCl>[CH3:5][CH:4]([NH:3][C:22](=[O:23])[C:21]1[CH:29]=[CH:30][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:3]3[C:4]4[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=4[CH2:6][O:7][C:2]3=[O:1])[CH2:17][CH2:16]2)=[CH:19][CH:20]=1)[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from step (i) (0.29 g) in a mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was stirred at room temperature for 1 h. The solution was evaporated under reduced pressure, the residue dissolved in N,N-dimethylformamide then bromo-tris-pyyrolidino-phosphonium hexafluorophosphate (0.16 g), isopropylamine (0.06 ml) and N,N-diisopropylethylamine (0.06 ml) added. The solution was stirred at room temperature for 16 h then evaporated under reduced pressure. Purification was by chromatography eluting with (1:5) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:29]([CH3:28])(=[O:31])=[O:30])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1C(=O)N(S(C)(=O)=O)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and methanesulfonyl chloride to give 3-isopropyl-1-methanesulfonyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one as an off-white solid. MS: 454.4 ([M+NH4]+)
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:20]([N:22](CC)CC)[CH3:21].C(N)C>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:22][CH2:20][CH3:21])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Reactant: CCN(CC)CC
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(CC)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 70 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.55ml of ethylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 4 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.63g (Yield 70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:34][C:35]1[N:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>O1CCCC1.O>[C:11]([O:10][C:9](=[O:15])[N:8]([CH2:7][C:4]1[CH:3]=[C:2]([Br:1])[N:6]([S:41]([C:38]2[CH:39]=[N:40][C:35]([CH3:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])[CH:5]=1)[CH3:16])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
To a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 31 mg) at 0° C., and the mixture was stirred at the same temperature for 10 min. A solution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3-ylsulfonyl chloride (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a brown oil (yield 213 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]=[C:12]([CH3:21])[CH2:13][C:14]([O:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].C(OCC)(=O)C>N1CCCCC1.C(O)(=O)CCCCC.C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:12](=[O:11])[CH3:21])[C:14]([O:16][CH:17]1[CH2:18][CH2:19][CH2:20]1)=[O:15]
Reactant: CC(=O)CC(=O)OC1CCC1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCC1
Temperature: 25 °C

Procedure:
A solution of 2,3-dichlorobenzaldehyde (1.57 g, 8.9 mmoles), cyclobutyl 3-oxobutanoate (1.4 g, 8.9 mmoles), piperidine (8 drops) and hexanoic acid (11 drops) in dry benzene (100 ml) was heated at reflux for 12 hours using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo to leave the crude sub-title compound as an oil 3.5 g. Chromatography on silica eluting with petroleum ether (60°-80° )/ethyl acetate mixtures afforded the sub-title compound as an oil, 1.7 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8](OCC)=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.CCOC(C)=O>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[C:7]([CH2:8][OH:9])=[CH:6][NH:5][N:4]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.00 g, 24 mmol) was dissolved in dry THF (50 mL). LiAlH4 (912 mg, 24.4 mmol) was added portionwise with care. The reaction mixture was stirred at RT for 3 h. MeOH (50 mL) was added dropwise and stirring continued for 30 min before concentrating in vacuo to give an off white solid. EtOAc (50 mL) was added and the solid was stirred for 30 min before filtering. The filtrate was concentrated and this procedure was repeated 4 times before the filtrates, after concentration in vacuo, were combined and purified by flash column chromatography (silica gel; eluent EtOAc:heptane, 4:1) to give the desired product (2.1 g, 12.6 mmol, 53%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:12](=[O:24])[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C=O)C>[CH3:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[C:12]1=[O:24]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
The product is produced as described in example 1 from 1.41 g of NaH (80% suspension in mineral oil), 14.3 g of 5-phenyl-1-(3-trifluoromethylphenyl)-4-imidazolin-2-one, 100 cc. of DMF, 11.1 g of 8-bromocaprylic acid methyl ester and 1.41 g of NaJ.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.21 g, 0.56 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.12 g, 0.56 mmol), and Cs2CO3 (0.12 g, 0.61 mmol) were suspended in DMSO (3.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.13 g, 0.67 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (40 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (2×30 mL). The resulting organic solution was dried over Na2SO4 and filtered. Activated charcoal was added to the filtrate; the resulting suspension was filtered through a celite plug with 80:18:2 CH2Cl2/MeOH/NH4OH; and the filtrate was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (130 mg, 45%) as an off-white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (dd, J=7.5, 7.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.28 (dd, J=8.5, 8.5 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.58 (s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.0 Hz, 2H), 3.03 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H), 1.35-1.27 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:13]1[C:21]2[CH2:20][CH2:19][NH:18][CH:17]([CH2:22][OH:23])[C:16]=2[CH:15]=[CH:14]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:18]2[CH2:19][CH2:20][C:21]3[O:13][CH:14]=[CH:15][C:16]=3[CH:17]2[CH2:22][OH:23])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: OCC1NCCc2occc21
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCc2occc2C1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
A solution of 3,4-dichlorophenyl acetic acid (4.6 g) in dry dichloromethane (100 ml) was treated with 1,1'-dicarbonyldiimidazole (3.6 g). The mixture was stirred at ambient temperature for 30 min. A solution of the product of stage (i) (1.13 g) in dry dichloromethane (20 ml) was added and the mixture was stirred at ambient temperature for 20 h. The mixture was washed with aqueous sodium carbonate solution (1M; 2×100 ml), dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in tetrahydrofuran (50 ml) and a solution of lithium hydroxide (0.575 g) in water (40 ml) was added. The mixture was vigorously stirred at ambient temperature for 80 min. The organic solvent was removed in vacuo and the aqueous residue was extracted with dichloromethane (50 ml). The organic extract was dried (Na2SO4) and evaporated in vacuo to give a solid residue which was crystallised from methylacetate and hexane to give the title compound as a pale yellow solid (1.81 g) m.p. 155°-6°.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:34])=[CH:25][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 0.99 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (188 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (283 mg, 1.48 mmol) and 1-hydroxy-1H-benzotriazole (151 mg, 0.99 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (191 mg, 41%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1>>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])[N:3]=[CH:4][N:5]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: Fc1c(Cl)ncnc1Cl
Product: C[C@@H]1CCC[C@H](C)N1c1ncnc(Cl)c1F
Temperature: 70 °C
Reaction time: 11 h
Yield: 57.5 %

Procedure:
0.25 g of 4,6-dichloro-5-fluoropyrimidine and 0.34 g of cis-2,6-dimethylpiperidine were mixed and stirred for 11 hours at 70° C. The reaction mixture was subjected to silica gel column chromatography to obtain 0.21 g of 4-chloro-6-(cis-2,6-dimethylpiperidino)-5-fluoropyrimidine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]#[CH:14])[CH:8]=[CH:7][C:6]=1[C:15]1[NH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:23]=1)[C:2]#[CH:3].C([O-])(=O)/C=C/C([O-])=O>>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:6]([C:15]2[NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[N:23]=2)=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:10]=1)[CH:13]=[CH2:14]
Reactant: C#CCOc1ccc(-c2nc3cnccc3[nH]2)c(OCC#C)c1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: C#CCOc1cc(OCC=C)ccc1-c1nc2cnccc2[nH]1

Procedure:
2-(2,4-Bispropargyloxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 195°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:49])[C@@H:10]([CH3:48])[NH:11][C:12](=[O:47])[C@@H:13]([CH2:22][CH2:23][CH2:24][CH:25]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[NH:14]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([CH2:7][O:8][C:9](=[O:49])[C@@H:10]([CH3:48])[NH:11][C:12](=[O:47])[C@@H:13]([CH2:22][CH2:23][CH2:24][CH:25]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@H](N)CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 105.6 %

Procedure:
A solution of 40b (251 mg, 0.37 mmol) in TFA (870 μl) is stirred for 30 min at 0° C. The TFA is removed and the oil is taken up in EtOAc and washed with saturated NaHCO3 solution. Drying and removal of the solvent gives 3b (225 mg, slight excess) which is used in subsequent reactions without further handling: NMR δ 1.39 (d, 3 H) and 1.20-1.70 (overlapping m, 4 H), 1.82 (br s, 2 H), 3.23 (br s, variable, 2 H), 3.33 (br s, 1 H), 4.39 (m, 1 H), 4.47 (apparent quintet, 1 H), 5.03-5.13 (m, 6 H), 5.27 (br d, 1 H), 7.35 (m, 15 H), 7.95 (br d, 1 H); MS (FAB) m/z 576 (M+H), 598 (M+Na).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:17]=2[N:18]=[C:19]([C:21]([O:23]CC)=[CH2:22])[CH:20]=1)=[O:14].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][C:4]2[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])=[O:14])[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:30])[CH3:31])[C:17]=2[N:18]=1)(=[O:23])[CH3:22]
Reactant: C=C(OCC)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
35% HCl (4 mL) was added to the N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-ethoxyvinyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 0.293 mmol) at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, saturated NaHCO3 solution was added to it and extraction was carried out by using 5% MeOH/DCM, the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired compound (90% yield). LCMS: 382.10 (M+1)+; HPLC: 99.55% (@ 254 nm) (Rt;6.316); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (bs, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 5.89 (s, 1H), 5.35-5.29 (m, 1H), 4.36 (d, 2H, J=4.0 Hz), 2.75 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.56 (d, 6H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:8]([CH3:12])[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1c(C)ccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Cl)c1CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution of 1.9 g (10.0 mmoles) of methyl 2-chloro-4-methylnicotinate dissolved in 5.0 ml of THF was gradually added, at −65 to −60° C., to a suspension of 0.4 g (10.0 mmoles) of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and at −20° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 38.2%) of (2-chloro-4-methylpyridin-3-yl)methanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=1.O>CN(C=O)C>[CH3:25][C:17]1[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=[C:15]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:16]=1
Reactant: OCCOC1CCCCO1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCOC2CCCCO2)nn2c(N)nnc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
2-(Tetrahydropyran-2-yloxy)ethanol (3.85 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise. After 40 min, the mixture was admixed with water and extracted by shaking four times with dichloromethane. To eliminate the excess alcohol, the mixture was chromatographed first through a short silica gel column with MtB ether and then with 8:2 dichloromethane/methanol. The clean product fractions were combined and dried. 678 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][Si:18]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:16])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: COc1cc(CCC[Si](OC)(OC)OC)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In the same reactor vessel, the 3-(4-acetoxy-3-methoxyphenyl)propene was heated to 80° C. and then charged with chloroplatinic acid (0.79 grams). Trimethoxysilane (1990 grams, 16.3 moles) was added with stirring to the reaction mixture over a period of 40 minutes. An ice bath was used to maintain the reaction mixture at a temperature of between 100 and 108° C. After the addition of the trimethoxysilane, the reaction mixture was held at 90° C. for 1 hour and then the mixture was cooled to room temperature. The product was distilled under vacuum at 143° C. and 1 mm Hg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11](=O)[CH3:12])[CH:8]=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[N:10]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(OCC(F)(F)F)n1
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OCC(F)(F)F)n1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (0.35 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone (0.48 g, 2.17 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.