Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]([C:31]#[N:32])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5.48 mg, 0.0275 mmol), 3-(1-aminoethyl)-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.00480 mL, 0.0276 mmol) in ethanol (0.05 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H17FN7 (M+H)+: m/z=410.2; Found: 410.1.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([C@@H:30]2[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]2[O:32][C:33](=[O:35])[CH3:34])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1
Reactant: Clc1cc2[nH]c(Br)nc2c(Cl)c1Cl
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2c(Cl)c(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
2-Bromo4,5,6-trichloro-1H-benzimidazole (0.3 g, 1 mmol), acetonitrile (10 mL), and N,O-bis(trimethylsilyl)acetamide were stirred at 70° C. for 15 min., giving a homogeneous solution. To the solution was then added 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The resulting mixture was allowed to stir at 70° C. for 20 min. The mixture was then allowed to cool to RT and was diluted with ethyl acetate and was washed with a saturated aqueous NaHCO3 solution, dried over NaSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using chloroform as eluent and then recrystallization from methanol afforded 0.29 g (58%) of the title compound as white crystals; m.p. 160-162° C.; 1H NMR (DMSO-d6) δ: 8.14 (s, 1H), 6.16 (d, 1H), 5.63 (t, 1H), 5.27 (dd, 1H), 4.26 (m, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([CH2:6]N(C)C)=[C:4]([OH:13])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]([OH:13])=[C:5]([CH3:6])[CH:10]=1
Reactant: CN(C)Cc1cc(F)c(F)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(F)c(F)cc1O

Procedure:
214 g of 4,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine are initially charged in 700 ml of acetic acid in an autoclave, admixed with 50 g of palladium/activated carbon (5%) and heated with 70 bar of hydrogen to 100° C. for 26 hours. The autoclave is cooled and decompressed. The catalyst is filtered off and washed with acetic acid, and the filtrate is admixed with 3 000 ml of water. This aqueous solution is extracted three times with methyl tert-butyl ether. The combined organic phases are washed once with water and dried, and the solvent is distilled off under reduced pressure. The crude product is fractionally distilled under reduced pressure. The distillate can be further purified by crystallization. 98 g (58% of theory) of a colourless solid are obtained having a melting point of 68-70° C. and a boiling point of 78-80° C. at 13 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[F:21][C:4]1[CH:3]=[C:2](/[N:1]=[CH:30]/[C:28]2[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=2)[CH2:10][CH2:9]1
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 85 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7f, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (9f, 352 mg, 85%).
Reaction SMILES: O[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31].C(C(CCCC)C([O-])=[O:39])C.[Sn+2].C(C(CCCC)C([O-])=O)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:30]([NH:32][C:33](=[O:39])[O:34][C@H:6]1[CH2:2][CH2:3][N:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])=[CH:9][CH:8]=2)[CH2:5]1)[CH3:31]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](O)C2)cc1
Reactant: CCN=C=O
Agent: [Sn+2]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)O[C@H]1CCN(c2ccc(C(=O)Nc3ccccc3N)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of 161 (100 mg, 0.25 mmol) and ethyl isocyanate (29 μL, 28 mg, 0.375 mmol) in dichloromethane (5 mL) was treated with tin(II) 2-ethylhexanoate (44 μL, 55 mg, 0.135 mmol). The reaction mixture was stirred overnight at r.t. under nitrogen, concentrated and the residue was purified by flash chromatography using gradient 70 to 90% EtOAc in hexanes as an eluent. The material obtained was then dissolved in 2:1 mixture of dichloromethane and TFA (3 mL), stirred for 30 min and concentrated. The residue was then dissolved in EtOAc (5 mL) and washed with saturated NaHCO3 solution (5 mL), dried over Na2SO4, filtered and concentrated to afford title compound 162 (39 mg, 42% yield). 1H NMR: CDCl3 δ(ppm): 7.7 (d J=8.8 Hz, 2H), 7.6 (s, 1H), 7.2 (d, J=7.6 Hz, 1H), 7.0 (t, J=8.8 Hz, 1H), 6.8 (t, J=7.8 Hz, 2H), 6.5 (d, J=8.8 Hz, 2H), 5.3 (s, 1H), 4.6 (s, 1H), 3.9 (s, 2H), 3.6 (m, 1H), 3.4 (m, 3H), 3.1 (m, 2H), 2.2 (m, 2H), 1.2 (s, 1H), 1.1 (m, 3H). LRMS (ESI): (calc) 368.18 (found) 369.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH:30]=O)=[CH:24]3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:29][CH:28]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of 5-bromo-2-oxindole (46 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (64%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:30])[CH3:29].Cl>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:30][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.47 g, 1.09 mmol), ethanamine (1 ml, 70% in water) and ACN (7 ml). Yield: 0.278 g, 83%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 267° C. MS m/z (rel. intensity, 70 eV) 305 (M+, 4), 63 (3), 59 (4), 58 (bp), 56 (5). [α]=−62° (MeOH).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5]([OH:18])([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>CCOC(C)=O.[Pd]>[F:1][C:2]1([F:19])[CH2:3][CH2:4][C:5]([OH:18])([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1(O)CCC(F)(F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1(O)CCC(F)(F)CC1

Procedure:
Benzyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate (2.76 g, 10.21 mmol) was dissolved in 68 mL of EtOAc and a suspension of 10% Palladium on Carbon (1.1 g in 5 mL of EtOAc) was added. The mixture was stirred at room temperature under at atmosphere of hydrogen for 45 minutes (balloon), and the reaction mixture was filtered through a glass micropore filter and concentrated under vacuum to provide 4,4-difluoro-1-hydroxy-cyclohexanecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc([C@@H](C)O)ccc1Br
Yield: 71.2 %

Procedure:
A mixture of 1-(4-bromo-3-methylphenyl)ethanone (27.3 g, 128 mmol) and (S)-2-Methyl-CBS-oxazaborolidine (3.6 g, 12.8 mmol) in dichloromethane (500 mL) was added dimethylsulfide-borane (64 mL, 2M in tetrahydrofuran) dropwise at −20° C. and maintained at the same temperature for 2 hours. Acetic acid (15 mL) was added to quench the reaction. The resultant mixture was concentrated to give a residue. Then the mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give (R)-1-(4-bromo-3-methylphenyl)ethanol (19.6 g, 71%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (11.88 g, 40.0 mmol) and NH4Cl (22.4 g, 419 mmol) in EtOH (200 mL) and water (200 mL) was treated portion-wise with iron powder (22.4 g, 401 mmol), stirred for 0.5 h, treated with additional NH4Cl (22.4 g, 419 mmol) and iron powder (22.4 g, 401 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth and washed with EtOAc and DCM. The filtrate was washed with water, the aqueous layer back-extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (6.4 g, 60%). MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH:29]=[C:30]([CH3:32])[CH3:31]>C(O)C>[CH2:28]([N:33]1[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:37][CH2:38]1)[CH:29]=[C:30]([CH3:32])[CH3:31]
Reactant: CC(C)=CCN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 62 %

Procedure:
A mixture of 6.6 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one, 2.56 g of sodium carbonate and 4.0 g of 1-prenylpiperazine was refluxed in 90 ml of absolute ethanol for 2 hours. Then, the reaction mixture was vacuum filtered while still hot and the filtrate was evaporated to a volume of about 20 ml. The crystallized precipitate was vacuum filtered and the product was crystallized from isopropanol to obtain a 62% yield of 5,11-dihydro-11-[3-(4-prenyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][CH2:14]2.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:20]=[CH:19][C:18]=1[C:16]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: Clc1ccc(Br)cc1
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A Grignard-solution prepared from 220 grams (1.15 mol) of p-chlorobromobenzene and 29 grams of magnesium turnings (1.2 mol) in 1500 milliliters of dry ether was added dropwise in the course of one hour to a suspension of 213 grams of 5-bromphthalide (1 mol) in 1500 milliliters of dry tetrahydrofuran. The temperature was not allowed to rise over 10 degrees Centigrade. After the addition was completed the reaction mixture was stirred for three hours at room temperature. The mixture was then poured into 2 liters of icewater and 100 milliliters of saturated aqueous ammonium chloride were added. The etherphase was separated and the water-tetrahydrofuranphase extracted once with 500 milliliters of ether. The etherphase was washed with water, dried over anhydrous magnesiumsulphate, filtered and evaporated in vacuum to yield 320 grams of 2-hydroxymethyl-4-bromo-4'-chloro-benzophenone in the form of a yellow oil which was not purified further but used directly in the next step. The 320 grams of oil were dissolved in 200 milliliters of dry tetrahydrofuran and added dropwise to a great excess of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran under gentle reflux. After completed addition the mixture was refluxed over night. The reaction mixture was then poured into 5 liters of icewater and 200 milliliters of saturated aqueous ammonium chloride solution added. The mixture was extracted with a total of 2500 milliliters of ether. The etherphase was then extracted with 20% aqueous acetic acid to acid reaction, whereupon the acetic acid solution was made alkaline with 10 N sodiumhydroxide solution. After cooling, the oil, which separated out, was extracted twice with 500 milliliters of ether. The combined ether extracts were dried over anhydrous potassium carbonate, treated with active carbon and evaporated in vacuum. The remaining oil consists of somewhat impure (4-bromo-2-(hydroxymethyl)phenyl)-(4-chlorophenyl)-(3-dimethylaminopropyl)methanol which was used in the next step without further purification. Yield: 219 grams.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C@H:11]([O:14][CH2:15][O:16][CH3:17])[CH:12]=[CH2:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C@H:11]([O:14][CH2:15][O:16][CH3:17])/[CH:12]=[CH:13]/[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCCCCCCCCCCC
Reactant: C=C[C@@H](OCOC)[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](OCOC)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of alcohol 6 (230 mg, 0.88 mmol) in CH2Cl2 (8 mL) was added 1-pentadecene (741 mg, 3.52 mmol). The solution was degassed twice using N2 (2×10 min). To the reaction mixture was added benzylidene[1,3-bis(2,4,6-trimethyl -phenyl)-2-imidazolidinylidene]dichloro-(tricyclohexylphosphine)ruthenium catalyst (22.4 mg, 0.026 mmol) at rt under N2. After the reaction mixture was stirred for 4 h under reflux, the solvent was removed and the product was purified by chromatography (hexane/EtOAc 4:1) to afford 7 (280 mg, 72%): Rf0.45 (EtOAc/hexane 1:3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.0 Hz), 1.25 (m, 24H), 1.44 (m, 9H), 2.06 (q, 2H, J=7.7 Hz), 2.89 (d, 1H, J=5.2 Hz), 3.38 (s, 3H), 3.67 (m, 2H), 3.94 (dt, 1H, J=3.2, 11.1 Hz), 4.22 (dd, 1H, J=5.0, 7.6 Hz), 4.53 (d, 1H, J=6.6 Hz), 4.67 (d, 1H, J=6.6 Hz), 5.26 (d, 1H,J =7.6 Hz), 5.36 (dd, 1H, J=8.0, 15.4 Hz), 5.75 (dt, 1H, J=6.6, 14.6 Hz); 13C NMR (CDCl3) δ 14.1, 22.7, 28.4, 29.0, 29.1, 29.3, 29.4, 29.6, 29.7, 31.9, 32.3, 54.9, 55.6, 62.3, 76.1, 78.3, 79.4, 93.8, 125.9, 136.9, 155.9; ESI-HRMS [M+Na]+C25H49NO5Na calcd for m/z 466.3508, found 466.3514.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14].O.[CH3:16][N:17](C)[CH:18]=O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([N:17]([CH3:18])[CH3:16])[C:6]=2[C:13]#[N:14]
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc2cc(Cl)cnc2c1C#N
Yield: 87 %

Procedure:
110 g of 3,7-dichloro-8-cyanoquinoline in 500 ml of dimethylformamide were refluxed for 20 hours, the solution was cooled, an amount of water corresponding to half the volume of the solution was added, and the precipitated solid was filtered off under suction. 100 g of 3-chloro-8-cyano-7-dimethylaminoquinoline of melting point 174° C. were obtained. Yield: 87% of theory.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)(=[O:4])=[O:3].C(=O)(OCC=C)O[CH2:24][CH:25]=[CH2:26].C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][S:2]([CH:5]([C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)[CH2:26][CH:25]=[CH2:24])(=[O:4])=[O:3]
Reactant: COc1nc2cc(Cl)c(Cl)c(CS(C)(=O)=O)c2nc1OC
Reactant: C=CCOC(=O)OCC=C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CCC(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methyl methyl sulphone (50 mg, 0.142 mmol) (Preparation 29) and diallyl carbonate (41 μl, 40 mg, 0.285 mmol) in dry tetrahydrofuran (0.8 ml) was added via cannula to a mixture of tris(dibenzylideneacetone)dipalladium (0 ml).chloroform adduct (7.4 mg, 0.007 mmol) and 1,2-bis(diphenylphosphino)ethane (11.3 mg, 0.028 mmol) in dry tetrahydrofuran (0.6 ml) under nitrogen at room temperature. The mixture was stirred at room temperature for 5 minutes and then at reflux for 2 hours. The mixture was allowed to cool, was diluted with dichloromethane and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 3:1 hexane:ethyl acetate) to give 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphone as a mixture of diastereoisomers (approximately 20:1 by
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[CH:10]([CH:12]=[CH2:13])=[O:11]>O1CCCC1>[CH:12]([CH:10]([OH:11])[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)=[CH2:13]
Reactant: BrCCC1OCCO1
Reactant: C=CC=O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)CCC1OCCO1
Temperature: -78 °C
Yield: 46 %

Procedure:
A dry, 3-necked flask equipped with argon inlet, stirring bar, and dropping funnel was charged sequentially with magnesium turnings (1.047 g, 43.05 g-atom) and a solution of 2-(2-bromoethyl)-1,3-dioxolane (6 g, 33.14 mmole) in tetrahydrofuran (70 ml). The reaction vessel was placed in an ultrasonic cleaning bath and subjected to sonication for 2.5 hours with occasional swirling while maintaining the bath temperature at 25°-30° C. The brown mixture was then cooled to -78° C. and treated dropwise with freshly distilled acrolein (2.21 ml, 33.14 mmole) in tetrahydrofuran (15 ml). The resulting thick mixture was stirred at -78° C. for an additional 30 minutes, the cooling bath was replaced with an ice bath and the reaction was quenched with a saturated sodium sulfate solution (ca. 30 ml), followed by solid sodium sulfate. The clear supernate was decanted from the precipitated solids which were washed with ethyl acetate (3×100 ml). The combined washings were dried (sodium sulfate), filtered, and concentrated in vacuo of 4.28 g of oil. The crude product was chromatographed on 140 g of silica gel (230-400 mesh) with 40% ethyl acetate:hexane to afford 2.41 g of the title compound as a clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])([CH3:29])[CH3:28])#[N:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=3)[N:13]=2)[CH:23]=1)=[O:34])([CH3:29])[CH3:28])#[N:26]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 70.3 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (92 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (160 mg, 70%) was obtained as a white powder.