Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:20])=O)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)Cl>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]#[N:20])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Yield: 109.7 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxamide (300 mg) in anhydrous DMF (7 ml) at 0° C. was treated dropwise with POCl3 (237 uL). The ice-bath was removed and after 2 hours the mixture was partitioned between water and Et2O. The aqueous layer was re-extracted with Et2O and the combined extracts separated, washed with water (x2), brine, then dried (MgSO4) and concentrated, giving a yellow oil (312 mg). The oil was taken up in cyclohexane and purified by SPE (Si, 10 g) eluting with EtOAc/cyclohexane mixtures. Concentration of the product fractions gave the title compound as a colourless oil (150 mg, 53%). m/z. 330.3[MH+].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[O:3][C:48](=[O:49])[C:47]([S:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH:37]([CH3:38])[CH3:39])=[C:51]([OH:52])[CH:1]=2)=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3ccccc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4-benzyloxyacetophenone (0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g, 0.675 mmol), triethylamine (0.14 g, 1.35 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (0.210 g, 0.675 mmol). m.p. 163-165° C.; 1H NMR (400 MHz, DMSO-d6) δ1.28 (d, 6H), 3.4 (m, 1H), 5.22 (s, 2H), 6.64(s,1H), 6.92 (d, 1H), 7.06 (t, 1H), 7.11(t, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.36 (q, 2H), 7.42 (d, 2H), 7.49 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: NCCN1CCCC1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Yield: 72.4 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 29.9 mmol) reacted with 1-(2-aminoethyl)pyrrolidine (4.1 g, 35.9 mmol) to give 5.7 g (73%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:12]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH3:24])[C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:32]1[CH:37]=[CH:36][C:35]([Se:38]Br)=[CH:34][CH:33]=1.CN(C)C=O>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:12]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH3:24])[C:13](=[O:22])[CH:14]([Se:38][C:35]3[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=3)[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N(C(=O)C=Cc1ccccc1)[C@H](C(N)=O)c1ccc(Cl)cc1
Reactant: Br[Se]c1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C([Se]c2ccccc2)C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
Silver triflate (1.69 g, 6.6 mmol) was added to a stirred solution of (S)-α-(4-chlorophenyl)-α-[(R)-N-[1-(4-chlorophenyl)ethyl]-N-(cinnamoyl)amino]acetamide (1.5 g, 3.3 mmol), in acetonitrile (120 mL). To the resulting solution was successively added benzeneselenyl bromide (1.54 g, 6.53 mmol) and dimethylformamide (5.2 mL). After 6 h, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and 1N sodium hydrogenocarbonate (70 mL), dried (Na2SO4), and evaporated. Purification by column chromatography (AcOEt/hexanes, 1:3) afforded the title compound, which was recrystallized from Et2O to give colorless prisms (855 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 1.68 (d, J=7.0 Hz, 3H, CH3), 4.29 (d, J=12.2 Hz, 1H, CH), 4.79 (d, J=12.2 Hz, 1H, CH), 5.28 (s, 1H, CH), 6.21–6.25 (m, 3H, ArH), 6.31 (q, J=7.0 Hz, 1H, CH), 6.71–6.76 (m, 4H, ArH), 6.93–7.11 (m, 6H, NH+5ArH), 7.34–7.40 (m, 4H, ArH), 7.50 (d, J=8.4 Hz, 2H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C31H26Cl2N2O2Se: 608.0; found: 609.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:15]([N+:22]([O-:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[N+:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])C(CCC1CCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 230 mg (0.688 mmol) 2-(3-nitro-3-phenyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 3.5 ml methanol were added 860 ul (0.3.44 mmol) of a 4M HCl solution in dioxane. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo. The residue was dissolved in water. The mixture was basified with a saturated sodium bicarbonate solution and extracted 6 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 96 mg (y: 59.6%) of the title compound as a white solid. MS (m/e): 235.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=O)[NH:24][C:25]=1[CH3:26]>N1CCCCC1.C(O)C>[CH3:30][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=[C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)[NH:12][C:11]2=[O:15])[NH:24][C:25]=1[CH3:26]
Reactant: O=C1Cc2ccc(-c3cccs3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccs4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-thiophen-2-yl-1,3-dihydroindol-2-one (100 mg, 0.46 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-thiophen-2-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: C([NH2:5])(C)(C)C.[F:6][C:7]([F:14])([F:13])[CH2:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1>[F:6][C:7]([F:14])([F:13])[CH2:8][S:9]([NH2:5])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
Tetrahydrofuran (6 mL) was added to tert-butylamine (220 mg, 3.0 mmol), and 2,2,2-trifluoroethanesulfonyl chloride (300 mg, 1.6 mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated off under reduced pressure. To the residue, trifluoroacetic acid (3.3 mL) was added and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=100/0 to 5/1) was performed to give 2,2,2-trifluoroethanesulfonamide (Compound GC) (66 mg, yield: 25%).
Reaction SMILES: F[C:2]1C=CC(N(C2C=CC(OC3C=CN=CC=3)=CC=2)C(=O)CC(N)=O)=CC=1.Cl[C:29]1[N:34]=[CH:33]N=[C:31]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][C:46](=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)=[S:44])=[CH:38][C:37]=2F)[CH:30]=1>>[F:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][C:46]([NH:45][C:43]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][C:31]3[CH:2]=[CH:33][N:34]=[CH:29][CH:30]=3)=[CH:37][CH:38]=2)=[S:44])=[O:55])=[CH:49][CH:50]=1
Reactant: NC(=O)CC(=O)N(c1ccc(F)cc1)c1ccc(Oc2ccncc2)cc1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccncc2)cc1
Yield: 10 %

Procedure:
The title compound was prepared using 4-(4-aminophenoxy)pyridine (Compound A of Example 1) and a similar procedure outlined for the preparation of Compound C of Example 2. Yield: 10%. 1H NMR (CDCl3) δ 12.3 (s, 1H), 8.63 (s, 1H), 8.49, (d, 2H, J=6.2 Hz), 7.71 (d, 2H, J=8.9 Hz), 7.31-7.27 (m, 2H), 7.14-7.09 (m, 4H), 6.90 (dd, 2H, J=4.8, 1.4 Hz), 3.73 (s, 2H); MS (ESI+) m/z 382.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH:29][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (1.76 g, 11.1 mmol) and DIEA (1.93 ml, 11.1 mmol) in THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.39 mmol) in THF (5 ml) at 25° C. After addition, the reaction mixture was stirred at 80° C. for 48 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:DCM:EtOAc=2:1:1) to give the title compound as a yellow solid (0.62 g, 32%). NMR (400 MHz) 12.37 (s, 1H), 9.83 (s, 1H), 8.25 (m, 1H), 7.98 (d, J=11.2 Hz, 1H), 6.75 (m, 1H), 5.95 (s, 1H), 1.90 (m, 1H), 0.96 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23][C:24]1[C:25]([CH2:32]Cl)=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[C:25]([CH2:32][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Product: COc1ccnc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1OC
Yield: 26 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 3,4-dimethoxy-2-chloromethylpyridine hydrochloride. Yield: 26%. MS M+H calculated 360.2. Found 360.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.0 μM.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]([C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:16][CH:15]=[C:14]1[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]([C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=[C:14]1[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: C[Si](C)(Cl)C1=Cc2c(ccc3c2ccc2ccccc23)C1
Reactant: CC(C)(C)N
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(ccc3c2ccc2ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[I] phenanthrene-2-yl) dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (CeliteTM), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(CCO)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(CCO)CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Experimental Procedure: Triphenylphosphine (77.0 mg, 0.29 mmol) and DIAD (60.0 mg, 0.29 mmol) were dissolved to a 1:1 mixture of THF and toluene (2 mL); then mono-demethylated piperlongumine (40.0 mg, 0.13 mmol) was added. After 10 min, N-methyldiethanolamine (120 mg, 0.06 mmol) was added to the mixture; the reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum. The crude product was purified by preparative TLC(CH2Cl2/MeOH=9/1) to afford the desired product in 78% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])[CH2:13][CH2:12]1.C(N)(C)(C)C>[Cu]I.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.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[O:22])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCC(=O)N1CCN(C)CC1
Reactant: OCc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CCC#Cc2cccc(CO)n2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a 50 mL round-bottom flask, 484 mg of 2-bromopyridine-6-methanol, 510 mg of 1-(4-methylpiperazin-1-yl)pent-4-yn-1-one, 20 mg of BHT, 162 mg of copper(I) iodide, 118 mg of tetrakis(triphenylphosphine)palladium (0), 375 mg of t-butylamine and 7.5 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. The DMF was removed under reduced pressure, then saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=600:20:1) to give 540 mg of 5-(6-hydroxymethylpyridin-2-yl)-1-(4-methylpiperazin-1-yl)pent-4-yn-1-one as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]=[C:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:35][O:36][NH:37][CH3:38]>C(Cl)Cl>[CH3:35][O:36][N:37]([CH3:38])[C:15]([CH:13]1[CH2:12][C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[CH2:14]1)=[O:17]
Reactant: O=C(C=C1CC(C(=O)O)C1)OCc1ccccc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(=CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
To an ice cold solution of 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid (2.0 g, 8.12 mmol), N-Methyl-morpholine (2.70 ml, 24.36 mmol) in DCM (50 ml) was added isobutyl chloroformate (1.70 ml, 12.99 mmol) drop-wise over 5 min. After an additional 5 min, methoxy(methyl)amine hydrochloride (1.58 g, 16.24 mmol) was added and the mixture was stirred overnight whilst allowing to warm to RT. The reaction mixture was then diluted with DCM (30 ml), washed with 0.1N HCl (50 ml) then sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with EtOAc:heptanes from 1:9 to 3:7 gave the desired product (1.54 g, 65%); MS (ESI+) for C16H19NO4 m/z 290.10 [M+H]+; HPLC purity 100% (ret. time, 1.86 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 2.96 (1 H, ddd, J=16.98, 8.79, 1.81 Hz), 3.17-3.30 (4 H, m), 3.30-3.48 (2 H, m), 3.51-3.63 (1 H, m), 3.64-3.75 (3 H, m), 5.15 (2 H, s), 5.73 (1 H, quirt, J=2.25 Hz), 7.29-7.42 (5 H, m).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=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>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[CH:35][C:34]([CH3:38])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(Br)cc21
Reactant: CB1OB(C)OB(C)O1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(C)cc21
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Purge a mixture of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.400 g, 0.672 mmol), trimethylboroxine (0.084 g, 0.672 mmol), and potassium carbonate (0.279 g, 2.02 mmol) in anhydrous tetrahydrofuran (5 mL) with nitrogen, then add tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.067 mmol) and stir at reflux for 1 h. Cool the mixture to room temperature and dilute with ethyl acetate (30 mL) and wash with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 3:1), to provide the title compound as a white solid (0.156 g, 44%): ESI MS 531 (M+H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:30])[C:7]([CH3:29])([CH3:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])C>O.C(O)C>[O:27]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([OH:22])=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:29])([CH3:28])[C:6]([OH:30])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 13 %

Procedure:
A solution of KOH (25 g) in water (50 mL) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (10.69 g, 155 mmol) in ethanol (400 mL), then heated at reflux for 4 h. After cooling, the solution was evaporated to a volume of ca. 50 mL and diluted with water (800 mL). The organic impurities were removed by extracting with dichloromethane (2×200 mL). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid (50 mL) and extracted with methyl tert.-butyl ether (MTBE, 3×200 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the crude product (9.51 g) as an oil. Crystallization from hexanes/MTBE (50 mL:25 mL) afforded 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (6.92 g, 79%) as waxy, white crystals. M.p.: 83-84° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 12.03 (s, 2 H), 2.37 (t, 4 H, J=7.3 Hz), 1.52-1.34 (m, 8 H), 1.28-1.10 (m, 8 H), 1.06 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 210.5, 178.8, 41.7, 41.2, 29.1, 25.0, 24.4, 23.1. HRMS (LSIMS, gly): Calcd. for C19H35O5 (MH+): 343.2484, found: 343.2485.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[N:28]=3)[C:21]3[CH:34]=[CH:35][CH:36]=[CH:37][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)C(=O)[O-])(C)C>CC(O)C.Br.C(O)(=O)C>[NH2:5][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[N:28]=3)[C:21]3[CH:34]=[CH:35][CH:36]=[CH:37][C:20]=3[N:19]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)N(CCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1)C(=O)[O-]
Agent: Br
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Yield: 18.7 %

Procedure:
A mixture of compound (7) (0.0026 mol) in 2-propanol (30 ml) and HBr/acetic acid (2 ml) was stirred and refluxed for 90 minutes and then cooled. The solvent was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried. This fraction was purified again by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried, yielding 0.23 g of (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine (compound 9).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1.N1C=CC=CC=1>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(NS(=O)(=O)c2cn(C)cn2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.424 mmol) of the compound from example 42A are reacted with 307 mg (1.70 mmol) of 1-methylimidazole-4-sulfonyl chloride and 0.34 ml (4.24 mmol) of pyridine in 5 ml of tetrahydrofuran.