Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:5][CH2:6][O:7][C:8]1[NH:9][CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1.[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:31][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([F:1])[C:19]=1[O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)[CH2:5][CH2:6][O:7][C:8]1[N:9]([CH3:32])[CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To the solution of 2-(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethoxy)-5-ethylpyrimidin-4(1H)-one (30 mg, 0.068 mmol) and DIPEA (0.03 ml, 0.172 mmol) in DCM (1.5 ml) was added MeI (0.025 ml, 0.407 mmol). The solution was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (12 mg, 0.026 mmol, 38.8% yield). LCMS: rt=3.10 min, [M+H+]=457
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CO.C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: COC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Yield: 98.7 %

Procedure:
A solution of 184 (100 mg, 0.24 mmol) and Cs2CO3 (312 mg, 0.96 mmol) in MeOH (10 mL) and CH2Cl2 (15 mL) was stirred for 1.5 h. Water was added and the mixture was extracted with CH2Cl2 (×3). The combined organic extracts were washed with water, brine and dried. The solvent was evaporated and the residue was dissolved in CH2Cl2MeOH and, solvents were evaporated under reduced pressure until precipitation began. The precipitate was filtered off and washed with MeOH to give methyl 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxylate (186) (76 mg, 100%): mp 161-163° C.; 1H NMR [(CD3)2SO] δ 8.40 (dd, J=1.6, 0.6 Hz, 1H), 8.22 (dd, J=9.1, 0.4 Hz, 1H), 7.82 (dd, J=9.1, 1.7 Hz, 1H), 7.78 (s, 1H), 6.49 (d, J=1.6 Hz, 1H), 4.35-4.28 (m, 1H), 3.93 (s, 3H), 3.89-3.82 (m, 2H), 3.79-3.69 (m, 2H). HRMS (CI) calcd. for C15H1335ClN2O4 (M+) m/z 320.0534, found 320.0563.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:10]([C:8]1[O:9][C:5]3[C:4]([F:14])=[CH:3][C:2]([F:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:19]2
Reactant: O=C(O)c1cc2cc(F)cc(F)c2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(F)c2o1
Reaction time: 0.33 h

Procedure:
55 mg (0.28 mmol) of 5,7-difluoro-1-benzofuran-2-carboxylic acid, 50 mg (0.25 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 114.6 mg (0.3 mmol) of HATU, 117 mg (0.9 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure and the crude product is dissolved in 1N aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), shaken for about 20 min. The loaded ion exchanger is washed three times with in each case 30 ml of methanol, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. 40 mg (52% of theory) of the title compound are isolated.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CI.[CH3:26]COC(C)=O.O>CN(C=O)C.CC([O-])(C)C.[K+]>[NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:26])[CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCOC(C)=O
Reactant: NC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (61.4 mg) was dissolved in DMF (1 ml) To the solution were added 1M MeI solution in DMF (0.22 ml) and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=93:7, v/v) to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide, which was crystallized from EtOAc (20 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.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]>[CH3:22][O:23][C:24](=[O:35])[C:25]([CH3:26])([N:28]1[CH2:29][CH2:30][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:21]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Reactant: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (300 mg, 0.877 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (286 mg, 1.315 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (51 mg, 10 mol %) and DIPEA (0.61 mL, 3.5 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The crude reaction mixture was diluted with DCM (150 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording 2-Methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propionic acid methyl ester as an orange oil (0.674 g, quantitative). LCMS: RT1.88 min [M+H]+ 479.1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26](C(OC(C)(C)C)=O)[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][CH:28]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][CH:28]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CCOc1ccc2c(c1)cc(-c1nn(C(=O)OC(C)(C)C)c3ccc(OCc4ccccc4)cc13)n2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc2[nH]c(-c3n[nH]c4ccc(OCc5ccccc5)cc34)cc2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A solution containing 1.15 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-diethylaminoethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and 4 ml of trifluoroacetic acid in 5 ml of dichloromethane is stirred at 20° C. for 2 hours. The reaction mixture is evaporated under reduced pressure and the crude compound thus obtained is purified by chromatography (Nucleodur C18 column, 100-10, 250 mm×40 mm, reference No. 762020, series No. 3051181, Batch No. 2023; eluent A: water/0.07% trifluoroacetic acid, eluent B: acetonitrile/0.07% trifluoroacetic acid, gradient of composition A/B of 95%//5% to 5%/95% over 52 minutes at 75 ml/min, detection 300 nm). The fractions containing the expected compound are combined and evaporated under reduced pressure. The compound is taken up in ethyl acetate (20 ml), dried over magnesium sulfate and then evaporated under reduced pressure to obtain 320 mg of {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1H-indol-5-yloxy]ethyl}diethyl-amine, which is characterized.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[O:18]1[CH2:23][CH2:22][CH:21](/[CH:24]=[CH:25]/[C:26]#[N:27])[CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:25][C:26]#[N:27])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#C/C=C/C1CCOCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCOCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.25 g, 0.00644 mol) in acetonitrile (20 mL, 0.4 mol) was added (2E)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile (1.00 g, 0.00729 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.09 mL, 0.00729 mol). The resulting mixture was stirred at room temperature overnight. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to provide the desired product (1.30 g, 60.93%). LCMS (M+H) 332.4.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[C:20]1([C:26]2[C:34]3[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]4)=[N:32][CH:31]=[N:30][C:29]=3[S:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:16][CH:15]([CH2:17][NH:41][CH:38]1[CH2:39][CH2:40][N:35]([C:33]2[C:34]3[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][S:28][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:36][CH2:37]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 21 %

Procedure:
Synthesis followed SP6 (3 h), using 220 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 21% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 70% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]=[C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]([C:21]2[N:26]=[C:25]([CH2:27]S([O-])(=O)=O)[CH:24]=[CH:23][CH:22]=2)=[N:12]1.C(OCC)(=O)C>CN(C=O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:27][C:25]1[N:26]=[C:21]([C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:11](=[O:10])[N:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Sc1ccccn1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CSc3ccccn3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
2-mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.54 g, 87%) as pale yellow crystals.
Reaction SMILES: CC[O:3]C(CC1N=C(NC(CSC2[N+](CC=C)=C(N)CC(=O)N=2)=O)SC=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[N:32]2[C:37]=1[CH:36]=[N:35][C:34](SC)=[N:33]2.C(Cl)Cl.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].C(O)(=O)C>O>[Cl:28][C:29]1[CH:30]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[N:32]2[C:37]=1[CH:36]=[N:35][C:34]([OH:3])=[N:33]2
Reactant: CSc1ncc2c(Cl)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: C=CC[N+]1=C(N)CC(=O)N=C1SCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CN(c1ccccc1-c1cc(Cl)c2cnc(O)nn12)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
1553d) N-[2-(5-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide was dissolved in Methylene chloride (10 mL, 200 mmol) and m-Chloroperbenzoic acid (235 mg, 1.05 mmol) was added. After 90 min, additional m-Chloroperbenzoic acid (135 mg, 0.602 mmol) was added. Formation of the sulfoxide was concomitant with sulfone formation. After 1 h, the mixture was partitioned between satd. NaHCO3 (20 mL) and EtOAc (50 mL); the aq. was extracted with EtOAc (2×20 mL) and the comb. org. washed with brine:satd. NaHCO3 (40 mL). After drying, the mixture was conc. in vacuo. The crude N-[2-(5-Chloro-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide was dissolved in 1,4-Dioxane (4.00 mL) then treated with 5.0 M of Sodium hydroxide in Water (1.00 mL, 5.00 mmol) and heated to 60° C. for 2 h. The mixture was cooled, treated with Acetic acid (0.400 mL, 7.04 mmol) and water (2 mL), then partitioned between water and DCM (30 mL each), sept. and extr. with DCM (3×20 mL), dried and conc. in vacuo. The residue was applied to a 5 g ISCO cartridge, then purified (24 g SiO2, 10-100% EtOAc:Hex) to afford N-[2-(5-Chloro-2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.129 g; Yield=47.2% over 4 steps) as an orange foam. LCMS (HPLC): 0.76 min, m/z=353 (M+H); 1H-NMR (DMSO-d6): 11.87 (br s, 1H), 9.01 (s, 1H), 7.69 (m, 2H), 7.59 (m, 2H), 7.50 (m, 1H), 6.99 (s, 1H), 3.19 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37]N)[CH:29]=1.C(C1C=CC(OCC2C=CC(C([NH2:54])=O)=C(OCC)C=2CCCCC2C=NC=CC=2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[C:12]([CH:16]=[CH:17][C:18]=2[CH2:37][CH2:36][CH2:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:13]([NH2:54])=[O:14])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCc2cccc(C(=O)O)c2OCC)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(N)=O)c(OCC)c2CCCCc2cccnc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2c(CCCCc3cccnc3)ccc(C(N)=O)c2OCC)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
3-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid was allowed to react with 3-pyridine butanamine according to the procedure of Example 32 and the product was purified by recrystallization from methylene chloride-ether to give, 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy-methyl]-2-ethoxy-[4-(3-pyridinyl)butyl]benzamide, the title compound, mp 107°-109° in 73% yield.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42](I)=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C1(C)C=CC=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:11]4[CH:10]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:9]=3)=[CH:21][CH:20]=2)=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)c2cccnc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-benzimidazole (8.9 g, 22.4 mmol), 8-(tert-butyldimethylsilyl-oxy)-5-iodoquinoline (7.2 g, 18.69 mmol), toluene (110 ml) and dioxane (110 ml) is degassed by passing through of N2 for 30 min. Pd(OAc)2 (9 mg, 0.04 mmol) and tris-o-tolylphosphine (75.6 mg, 0.25 mmol) is then added, and the mixture is heated at 80° C. for 8 h. After cooling to room temperature, the mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on silica and crystallisation (7.9 g, 80%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>CCOCC.CC#N>[I:46][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCO)ccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCI)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The mixture of tert-butyl 6-(2-hydroxyethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (5.6 g, 19.09 mmol), triphenylphosphine (6.51 g, 24.82 mmol), imidazole (1.82 g, 26.72 mmol), and a mixture of CH3CN and dry ether (1:1) was cooled to 0° C. Iodine (6.78 g, 26.72 mmol) was slowly added. The resulting mixture was stirred for 2 hour and then ether (150 mL) was added, washed successively with saturated aqueous Na2S2O3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 20% EtOAC/Hex) to afford a yellow solid (6.6 g, 86% yield). H NMR (CDCl3) δ 1.55 (s, 9H), 2.93 (s, 3H), 3.18 (t, 2H), 3.30 (t, 2H), 3.458(t, 2H), 3.85 (t, 2H), 6.85(q, 2H). LC-MS (M+H) 404.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(=O)C.C(N(CC)CC)C.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35]>CN(C=O)C>[C:5]([O:4][CH:1]([N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:26](=[CH:25]/[C:20]2[NH:21][C:22]([CH3:24])=[CH:23][C:19]=2[CH3:18])/[C:27]1=[O:35])[CH3:2])(=[O:7])[CH3:6]
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
A mixture of acetic anhydride (2.1 g, 20 mmol), acetaldehyde (4.4 g, 100 mmol), triethylamine (2.0 g, 20 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol) in DMF (30 mL) was stirred at room temperature for 3 days. The solvents were removed and the residual oil was chromatographed on silica gel to give, as the first product eluted from the column, 2.5 g of product, which was crystallized from ether to give 2.1 g of the title compound, mp 107-110° C. HPLC Rt 6.78 min. 1H NMR (CDCl3) δ1.81 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 5.98 (s, 2H), 7.00-7.20 (m, 3H), 7.25 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H) and 13.0 (br s, 1 H). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.33; H, 6.18; N, 8.60.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].CCN(CC)CC>CC#N>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][N:3]2[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:24][CH:25]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (257 mg, 0.63 mmol) and bromoacetic acid tert-butyl ester (110 μL, 0.75 mmol) in CH3CN (4.0 mL) at rt was added Et3N (270 μL, 1.9 mmol). After 18 h at rt, the suspension was partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (218 mg, 77%). MS (ESI): mass calcd. for C25H29N3O3S, 451.19; m/z found, 452.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.39 (m, 1H), 7.34-7.25 (m, 3H), 3.75 (m, 2H), 3.43 (br s, 1H), 3.33 (m, 3H), 2.88 (m, 2H), 2.82 (br d, J=10.0 Hz, 1H), 2.70 (dd, J=10.0, 2.2 Hz, 1H), 1.78 (s, 2H), 1.48 (s, 9H).