Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][OH:29])=[CH:25][CH:26]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC=O)cc3)CC2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CCO)cc3)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product of step B (70 mg, 0.18 mmol) was dissolved in DCM/MeOH (1/1, 4 mL) at 0° C., and sodium borohydride (30 mg, 0.8 mmol) added. The solution was stirred at 0° C. for 1 h. The solution was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) followed by reverse phase HPLC (C18, 10-100% water/acetonitrile with 0.1% formic acid gradient) which yielded the title compound. MS (ESI) m/z 396 [M+H]+. GPR119 Human EC50: 2.5 nM
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:32][CH2:31][O:33][CH2:34][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: C([O:4][C:5]1[C:6]2[C:11]([CH:12]=[C:13]([O:18][CH2:19]C)[C:14]=1[O:15][CH2:16]C)=[N:10][C:9](=[O:21])[C:8](=[O:22])[N:7]=2)(=O)C.[OH-].[Na+].Cl>O>[OH:4][C:5]1[C:6]2[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[O:15][CH3:16])=[N:10][C:9](=[O:21])[C:8](=[O:22])[N:7]=2
Reactant: CCOc1cc2c(c(OC(C)=O)c1OCC)=NC(=O)C(=O)N=2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Yield: 91 %

Procedure:
5-Acetyloxy-6,7-dimethoxy-2,3-quinoxalinedione (47) (30 mg, 0.107 mmol) was added to a single-necked 15-mL flask. Sodium hydroxide aqueous solution (2 N, 1 mL) was added to the flask under nitrogen with stirring. The solution was then stirred at room temperature for 24 h. The solution was diluted with water (3 mL) and then acidified with HCl (4 N, 1 mL) to pH=2 to give a brown solid, which was collected by filtration and dried in vacuo, giving 23 mg (86%) of the title compound; mp 285-286° C. (dec); 1H NMR (DMSO-d6, 300 MHz) δ 3.688 (s, 3 H), 3.694 (s, 3 H), 6.227 (s, 1 H), 9.769 (s, 1 H), 11.016 (s, 1 H), 11.658 (s, 1 H). EIMS m/e 238 (100, M+), HPLC purity>96%.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:19]3[O:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][O:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][C:5]([CH3:36])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:13][CH:12]=4)[N:18]=3)[CH:24]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccc(F)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-[4′-fluorobiphenyl-3-yl]-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-(4-{2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid (7.57 g, 67%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.12 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, DMSO-d6) δ8.02 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.77-7.73 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.30 (t, J=9.2 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 6.78 (d, J,=9.2 Hz, 2H), 4.14 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.39 (s, 6H); MS (EI) 476.2 (M+H)+, 474.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O>CC(C)=O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)c(C)s1
Yield: 104.3 %

Procedure:
30 mg (0.122 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2 mL of reagent grade acetone. 2-bromo-4′-methoxy acetophenone (0.146 mmol; 28 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo to afford 46 mg (90% yield) of methyl 4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([NH:22][C:23]3[N:28]=[C:27]([N:29]([CH:39]4[CH2:41][CH2:40]4)CC4C=CC(OC)=CC=4)[C:26]4=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]4[N:24]=3)[C:15]=2[Cl:47])[CH2:10][CH:9]1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=O)(C)(C)C.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[Cl:47][C:15]1[C:16]([NH:22][C:23]2[N:28]=[C:27]([NH:29][CH:39]3[CH2:40][CH2:41]3)[C:26]3=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]3[N:24]=2)=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:48]([N:49]([CH3:51])[CH3:50])=[O:52])[CH2:10]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 135.1 %

Procedure:
Tert-butyl-4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (200 mg, 0.275 mmol) was taken up in DCM (2 mL) and cooled to 0° C. 2,6-Lutidine (0.096 mL, 0.826 mmol) was added, followed by drop wise addition of TMS-OTf (0.149 mL, 0.826 mmol). The reaction was stirred at 0° C. for 10 min, then brought to room temperature and stirred for 20 min. The reaction was quenched with 2M K3PO4 solution and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 188 mg of a yellow solid. The material was purified by flash column chromatography (0-70% 10% MeOH/DCM; 24 g column). 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (133 mg) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[O:11].[H][H]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11]
Reactant: [H][H]
Reactant: O=CCCc1ccccc1O
Product: OCCCc1ccccc1O

Procedure:
A process as claimed in claim 1, wherein the 3-(hydroxyphenyl)propionaldehyde I obtained as the product in a first step is hydrogenated in a second step by reaction with hydrogen in the presence of a hydrogenation catalyst at from 0° to 250° C. and under from 0.1 to 300 bar to obtain the corresponding 3-(hydroxyphenyl)propanol of the formula II ##STR14## where R1, R2, R3 and R4 have the same meanings as in claim 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]([C:23]2[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:25][C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[C:28]([C:38](=[O:41])[NH:39][CH3:40])[C:27]=3[CH:42]=2)=[CH:9][N:8]=1)(=O)=O.[CH2:51]([Sn](CCCC)(CCCC)C=C)[CH2:52]CC.[Li+].[Cl-]>CN(C=O)C.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>[F:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[C:13]([C:12]1[N:11]=[C:10]([C:23]3[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:45])=[O:46])=[CH:25][C:26]4[O:30][C:29]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[C:28]([C:38]([NH:39][CH3:40])=[O:41])[C:27]=4[CH:42]=3)[CH:9]=[N:8][C:7]=1[CH:51]=[CH2:52])[NH:14]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc(OS(=O)(=O)C(F)(F)F)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a mixture of 3-(4-fluoro-1H-indol-2-yl)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyrazin-2-yl trifluoromethanesulfonate (30 mg, 0.04 mmol), tributyl(vinyl)stannane (16 mg, 0.05 mmol) and LiCl (5 mg, 0.12 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg) under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 1 h, concentrated and purified by prep-TLC (PE:EA=1:1) to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-vinylpyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 8.10 (s, 1H), 7.86˜7.89 (m, 2H), 7.57˜7.61 (m, 2H), 7.38˜7.44 (m, 3H), 7.04˜7.19 (m, 3H), 6.71 (t, J=8.0 Hz, 1H), 6.50˜6.54 (m, 1H), 5.89 (br s, 1H), 5.71˜5.74 (m, 1H), 3.11 (s, 3H), 2.91 (s, 6H). MS (M+H)+: 614.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([C:24]([OH:31])([CH3:30])[CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:44].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:44][C:17]([C:19]4[S:20][C:21]([C:24]([OH:31])([CH3:30])[CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(OC)C(C)(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(OC)C(C)(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxy-2,2-dimethoxy-1-methylethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.14 g), ammonium acetate (0.76) and acetic acid (8 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.55 g, yield 50%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 561 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54](Cl)(=[O:56])=[O:55])(=[O:44])=[O:43])=[C:37]([CH3:58])[CH:36]=1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:58])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:9][CH2:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:15][CH2:14]2)(=[O:55])=[O:56])(=[O:44])=[O:43])=[C:39]([CH3:41])[CH:40]=1
Reactant: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CC2)CCC(OCCN2CCCC2)(c2cccnc2)CC3)c(C)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
9-(Pyridin-3-yl)-9-(2-(pyrrolidin-1-yl)ethoxy)-3-azaspiro[5.5]undecane (0.26 mmol, 1 eq) was dissolved in methylene chloride (3 ml) at 0° C., triethylamine (1.04 mmol, 4 eq) was added, and 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (0.26 mmol, 1 eq), dissolved in methylene chloride (2 ml) was added to the mixture. After 1 h at room temperature, the mixture was diluted with methylene chloride (20 ml). The organic phase was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (1-5% methanol in methylene chloride). Yield: 47%. MS, Rt=3.6 min, m/z=731.5 [MH]+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11]CC2C=CC=CC=2)=[C:4]1[CH2:19][O:20][CH3:21]>CO.O.[Pd]>[ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([OH:11])=[C:4]1[CH2:19][O:20][CH3:21]
Reactant: COCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COCc1c(O)c(=O)cc(C)n1C
Yield: 86.5 %

Procedure:
1,6-Dimethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one hydrochloride (1.55 g, 5 mmol) was dissolved in methanol (40 ml)/water (10 ml) and hydrogenated for 4 hours in the presence of 5% Pd/C (0.3 g). Following filtration the filtrate was concentrated in vacuo and the crude material recrystallised from methanol/diethyl ether gave the pure title compound (0.95 g, 86.5%) as a white crystalline solid. m.p. 156-159° C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)C3)=[CH:27][CH:28]=2)[N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12
Temperature: 80 °C

Procedure:
The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8 mg 0.200 mmol), 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline(79.1 mg, 1.2 eq.), Pd(PPh3)4 (14.0 mg, 6% eq.) and Na2CO3 (53.0 mg, 2.5 eq.) in DMF (5 ml)/H2O (1 ml) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under N2. After that time, the reaction mixture was treated with H2O (20 ml), and was then extracted with CH2Cl2 (2×25 ml). The extracts were washed with H2O (2×20 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, the crude yellow oil (105 mg) was purified by MS directed purification system to obtain a yellow solid of 3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.09 (m, 1H), 2.15-2.22 (m, 1H), 2.48-2.56 (m, 2H), 2.62-2.72 (m, 2H), 3.85 (quintet, 1H, J=8.4 Hz), 5.27 (s, 2H), 7.09-7.10 (d, 1H, J=4.8 Hz), 7.15-7.16 (d, 1H, J=4.8 Hz), 7.36-7.39 (m, 1H), 7.86-7.90 (m, 1H), 7.97(m, 2H), 8.31-8.33 (d, 1H, J=8.8 Hz), 8.43 (s, 1H), 8.59-8.61 (d, 1H, J=8.8 Hz), 8.67-8.69 (d, 1H, J=7.6 Hz), 8.75-8.76 (d, 1H, J=4.0 Hz); MS(ES+): 393.4 (M+1), tR(polar-5 min)=2.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([CH:12]([CH2:24][CH2:25][CH2:26][CH:27]([OH:37])[CH2:28]OC1C=CC(F)=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])[CH3:10]>>[C:9]([CH:12]([CH2:24][CH2:25][CH2:26][CH:27]([OH:37])[CH2:28][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])[CH3:10]
Reactant: Fc1ccc(S)cc1
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Product: CCOC(=O)CCCCCCC(CCCC(O)CSc1ccc(F)cc1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of 4-fluorothiophenol is substituted for the 4-fluorophenol of Example 1, Step E.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([O:18]CC3C=CC=CC=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In methanol was suspended 151 g (452 mmol) of phenylmethyl 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylate, 15 g of 5% palladium-active carbon was added to the suspension and the mixture was stirred under hydrogen stream at room temperature overnight. After removing the catalyst by filtration, the catalyst was washed three times with a mixed solvent of chloroform-methanol, and the organic layers were combined and the solvent was distilled off under reduced pressure to obtain 112 g (Yield: 100%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH3:16])=[CH:4][N:3]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[CH:18]1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:26][C:21]3[C:20]4[CH:19]=[CH:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:3][CH:4]=[C:5]([CH3:16])[CH:6]=2)[N:9]=1
Reactant: Cc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Reactant: Nc1cccc2[nH]ccc12
Product: Cc1cnc(Nc2cccc3[nH]ccc23)c(-c2nc(C)nc(N)n2)c1

Procedure:
The experimental procedure for this compound was the same as Example 22, Step 2 using 4-(2-chloro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 1H-indol-4-amine (Bionet Research, Cornwall, UK). LCMS (API-ES) m/z 332 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.84 (s, 1H); 11.34 (s, 1H); 8.62 (d, J=1.17 Hz, 1H); 8.24 (d, J=0.59 Hz, 1H); 8.14 (d, J=0.59 Hz, 1H); 7.84 (d, J=0.59 Hz, 1H); 7.33 (br. s., 1H); 7.05 (s, 1H); 7.04 (d, J=3.33 Hz, 1H); 6.65 (d, J=1.17 Hz, 1H); 3.17 (d, J=2.74 Hz, 3H); 3.16 (br. s., 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:35])[N:14]([CH3:34])[N:15]=[C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:21])=[O:20])[C:17]=1[OH:18])[CH3:2].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:35])[N:14]([CH3:34])[N:15]=[C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:21])=[O:20])[C:17]=1[O:18][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)[CH3:2]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1nn(C)c(=O)c(-c2c(CC)cc(C)cc2CC)c1O
Reactant: COc1ccc(CCl)cc1
Product: CCCCCCCCCCCCS(=O)(=O)c1nn(C)c(=O)c(-c2c(CC)cc(C)cc2CC)c1OCc1ccc(OC)cc1
Yield: 57 %

Procedure:
The procedure was performed by the method similar to Production Example 21 using 4-(2,6-diethyl-4-methylphenyl)-6-dodecylsulfonyl-5-hydroxy-2-methyl-3(2H)-pyridazinone and 4-methoxybenzyl chloride as a starting material to give 4-(2,6-diethyl-4-methylphenyl)-6-dodecylsulfonyl-5-(4-methoxybenzyl)oxy-2-methyl-3(2H)-pyridazinone (yield: 57%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[N:34][C:27]=2[NH:26]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:35]([C:33]5[CH:32]=[CH:31][C:28]6[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)=[O:36])[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CSc2ccc(C(=O)N[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)C[C@H]3O)nc2N1
Yield: 59 %

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (79 mg), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (for a synthesis see WO2003087098, Example 301(b)) (50 mg), triethylamine (0.066 ml) and HATU (95 mg) in DMF (2 ml) according to the general method of Example 9 in 59% yield.