Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)[C:5](=[O:20])[C:4]=2[CH:3]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17]2[C:13](=[CH:12][C:11]([N:6]3[CH:7]=[CH:8][C:9]4[O:10][C:2]([Br:1])=[CH:3][C:4]=4[C:5]3=[O:20])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cn1ncc2cc(-n3ccc4oc(Br)cc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a solution of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (1.13 g, 3.41 mmol) in DMSO (10.5 mL) was added methyl bromoacetate (0.64 mL, 6.8 mmol) and Cs2CO3 (4.44 g, 13.6 mmol). The reaction mixture was stirred at ambient temperature for 18 h; then additional methyl bromoacetate (0.30 mL) was added. After 3 h, additional methyl bromoacetate (0.30 mL) was added. The reaction mixture was stirred for 3.5 h and then the reaction mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (4×25 mL). The extracts were washed with brine (3×25 mL), dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MTBE, 4:1) yielded the title compound (0.77 g, 56%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (s, 1H), 7.43 (s, 2H), 7.30 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.60 (d, J=7.0 Hz, 1H), 5.21 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH2:25](Br)[CH3:26].O>C1C=CC=CC=1>[CH2:25]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1)[CH3:26]
Reactant: CCBr
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (0.08 g) in benzene was added a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.5 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. to the reaction mixture was added a solution of ethyl bromide (0.22 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)#[N:25]
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(Cl)cc1-c1cn[nH]c1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cn[nH]c1
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
25.0 mg (0.05 mmol) of 4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 10.5 mg (0.08 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 5.8 mg (10 mol %) of Pd(PPh3)4, 20.7 mg (0.15 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: [C:1]([C:5]1[Se:13][C:12]2[C:11](=[O:14])[NH:10][N:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.[I-].[K+]>CC(C)=O>[C:1]([C:5]1[Se:13][C:12]2[C:11](=[O:14])[N:10]([CH3:15])[N:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc2nn[nH]c(=O)c2[se]1
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2cc(C(C)(C)C)[se]c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 6-(tert-butyl)-3H-selenopheno[3,2-d]1,2,3-triazin-4-one (2.0 g, 7.78 mmol) in acetone (70 mL) was added sequentially potassium carbonate (2.14 g, 15.56 mmol), iodomethane (0.58 mL, 9.3 mmol) and potassium iodide (catalytic) at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using chloroform-methanol (95:05) as eluents to give the product as a off-white color solid (1.0 g, 47%), which was recrystallized from chloroform-methanol (700 mg, 34%), mp 98-100° C. IR (neat) νmax 2961, 1679, 1242, 1220, 1001, 969 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.58 (1H, s, H-7), 4.04 (3H, s, —NCH3), 1.48 (9H, s, tert-butyl); 13C NMR (100 MHz, CDCl3): δ 176.0, 157.5, 154.7, 128.8, 121.5, 37.5, 37.3, 32.5; LC-MS (positive ion mode): m/z 292, 294 (M+Na)+.
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)=[O:2].[CH3:45][Mg]Br.C([SiH](CC)CC)C>C1COCC1>[OH:2][CH:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][NH:11][C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38])=[O:35])[N:4]=1)[CH3:45]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12
Reactant: C[Mg]Br
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(C)O)c12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(R)-1-(4-Formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (114 mg, 0.196 mmol) was dissolved in THF (3 mL), cooled to −78° C., and charged with methylmagnesium bromide (0.196 mL, 0.588 mmol). The reaction was allowed to warm to 0° C. and stirred for 10 min. The reaction mixture was quenched with saturated ammonium chloride (3 mL), extracted with EtOAc (10 mL, ×2), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in TFA (0.8 mL), charged with triethylsilane (0.031 mL, 0.196 mmol), and stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (2 mL) and TEA (1 mL) to free-base the product. The solvents were removed in vacuo and the residue was purified by flash chromatography (10-100% EtOAc/DCM) to give 1-(4-(1-hydroxyethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((R)-1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3].[Cl:14][S:15](O)(=[O:17])=[O:16].S(Cl)(Cl)=O>C(Cl)Cl>[Cl:14][S:15]([C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A solution of 2-n-propoxybenzoic acid (20 g, 111 mmol) in DCM (40 ml) was added dropwise over 30 min to a mixture of chlorosulphonic acid (30 ml, 440 mmol) and thionyl chloride (8.1 ml, 110 mmol) at −10° C. whilst keeping the temperature below 0° C. The mixture was slowly warmed to 20° C. and stirred for 18 h. The reaction mixture was cautiously poured onto crushed ice (260 g), keeping the temperature below 0° C. The ice slurry was stirred for 20 min and then the precipitated white solid was filtered, washed with H2O (20 ml), dissolved in DCM (200 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a yellow solid (31.2 g, 103 mmol, 92%); mp 121-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[O:15][CH3:16].Br[CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[O:15][CH3:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCBr
Reactant: COc1cc(C2=NNC(=O)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC

Procedure:
11.0 g of 6-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-3[2H]pyridazinone are heated under reflux together with 8.2 g of 1-bromobutane and 8.3 g of potassium carbonate in 150 ml of anhydrous acetone for 20 hours. Thereafter, the starting compound can no longer be detected by thin-layer chromatography. The suspension is filtered hot, the filter cake is washed out with hot acetone and the filtrates are combined and evaporated in vacuo. The semi-solid residue [6-(4-n-butoxy-3-methoxyphenyl)4,5-dihydro-3[2H]pyridazinone]is taken up in 50 ml of ethanol, 10.0 g of sodium hydroxide in 200 ml of water and 14.6 g of sodium meta-nitrobenzenesulfonate are added and the mixture is heated under reflux for 2 hours. After cooling, it is acidified to pH 1-2 with concentrated hydrochloric acid, the crystalline solid is filtered off with suction and the solution is extracted several times with chloroform. The residue from the chloroform extract is combined with the crystals and the product is recrystallized from ethanol/ethyl acetate. 8.7 g (63.7% of theory) of the title compound of m.p. 193° are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 97.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (30 g, 0.16 mol) in acetonitrile (300 mL) was added K2CO3 (114.9 g, 0.83 mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. The reaction mixture was refluxed for 16 h. The reaction mixture was then filtered and the solid residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (50 g, 93.4%) as a solid.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13])=[NH:5])#[N:2].[ClH:14].C([OH:18])(C)C>>[ClH:14].[ClH:14].[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]([NH2:2])=[O:18])=[NH:5]
Reactant: Cc1[nH]cnc1CNC(=N)NC#N
Reactant: CC(C)O
Agent: Cl
Product: Cc1[nH]cnc1CNC(=N)NC(N)=O

Procedure:
1.80 g. (0.0101 mole) N-cyano-N'-[(5-methyl-4-imidazolyl) methyl] guanidine is taken up in 100 ml. isopropanol. 2.5 ml. conc. HCl is added. The reaction mixture is then heated for 20 minutes to reflux and refluxed for 65 minutes to obtain complete hydrolysis. The mixture is then cooled and filtered. The material is then recrystallized from MeOH/CH3CN to obtain 1-[(5-methyl-4-imidazolyl)methylamidino]urea dihydrochloride with a m.p. of 214°-214.5° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[OH:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCc5ccccc5)c34)CC2)CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(O)c34)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
A mixture of methyl 4-{[4-(2-{[4-(benzyloxy)-1,2-benzisoxazol-3-yl]oxy}ethyl)piperidin-1-yl]-methyl}tetrahydro-2H-pyran-4-carboxylate (3.2 g, 6.3 mmol, EXAMPLE 7, step 5) and 10% Pd—C (0.30 g) in tetrahydrofuran (20 mL) and methanol (40 mL) was stirred at room temperature for 10 min under hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 3:1 to 3:2) to give 2.2 g (83%) of the title compound as a pale yellow solid.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: C#C[Si](C)(C)C
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 12, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with trimethylsilylacetylene to give the title compound as brown oil. MS: 503.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ncccn4)cc3)c12
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ncccn3)cc2)c2c(N)nccn12
Yield: 26.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide (intermediate 27) and acryloylchloride, to afford the title compound (5.9 mg, 26.2%). Data: UPLC(C) Rt: 1.70 min; m/z 469.3 (M+H)+.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH3:17].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCCO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 91.6 %

Procedure:
Ferulic acid (4.85 g) and then n-propyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux overnight. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (5.48 g, 91.6%) as colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:14])[CH:10]2[CH3:13])[CH2:5][CH:4]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH2:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:24]([CH2:25][CH3:26])=[C:16]([Br:15])[CH:17]=3)[CH:12]=2)[CH2:7][CH2:8][N:9]1[CH3:14]
Reactant: CC1C2=CC(N)=CCC2CCN1C
Reactant: CCc1ccc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)Nc2ccc3c(c2)C(C)N(C)CC3)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline mono hydrochloride (0.106 g, 0.50 mmol) in dichloromethane (10 ml) was sequentially treated with 3-bromo-4-ethylbenzoyl chloride (0.124 g, 0.50 mmol) and triethylamine (0.3 ml, 2.2 mmol). The mixture was stirred at ambient temperature for 18 h. Evaporation in vacuo gave an oily residue which was purified by chromatography through silica gel eluting with (0.5% conc. ammonia: 4.5% methanol: 95% dichloromethane). The title compound was obtained as an off-white foam (0.149 g, 77%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[OH-].[Na+].[I:18]I>O>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[C:4]=1[I:18])[CH3:2]
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1I
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A mixture of 8.18 g (40.9 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone, 1.68 g (42.0 mmol) of sodium hydroxide, 10.42 g (41.0 mmol) of iodine and 50 mL of water was heated at 50° C. for 4 h. The mixture was cooled and filtered. The white solid collected was dried in a vacuum oven to leave 12.60 g (75%) of 6-ethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone. 1 H-NMR (d6-DMSO) δ 1.25(3H,t), 2.85(2H,q), 7.50(3H,m), 8.15(2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:36])[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Product: COc1ccccc1-n1nc2c(c1C(C)C)C(C)(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88, 3 equivalents of KHMDS and 2 equivalents of methyl iodide. The reaction mixture was stirred for 2 h at rt. The crude material was purified by silica gel column chromatography (hexane/EtOAc, 4:1) followed by preparative HPLC (Column: AG/PP/C-18-15/025. Flow: 20 mL/min. Gradient: 25% B; A=0.1% TFA in water, B=acetonitrile/MeOH, 1:1). tR: 6.92 min (HPLC 2); ESI-MS: 524.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4].Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:22][CH2:21]1.C>CS(C)=O.C(O)(C)C>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH2:22][CH2:21]2)=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc(NC(C)=O)ccc1O
Reactant: Fc1ccccc1N1CCN(CCCCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2F)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1.13 g of powdery sodium hydroxide are added under nitrogen atmosphere to a solution of 5.08 g of 4-acetamido-2-methoxyphenol in 70 ml of anhydrous dimethylsulfoxide. The mixture is stirred at 50° C. for 2 hours. A solution of 6 g of 1-(3-chloro-n-propyl)-4-(2-fluorophenyl)-piperazine in 20 ml of anhydrous dimethylsulfoxide is added dropwise at 20° C. to the mixture, and said mixture is stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture is poured into ice-water. The crystalline precipitates are collected by filtration, whereby a crude product is obtained. The mother liquor obtained after isolating the crude product is extracted with chloroform. The extract is washed with water, dried and then evaporated under reduced pressure to remove the solvent, whereby another crude product is obtained. Both crude products obtained above are dissolved in hot isopropyl alcohol and then treated with activated charcoal. 6.95 of 1-[3-(4-acetamido-2-methoxyphenoxy)-n-propyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless needles. Yield: 74%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:23])[C:19]([Cl:22])([Cl:21])[Cl:20])[CH2:11][C:10](=[O:12])[NH:9][C:7]1=[O:8])=[O:5])[CH3:2].S(Cl)([Cl:27])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:27][C:16]1[CH:15]=[C:14]([C:18](=[O:23])[C:19]([Cl:22])([Cl:20])[Cl:21])[N:13]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C:10](=[O:12])[NH:9][C:7]2=[O:8])[CH:17]=1
Reactant: CCOC(=O)C1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(n2cc(Cl)cc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a stirred solution of 2-ethoxycarbonyl-2-(2-trichloroacetylpyrrol-1-yl)succinimide (6.0 g) in chloroform (50 ml) was added dropwise a solution of sulfuryl chloride (4.8 g) in chloroform (5 ml) under ice cooling. The resulting mixture was stirred under ice cooling for 30 minutes, poured into water, and extracted with chloroform. The extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (2:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.5 g, 41.7%) as colorless crystals, mp 182°-185° C.