Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:44](Cl)(=[O:55])[O:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=1>CN(C=O)C.[NH4+].[Cl-]>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([C:44]([O:45][C:46]7[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=7)=[O:55])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(C(=O)Oc6ccc([N+](=O)[O-])cc6)CC5)cn4)sc23)c(F)c1)NC1CC1
Yield: 64 %

Procedure:
To a solution of compound 49 (0.50 g, 0.96 mmol, scheme 15) and pyridine (0.11 g, 1.4 mmol) in DMF (4 mL) was added 4-nitrophenyl chlorocarbonate (0.23 g, 1.1 mmol). The resultant mixture was stirred at room temperature for 1 h, diluted with saturated NH4Cl aqueous solution and extracted with EtOAc-THF (4:1 mixture). The organic layer was collected, washed with saturated NaHCO3 aqueous solution, water and brine, dried over MgSO4 and concentrated. The residue was triturated with t-BuOMe, to afford title compound 595 (0.42 g, 64% yield) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.60 (s, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.35 (s, 1H), 8.30-8.26 (m, 3H), 7.91 (d, J=8.1 Hz, 1H), 7.74 (dd, J=2.4, 10.8 Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.39 (t, J=9.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 6.66 (d, J=5.1 Hz, 1H), 6.58 (s, 1H), 3.65 (brs, 4H), 3.49 (brs, 2H), 3.34 (brs, 4H), 2.58-2.54 (m, 1H), 0.70-0.63 (m, 2H), 0.47-0.43 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.[C:20]([NH2:24])(=[O:23])[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:24][C:20](=[O:23])[CH2:21][CH2:22][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: O=C1CCC2=C(CCN(Cc3ccccc3)C2)N1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
To a solution of 1-benzyl-4-piperidone (213 g, 1.13 mol) in toluene (700 ml) was added pyrrolidine (190 ml, 2.25 mol), the reaction mixture was fitted with a Dean-Stark head and heated to 150° C. for 18 h. The reaction mixture was cooled and evaporated under reduced pressure, p-toluenesulphonic acid (4.0 g, 0.022 mol) was then added to the residue followed by acrylamide (160 g, 2.25 mol). The reaction mixture was heated with rapid stirring to 90° C. for 1.5 h and then for a further 2 h at 120° C. The cooled mixture was then filtered and the solid obtained washed with acetone followed by ether. The mother liquors were combined, evaporated under reduced pressure and the residue partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure to afford a further batch of solid. The solids were combined and heated to reflux with 4-toluenesulphonic acid (10 g, 0.056 mol) in dioxane (400 ml) for 18 h. On cooling, a colourless crystalline product was formed which was filtered and washed with EtOAc to afford the subtitle compound as colourless crystals (176 g, 65%). Rf 0.1 (EtOAc). 1H NMR (CDCl3) δ: 2.20 (4H, d), 2.50 (2H, t), 2.70 (2H, s), 3.00 (2H,s), 3.65 (2H, s), 7.20-7.45 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:10])[CH3:14])[CH3:18]
Reactant: Cc1c(Cl)cccc1NN
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cccc(Cl)c1C

Procedure:
The title compound was prepared in accordance with the general method of example 25b) from a) (3-chloro-2-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[CH:11][CH:10]=1
Reactant: CN1CC=C(c2cccc3ccc(N(Cc4ccccc4)Cc4ccccc4)cc23)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCC(c2cccc3ccc(N)cc23)CC1
Reaction time: 22 h
Yield: 33.2 %

Procedure:
A mixture of 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphthalene (2.85 g, 6.81 mmol) and palladium hydroxide (20% on carbon, 2.06 g) in glacial acetic acid (60 mL) was hydrogenated 22 hours (starting pressure approximately 50 psi). Additional palladium hydroxide (1 g) was added and hydrogenation was continued 13 hours more. The reaction was filtered through celite. The filtrate was neutralized with 4N sodium hydroxide and extracted with methylene chloride. This organic phase was washed with brine, dried and concentrated to 1.3 g of brown oil. Crystallization from isopropanol gave 0.544 g (33%) of 7-amino-1-(1-methyl-4-piperidinyl)-naphthalene as light brown crystals. mp 169.5°-171° C. Analysis calculated for C16H20N2 ; C, 79.96; H, 8.39; N, 11.66. Found: C, 80.14; H, 8.42; N, 11.52.
Reaction SMILES: C(OCC([C:12]1([I:38])[C:17]([C:18]([NH2:20])=[O:19])=[C:16]([I:21])[C:15]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29][O:30]C(=O)C)=[C:14]([I:34])[CH:13]1[C:35]([NH2:37])=[O:36])COC(=O)C)(=O)C.[CH3:39][O-:40].[Na+].[Na]>CO>[OH:40][CH2:39][CH:17]([NH:37][C:35]([C:13]1[C:14]([I:34])=[C:15]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29][OH:30])[C:16]([I:21])=[C:17]([C:18]([NH:20][CH:23]([CH2:29][OH:30])[CH2:24][OH:25])=[O:19])[C:12]=1[I:38])=[O:36])[CH2:18][OH:19]
Reactant: CC(=O)OCC1COCC(=O)N1C1=C(I)C(C(N)=O)C(I)(C(COC(C)=O)COC(C)=O)C(C(N)=O)=C1I
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(NC(CO)CO)c1c(I)c(C(=O)NC(CO)CO)c(I)c(N2C(=O)COCC2CO)c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N'-Bis[2-(acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-[3-[(acetyloxy)methyl]-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 7c (1.03 g, 1 mmol) was added to a solution of sodium methoxide in methanol, prepared from sodium (23 mg, 1 mmol) and anhydrous methanol (20 ml). The solution was stirred for 4 hours at room temperature. The pH of the solution was then adjusted to 7 by the addition of Dowex-50 (H+) resin. The resin was filtered off and the solvent removed from the filtrate to obtain a white solid (0.8 g) which, upon purification by low pressure reverse phase column chromatography over the CHP-20P resin yielded pure N,N'-Bis[2-Hydroxy-1-(hydroxymethyl)ethyl]-5-[3-(hydroxymethyl)-5-oxo-morpholinyl]-2,3,6-triiodo-1,3-benzenedicarboxamide as a snow-white glassy solid (0.65 g, 79% yield).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5]C=C[CH:2]=1.[S:21]1C=CC(B(O)O)=C1>>[S:21]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:2]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccsc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and thiophene-3-boronic acid (159 mg, 1.24 mmol) were coupled to yield 2-thiophen-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 249 mg (82%) as a beige solid: m.p. 255-256° C.; 1H NMR (300 MHz, d6-DMSO) 3.08 (m, 2H), 3.43 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.67 (dd, J=7.5, 0.9 Hz, 1H), 7.74 (m, 1H), 7.78 (m, 1H), 8.03 (br t, 1H), 11.49 (br s, 1H). MS (electrospray, MH+) 269. Anal. (C15H12N2OS.0.35 H2O) C, H, N, S.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[F:21][C:22]1[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>ClCCl.O.CCCCCC>[CH2:19]([C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[S:14][C:13]=1[C:15]1[N:16]=[C:29]([C:28]2[CH:32]=[CH:33][C:25]([O:24][C:23]3[CH:34]=[CH:35][CH:36]=[CH:37][C:22]=3[F:21])=[CH:26][CH:27]=2)[O:18][N:17]=1)[CH3:20]
Reactant: O=C(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3F)cc2)n1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d) and 4-(2-fluorophenoxy)benzoic acid (0.13 g, 0.55 mmol) that was obtained in Example 10 (10e) in dichloromethane (1.5 ml) was added N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, hexane (2 ml) was added to the reaction mixture, and insoluble materials were removed by filtration, and the filtrate obtained was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (1 ml) was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 ml, 0.75 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (10 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 5:5) as the eluent to afford the title compound (0.18 g) in a yield of 89% as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[C:20]([Cl:27])=[CH:19][N:18]=1>C(O)(C)C>[Cl:27][C:20]1[C:21]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:2]=3[Cl:1])[CH2:10][CH2:9]2)=[C:22]([N+:23]([O-:25])=[O:24])[C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3c(F)cccc3Cl)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]
Reactant: CN(C)S(N)(=O)=O
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
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: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (26 mg, 0.21 mmol), N,N-Diisopropylethylamine (54 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) in DMF (2.5 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-25% MeCN in 0.5% NH4HCO3) to give target product (11.8 mg, 18%) as a white solid. LCMS (ESI) Method A: RT=5.57 min, m/z: 471.2 [M+H]; 1H-NMR (500 MHz, MeOH-d4,): δ 7.62 (d, J=6.0 Hz, 1H), 7.31 (d, J=10.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.40 (dd, J=8.0, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 2.86 (s, 6H), 2.61 (t, J=7.0 Hz, 2H), 1.68 (t, J=7.0 Hz, 2H), 1.20 (s, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.[OH-].[Na+:32]>C(#N)C.O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[O-:22])=[N:3]1.[Na+:32]
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A suspension of the product of Example 1H (55 mg, 0.13 mmol) in 1:1 acetonitrile-water was treated with 1N NaOH solution (130 μL 0.13 mmol) and stirred at 25° C. for 2 hours. The solution was then lyophilized to afford the title compound (59 mg, 100%) a fluffy white solid. 1H NMR (300 MHz, DMSO-d6): δ 5.52 (s, 1 H), 8.06 (d, J=7.72 Hz, 1 H), 7.64 (d, J=7.72 Hz, 1 H), 7.49 (m, 3 H), 7.30 (m, 3 H), 2.10 (m, 2 H), 1.67 (m, 2 H), 0.88 (m, 2 H), 0.59 (m, 8 H).
Reaction SMILES: FC[C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1.[F:38][CH2:39][CH2:40][CH2:41][CH2:42]C#C.FCC#C>>[F:38][CH2:39][CH2:40][CH2:41][CH2:42][C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: C#CCCCCF
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared according for the procedure for compound 6, with the exception that 6-fluorohex-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]9, 6-[18F]fluorohex-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[CH2:21]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:12]([F:13])([F:14])[F:15])[CH3:22]
Reactant: O=C(O)Cc1cc(Cl)ccc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (5-Chloro-2-trifluoromethyl-phenyl)-acetic acid (10.0 g, 47.2 mmol) in absolute EtOH (300 mL) at room temperature was added concentrated H2SO4 (4 mL) and the mixture was warmed to reflux. After 4 hrs, the reaction was cooled to room temperature, evaporated under reduced pressure, diluted with DCM (500 mL) and stirred over solid K2CO3. After 1 hr, the resulting mixture was filtered and concentrated to dryness to afford the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:49]1[N:50]=[C:51]([CH2:68][CH2:69][CH3:70])[N:52]([C:56]2[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]([F:67])([F:66])[F:65])=[CH:58][CH:57]=2)[C:53](=[O:55])[CH:54]=1)(=O)=O.[CH3:73][O:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][NH2:80])=[CH:77][CH:76]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[CH3:73][O:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][NH:80][C:49]2[N:50]=[C:51]([CH2:68][CH2:69][CH3:70])[N:52]([C:56]3[CH:57]=[CH:58][C:59]([O:62][CH2:63][C:64]([F:66])([F:67])[F:65])=[CH:60][CH:61]=3)[C:53](=[O:55])[CH:54]=2)=[CH:77][CH:76]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCCc1nc(OS(=O)(=O)C(F)(F)F)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(NCc2ccc(OC)cc2)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of palladium(II) acetate (49.0 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (189 mg) in toluene (20 mL) were added 6-oxo-2-propyl-1-[4-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyrimidin-4-yl trifluoromethanesulfonate (1.0 g), 4-methoxybenzylamine (0.43 mL) and cesium carbonate (1.77 g) at room temperature, and the mixture was stirred at 100° C. for 3 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) to give the title compound (462 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10]
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: BrCc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cccc(Br)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with 3-bromobenzylbromide, cesium carbonate and 10 mol-% tetrabutylammonium iodide as a catalyst in N,N-dimethylacetamide to give N-(3-bromobenzyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 416.2 ([M+H]+)
Reaction SMILES: OC[C@@H]1CCC[NH2+]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=2)[C:16]([O-:18])=[O:17])=[CH:11][CH:10]=1.C(O)=O>C(OCC)(=O)C>[C:29]([O:28][C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)[C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)[O-])c2ccc(Br)cc2)cc1
Agent: OC[C@@H]1CCC[NH2+]1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(Br)cc2)cc1
Reaction time: 0.33 h

Procedure:
A stirring slurry of 216.8 g of (R)-2-(4-Bromo-phenyl)-3-(4-tert-butoxycarbonyl-phenyl)-propionate (S)-2-hydroxymethyl pyrrolidinium in 2168 mL of ethyl acetate at 21° C. was treated 1084 mL of 10% aqueous formic acid. After 20 minutes, the separated organic phase was washed with water and dried over magnesium sulfate. The ethyl acetate solution was atmospherically displaced into heptanes to yield the product as a granular solid. 166.3 g (96% yield) of white solid, enantiomeric excess (“R” enantiomer) of 96.9% by chiral HPLC analysis as described above. HNMR: CDCl3, 1.50 (s, 9H), 2.96-3.00 (m, 1H), 3.32-3.37 (m, 1H), 3.73 (t, 1H), 7.03-7.08 (m, 4H), 7.35 (d, 2H), 7.76 (d, 2H)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH:6]=[CH:7][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)[CH2:4][O:3][C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1)#[N:11]
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from sodium hydride and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][C:14]=3[I:23])=[O:9])=[CH:4][CH:3]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI.CO.C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide(6.5 g) in anhydrous DMF (116.7 mL) is heated to 65° C. to solubilize the starting material. The solution is allowed to cool to room temperature. To this solution is added K2CO3 (7.68 g) and CH3I (8.65 mL). The reaction is stirred at room temperature overnight. The reaction is poured into H20 (1L) to precipitate the product. The solid is filtered, adsorbed onto silica, and chromatographed in 2 batches (eluent 100% CH2Cl2 (3L), 0.5% MeOH in CH2Cl2 (1L), and 1% MeOH in CH2Cl2 (9L)). Product-containing fractions are combined and condensed to afford 3.6 g (54%) of the desired product as a white solid.