Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.O[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: OCc1ccncc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccncc2)c(Cl)c1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a solution of 0.43 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0. 16 g of 4-(hydroxymethyl)pyridine and 0.39 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.30 g of diisopropyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, to which 20 ml of diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.29 g of 3,5-dichloro-4-(4-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (51% yield), m.p. 74.0° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O.O>[N:20]1([CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)cc(Cn2ccnc2)c1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (500 mg, 1.4 mmol), potassium carbonate (388 mg, 2.8 mmol), and imidazole (96 mg, 1.4 mmol) in N,N-dimethylformamide (4 mL) was heated at 70° C. for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 100% ethyl acetate afforded 242 mg (51%) of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1Cc1cccc(C(F)(F)F)c1
Yield: 75.1 %

Procedure:
In the same manner as in Example 51, the title compound (52 mg) was prepared from the compound (50 mg) obtained in Example 50 and 3-trifluoromethylbenzyl chloride (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:36][C:37]1[N:42]=[C:41]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccnc(Cl)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Yield: 62 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.03 mmol), 2,4-dichloropyrimidine (183.7 mg, 1.24 mmol), PdCl2(PPh3)2 (41.2 mg, 5.9%) and aqueous solution of Cs2CO3 (2 mol/L, 2 mL) in 1,4-dioxane (5 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried, and concentrated to give the residue, which was purified by column chromatography to give (R)-3-((S)-1-(4-(2-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (300 mg, 62%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:25][C:24]4[CH:23]=[C:22]([CH2:21][OH:20])[CH:29]=[CH:28][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(CO)c1
Product: OCc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(hydroxymethyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give [3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]methanol.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:38]1[CH2:37][CH2:36][N:35]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:34][CH:33]=2)[CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=[O:17])[NH:12]2)(=O)=O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=[O:17])[NH:12]2)#[N:21]
Reactant: CN(C)C=O
Reactant: O=C1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1CCC(=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
5-Trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one (1.5 g), zinc cyanide (1.3 g) and tetrakis(triphenylphosphine)palladium (0.59 g) were suspended in DMF (20 ml), and the suspension was stirred at 100° C. for 2 hours. The insoluble matter was filtered off, and ethyl acetate was added to the filtrate, followed by washing with water. The resulting mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 0.71 g (yield: 81%) of 5-cyano-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([Mg]Cl)[CH3:24]>C1COCC1.[Cu]I>[CH2:23]([C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[CH3:24]
Reactant: CC[Mg]Cl
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1CC

Procedure:
This compound is prepared from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate and ethylmagnesium chloride in THF at −10° C. in the presence of CuI as described in the following reference: Chemistry-A European Journal, 15(29), 7167-7179, S7167/1-S7167/121; 2009.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([C@@H:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][C:3]=1[F:39].[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][C:43]([CH3:55])=[N:42]1.[F-].[Cs+].CC(O)C.C(N(CC)CC)C>C(OCC)(=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:40][N:41]1[C:45]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:12]4[N:16]5[CH:17]=[C:18]([C@@H:21]([N:26]6[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]6)[C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:20][C:15]5=[N:14][N:13]=4)=[N:9]3)=[CH:4][C:3]=2[F:39])=[CH:44][C:43]([CH3:55])=[N:42]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(Br)cc5n4)n3c2)C(F)(F)F)C1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(-c2cc3nc(-c4nnc5ccc([C@@H](N6CC[C@H](NC(=O)OC(C)(C)C)C6)C(F)(F)F)cn45)ccc3cc2F)n(C)n1
Temperature: 100 °C
Yield: 74 %

Procedure:
A mixture of tert-butyl (S)-1-((R)-1-(3-(7-bromo-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.10 g, 0.16 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.073 g, 0.33 mmol) and cesium fluoride (0.065 g, 0.43 mmol) in 2-propanol (3.3 mL, 0.16 mmol) was degassed with nitrogen. Maintaining a nitrogen atmosphere, triethylamine (0.034 mL, 0.25 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.013 g, 0.016 mmol) were added, and the vessel sealed and heated at 100° C. for 17 hours. After cooling, the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a plug of Celite®, and concentrated under reduced pressure. Purification of the residue by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) provided the title compound (0.074 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:24][CH2:25][C:26]2[CH:30]=[CH:29][O:28][CH:27]=2)[C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]2[C:4]([CH3:23])([CH:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])[C:27]1[O:28][CH:29]=[CH:30][C:26]=1[CH2:25][CH2:24]2
Reactant: COC(=O)C1=C(C)N(CCc2ccoc2)C(C)=C(C(=O)OC)C1c1ccc(C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C1=C(C)N2CCc3ccoc3C2(C)C(C(=O)OC)C1c1ccc(C)cc1

Procedure:
To a solution of 1 millimole of the dimethyl 2,6-dimethyl-4-(4-methylphenyl)-1-[2-(3-furanyl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate intermediate thus prepared is added under an atmosphere of nitrogen, 3 millimoles of titanium tetrachloride and the mixture stirred overnight at room temperature to obtain the desired dimethyl 4,9,10,10a-tetrahydro-7,10a-dimethyl-9-(4-methylphenyl)-5H-furano[2,3-a]quinolizine-8,10-dicarboxylate product in the reaction mixture. Thereafter, the mixture is diluted with 25 milliliters of chloroform and 25 milliliters of water and the product recovered therefrom in a manner similar to that previously described.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[N:8][N:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[I-].[K+].[C:22](=O)([O-])[O-:23].[K+].[K+].CO>CC(C)=O>[F:17][C:16]1[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH2:18][O:23][CH3:22])=[N:8]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cn(-c2ncccc2F)nc1CBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(-c2ncccc2F)nc1COC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-bromomethyl-1-(3-fluoro-pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.13 g, 3.44 mmol) in acetone (23 mL), potassium iodide (200.1 mg), potassium carbonate (865.33 mg) and methanol (4.18 mL) are added. The mixture is stirred at room temperature for 48 hours. Methyl and ethyl ester of the desired compound are detected. Solvents are evaporated. Residue is diluted with dichloromethane and washed with water. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated. Crude is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to yield 599 mg of a mixture of both methyl and ethyl esters. MS (m/z): 266 (M+1) and 280 (M+1).
Reaction SMILES: Cl[Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][Si:5](Cl)([CH3:7])[CH3:6].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(N(CC)CC)C.P([O-])(O)(O)=O.[Na+].[Cl-].C([NH+](CC)CC)C>ClCCl>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][N:15]1[Si:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][Si:2]1([CH3:10])[CH3:9]
Reactant: NCc1ccc(F)cc1F
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: CC[NH+](CC)CC
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si]1(C)CC[Si](C)(C)N1Cc1ccc(F)cc1F

Procedure:
107.6 g (0.05 mol) of 1,2-bis(chlorodimethylsilyl)ethane are introduced into 200 ml of dichloromethane. A solution of 71.6 g (0.50 mol) of 2,4-difluorobenzylamine and 101.2 g (1.0 mol) of triethylamine in 300 ml of dichloromethane are added dropwise at room temperature over the course of 2.5 hours, to give a white suspension. The end of the reaction is checked by gas chromatography. 400 ml of 10% sodium dihydrogen phosphate solution are then added in order to dissolve the precipitated triethylammonium chloride. The organic phase is separated off, dried using magnesium sulfate, filtered and evaporated on a vacuum rotary evaporator. The turbid oil is taken up in 300 ml of petroleum ether, clarified and re-evaporated. 124.7 g of a colourless liquid which is purified by fractional distillation at 125°-127° C. and 15 mbar are obtained. 85.3 g (60% or theory) of pure product are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15]([CH3:16])=[N:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[C:8]=3[N:9]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c12

Procedure:
In analogy to Example 1 step (c) the title compound was synthesized starting from 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester and 4-benzyloxy-phenylboronic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C.[Ag]=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 84.3 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of dimethylformamide, and 14.0 g of silver oxide are added thereto. 42.6 g of methyl iodide are added to the mixture at room temperature under stirring, and the mixture is further stirred for 2 days in the dark. The reaction mixture is filtered to remove insoluble materials, and the filtrate is concentrated under reduced pressure. The residue obtained is dissolved in ethyl acetate. Then, the ethyl acetate solution is washed with water, dried and concentrated under reduced pressure. The residue thus obtained is washed with n-hexane. 8.45 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 84.3%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:10].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:10]
Reactant: Clc1cncc(Cl)n1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: [O-][n+]1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 15 grams (0.1 mole) of 2,6-dichloropyrazine in 120 milliliters of concentrated sulfuric acid, maintained at 5° C, was gradually added 30 grams (0.11 mole) of potassium persulfate. The reaction mixture was stirred overnight at room temperature and thereafter poured into 400 milliliters of ice water. The resulting solution was thoroughly extracted with chloroform and the extract washed with both a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. The chloroform was thereafter removed by evaporation leaving the 2,6-dichloropyrazine-1-oxide as a white solid residue. The product was recrystallized from methanol and was recovered in a yield of 10.2 grams (62 percent of theoretical). The product melted at 120°-123.5° C, and upon analysis was found to have carbon, hydrogen, nitrogen and chlorine contents of 29.20, 1.42, 17.01 and 42.40 percent, respectively, as compared with the theoretical contents of 29.09, 1.21, 16.97 and 43.03 percent, respectively, calculated for the above-named compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH:20]=[CH:21][CH3:22]>>[CH2:17]([NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH3:22]
Reactant: CC=CCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC=CCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 85° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and hex-4-enylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:20][C:21]3[CH:25]=[C:24]([CH3:26])[O:23][N:22]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Cc1cc(CBr)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2c(-c3cnn(C)c3)cc3cnc(Br)cc32)no1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 0.060 g, 0.217) in anhydrous DMF (0.8 mL) was added sodium hydride 60% (0.013 g, 7.8 mg, 0.325 mmol). The reaction mixture was stirred at room temperature for 5 minutes under argon, then a solution of 3-(bromomethyl)-5-methylisoxazole (0.057 g, 0.325 mmol) in anhydrous DMF (0.3 mL) was added. The stirring was continued at room temp for 1 hour and 50 minutes. The reaction mixture was diluted with ethyl acetate (40 mL) and the solution was washed with water (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 20% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 5% MeOH in ethyl acetate. The silica was removed by filtration, washed with 5% MeOH in EtOAc (2×5 mL), acetone (2×8 mL). The title compound was obtained as an off-white solid (0.065 g, 80%). 1H-NMR (500 MHz, DMSO-d6) 2.31 (s, 3H), 3.89 (s, 3H), 5.58 (s, 2H), 5.89 (s, 1H), 6.75 (s, 1H), 7.78 (s, 1H), 7.83 (s, 1H), 8.12 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:23][S:20]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=1)(=[O:22])=[O:21])(=[O:26])[CH3:25]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and acetyl chloride, gave N-acetyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].O>ClCCl>[CH3:8][S:9]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:25])([F:13])[C:21]([F:22])([F:23])[F:24])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCC(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Triethylamine (25.83 ml, 185.3 mmol) and methanesulfonyl chloride (6.9 ml, 88.9 mmol) were added dropwise to a solution of 6,6,7,7,7-pentafluoroheptan-1-ol (14.1 g, 74.1 mmol) in dichloromethane (350 ml) at 0° C., followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give 1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, Yield 82%).