Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][NH:13][C:14]=2[C:15]#[N:16])=[CH:6][C:5]=1[F:22].[NH2:23]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:23][N:13]1[C:14]([C:15]#[N:16])=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([F:22])[CH:6]=2)[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12]1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(N)c(F)c1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(N)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.7 g, 43 mmol) was added in portions to a solution of ethyl 4-(4-amino-3-fluorophenyl)-5-cyano-1H-pyrrole-3-carboxylate (9.0 g, 33 mmol) in DMF (290 mL). The suspension was stirred for 30 min and then (aminooxy)(diphenyl)phosphine oxide (9.9 g, 43 mmol) was added. The reaction was warmed (60° C.) for 4 h and then cooled to rt. The reaction was quenched by slow addition of water (10 mL) and the solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and the solution was washed with saturated aqueous sodium bicarbonate solution (2×250 mL) and brine (250 mL). The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with diethyl ether to give the desired product (7.8 g, 82%); 1H NMR (300 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.05 (dd, J=12.7, 2.0 Hz, 1H), 6.91-6.95 (m, 1H), 6.75 (dd, J=9.5, 8.4 Hz, 1H), 6.57 (s, 2H), 5.36 (s, 2H), 4.09 (q, J=7.0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); ES-MS m/z 289.0 (MH)+; HPLC RT (Method B) 2.61 min.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:12]=[CH:13][CH:14]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)(=O)C>CC(N(C)C)=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CCCCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 0.25 h
Yield: 150.9 %

Procedure:
0.965 g of potassium t-butoxide was added to a solution of 1.70 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7) in 30 ml of dimethylacetamide, whilst ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. A solution of 3.18 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)piperidine in 30 ml of dimethylacetamide was then added dropwise to the solution at the same temperature, and the mixture was stirred at 55° C. for 1.5 hours. At the end of this time, the reaction mixture was cooled, and 200 ml of ethyl acetate and 100 ml of water were added to the mixture, which was then shaken. The ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.54 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([CH2:36][CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:29][C:30]=1[CH2:36][CH3:37])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
In analogy to the procedure described in example 17 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-ethyl-benzaldehyde in the presence of triethylamine and di-n-butylboron trifiate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as yellow foam. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1/[C:11](/[CH3:20])=[CH:12]/[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[Cl-].[NH4+].O1CCCC1.CO>[Fe].O>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1/[C:11](/[CH3:20])=[CH:12]/[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)/C=C(\C)c1ccc(N)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Compound 5a (1.05 g), iron powder (1.11 g), and ammonium chloride (0.32 g) were added to a mixed solution of tetrahydrofuran (4 ml), methanol (4 ml), and water (4 ml). The mixture was stirred at 60° C. for 2 hours. The same amount of iron powder and ammonium chlorides were further added thereto, and the obtained mixture was stirred at 70° C. for 1 hour. After the reaction mixture was allowed to cool, and filtered, insoluble substances were filtered through Celite. The filtrate was condensed under reduced pressure to give Compound 5b (939 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:7].[BH4-].[Li+].O.Cl>O1CCCC1>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1C(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1C(O)c1cccs1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution, at room temperature, of 0.5 g of the product of Example 3 dissolved in 30 mL of dry tetrahydrofuran was added 0.1 g of lithium tetrahydridoborate (LiBH4). After stirring for 0.5 hour, 30 mL of water was carefully added following by acidification with concentrated hydrochloric acid. The reaction was extracted with methylene chloride, washed with water and brine and dried (MgSO4). Filtration and concentration of the filtrate in vacuo afforded 0.5 g of the subject compound as a light green oil which was used as such in the following example.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH4+:17].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]1([C:6]([NH2:17])=[O:7])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (0.5 g, 3.24 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.355 mL, 4.06 mmol) and 1 drop of DMF, stirred for 1 h at RT, added drop-wise to a solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in THF (5 mL) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth and rinsed well with 4:1 DCM/THF. The filtrate was saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 1-(trifluoromethyl)cyclopropanecarboxamide (440 mg, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.31 (s, 1H), 7.15 (s, 1H), 1.29-1.24 (m, 2H), 1.19-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[C:21]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22]
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40585.8 %

Procedure:
Compound 502 (100 mg, 0.239 mmol) was suspended in 1,4-dioxane (1 mL), and morpholine (0.063 mL, 0.72 mmol) was added thereto, followed by stirring overnight at 100° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was reslurried with ethanol to afford the entitled Compound 503 (109 mg, 97 mmol) as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=[O:36]>C1COCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[C:9]([CH:35]([OH:36])[C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C(O)c2ccc3ccccc3c2)nc1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of N,N-dimethyl imidazole-1-sulfonamide (commercially available from Aldrich) (2.0 g, 11.4 mmol) in THF (50 mL) at −78° C. was treated with nBuLi (4.6 mL of a 2.5 M soln) for 1 h. Solid tert-butyl-dimethylsilanyl chloride (TBSCl) (1.72 g, 11.4 mmol) in THF (10 mL) was added at rt for 16 h. The mixture was cooled to −20° C. and treated with nBuLi (4.6 mL of a 2.5 M soln) for 1 h. 2-Naphthaldehyde (1.78 g, 1.1.4 mmol) in THF (10 mL) was added and the mixture was stirred for 3 h at rt. The mixture was washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by chromatography on silical gel with 25% EtOAc:hexane to give 2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-I1) 2.6 g (50%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>ClCCl>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:21])=[CH:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Oxalyl chloride (6.6 ml, 76 mmol, 1.2 eq) is added into a cold (ice bath) solution of 4-benzyloxy-benzoic acid (14.38 g, 63 mmol, 1 eq) and triethylamine (43.8 ml, 315 mmol, 5 eq) in dichloromethane (400 ml). The dark red mixture is warmed to room temperature and stirred for 2 h and then cooled to 0° C. A solution of 2-amino-2-methyl-propan-1-ol (5.6 g, 63 mmol, 1 eq) in dichloromethane (20 ml) is added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the residue is dissolved in dichloromethane. This solution is washed once with water and the aqueous layer is extracted with dichloromethane. The organic layers are washed with a solution of 0.1 M sodium hydroxide and dried over magnesium sulfate. The solvent is removed under vacuum, to afford 15 g of 4-(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax1 as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1[CH2:16][CH2:17]Cl.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([N:24]2[C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=3[CH2:16][CH2:17]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)c1nc2ccnn2c(Cl)c1CCCl
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccnn2c2c1CCN2C1CCCC1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
In 48 ml of anhydrous DMF were dissolved 3.6 g of ethyl 7-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate. While stirring at room temperature under a nitrogen atmosphere, 7.3 ml of cyclopentylamine were added to the solution, and the mixture was stirred for 1 hour and 20 minutes. The reaction mixture was poured into 250 ml of ice water. Insoluble matter was collected by filtration and air-dried to obtain 3.20 g (yield: 85.3%) of ethyl 8-cyclopentyl-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]-pyrimidine-5-carboxylate. While stirring at -5 to 0° C., 1.16 g of this product were gradually added to mixed acid prepared by mixing 7.8 ml of concentrated sulfuric acid and 3.9 ml of 90% nitric acid. After being stirred for 5 minutes under the same conditions, the reaction mixture was poured into 200 ml of ice water, followed by extraction with chloroform. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was then distilled off, and the residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:1) to obtain 0.76 g (yield: 57.0%) of Compound 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]([CH2:11][CH:12]([OH:14])[CH3:13])[N:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[C:7]([NH2:8])=[CH:6][N:5]([CH2:11][CH:12]([OH:14])[CH3:13])[N:4]=1
Reactant: COc1nn(CC(C)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nn(CC(C)O)cc1N
Reaction time: 14 h

Procedure:
A nitrogen-flushed round bottom flask was charged with 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)propan-2-ol (345 mg, 1.72 mmol, 1.00 eq), 10% Pd/C (200 mg) and methanol (20 mL). The reaction mixture was sparged with hydrogen for 10 min then stirred vigorously under hydrogen atmosphere for 14 hr. The reaction mixture was then sparged with nitrogen, filtered through Celite®, and concentrated to give the title compound as an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (s, 1H) 4.70 (d, J=4.9 Hz, 1H) 3.89-3.77 (m, 1H) 3.74 (s, 3H) 3.73-3.55 (m, 2H) 0.97 (d, J=6.2 Hz, 3H). m/z (APCI+) for C7H14N3O2 172.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)=[O:26])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Cc1ccc(Oc2ccc(N)cn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(NC(=O)c3c[nH]c4ccccc34)cn2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
The 6-(6-methylpyridine-3-yloxy)-pyridine-3-amine (300 mg, 1.49 mmol) and indole-3-carboxylic acid (240 mg, 1.49 mmol) were dissolved in DMF (10 ml), DCC (280 mg, 1.49 mmol) was added to the solution, and then the mixture was stirred at 80° C. for 3 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a grey solid (340 mg, 66%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]#N)[CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:3][CH2:2]1.[OH-:15].[K+].[OH2:17]>C(O)C>[CH:1]1([C:4]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]([OH:17])=[O:15])[CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: O
Reactant: N#CCc1cccc(C(=O)C2CC2)c1
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1cccc(C(=O)C2CC2)c1

Procedure:
m-(Cyclopropylcarbonyl)phenylacetonitrile (8.1 g) and potassium hydroxide (3.36 g) in water (50 ml) and ethanol (50 ml) were heated under reflux for 5 hours and cooled. The mixture was washed with chloroform (2× 50 ml), acidified to pH 1 with 5N hydrochloric acid and extracted with ethyl acetate (2× 75 ml). The extracts were combined, washed with water, dried over magnesium sulphate, filtered and evaporated. The residue was distilled under reduced pressure and the fraction b.p. 170°/0.1 mm collected. The distilate solidified and the solid melted at 52°.
Reaction SMILES: C(N1CC[C@@H](C2C=CC=CC=2)[C@H](C(O)=O)C1)(OC(C)(C)C)=O.C(OC(N1CC[C@@H](C2C=CC=CC=2)[C@H](C([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[CH2:46][CH2:45]2)=O)C1)=O)(C)(C)C>>[CH3:57][C:51]1[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:50]=1[N:47]1[CH2:46][CH2:45][NH:44][CH2:49][CH2:48]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)CC2)c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](C(=O)O)C1
Product: Cc1ccc(C)c(N2CCNCC2)c1

Procedure:
In analogy to example 1, step 1, from trans-N-Boc-4-phenyl-nipecotic acid (CAS Reg. No.: [170838-49-0]) and 1-(2,5-dimethylphenyl)piperazine was prepared trans-3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester as a white foam, MS: 478.2 ([M+H])+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc3ccccc3n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(chloromethyl)quinolinehydrochloride (0.73 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.49 g, 26%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1>>[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=2)=[O:8])[CH:21]=1
Reactant: CC1(C)OB(c2cnccc2F)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnccc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=0.97 min, m/z=463.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.66-1.76 (m, 1H) 1.77-1.89 (m, 1H) 2.87-2.97 (m, 1H) 3.14-3.21 (m, 1H) 3.30 (s, 2H) 4.14-4.23 (m, 1H) 4.82-4.92 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.41-7.49 (m, 1H) 7.83 (d, J=8.99 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.61-8.67 (m, 1H) 8.68-8.77 (m, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:32])([CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:32])([F:16])[CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)COS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.1 ml, 6.6 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-phthalimido-1-propanol (1.4 g, 6 mmol), pyridine (0.5 ml, 6.6 mmol) in anhydrous dichloromethane (30 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 20:80) (1.7 g, 75%).
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([CH3:16])[CH:9]=[C:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]2=[N:4][C:3]=1[CH3:17].[CH3:18][N:19]1[C:23]([CH3:24])=[C:22](B(O)O)[C:21]([CH3:28])=[N:20]1.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>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.O.C(O)C>[CH2:12]([CH:11]([C:10]1[C:5]2[N:6]([C:2]([C:22]3[C:21]([CH3:28])=[N:20][N:19]([CH3:18])[C:23]=3[CH3:24])=[C:3]([CH3:17])[N:4]=2)[N:7]=[C:8]([CH3:16])[CH:9]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1nn(C)c(C)c1B(O)O
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: COCCOC
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nn(C)c3C)c(C)nc12
Yield: 6.4 %

Procedure:
3-Iodo-2,6-dimethyl-8-(1-ethyl-propyl)-imidazo[1,2-b]pyridazine (200 mg, 0.582 mmol), 1,3,5-trimethylpyrazole-4-boronic acid (233 mg, 1.53 mmol), Pd(PPh3)4 (13.4 mg, 0.01 mmol) are combined in a microwave pressure tube. Then 0.58 ml of 2N Na2CO3 and 3.0 ml of dimethoxyethane/H20/ethanol (7:3:2) solution is added. The mixture is microwaved at 155° C. for 20 minutes. Water is added and the mixture is extracted four times with ethyl acetate. The combined organics are dried over MgSO4, filtered, then evaporated to a residue which is chromatographed using hexanes, then 1:1 hexanes:ethyl acetate, then 100% ethyl acetate to give the title compound (6.4%) as a yellow oil. 1H-NMR (DMSO-d6): δ6.86 (s, 1H); 3.73 (s, 3H); 3.06-3.10 (m, 1H); 2.41 (s, 3H); 2.22 (s, 3H); 2.03 (s, 3H); 1.93 (s, 3H); 1.74-1.83 (m, 4H); 0.77 (t, J=7.26 Hz, 6H) ppm. MS/ES+=327 (100%, M+2).