Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][C:23]([CH:30]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][C:23]([CH2:30][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1C(C)(C)C
Yield: 76.7 %

Procedure:
Compound 64 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:30][C@H:31]([C:35]([OH:37])=[O:36])[C@@H:32]([CH3:34])O.[C:38]([OH:41])(=[O:40])C.C(O)C(F)(F)F.ClCCl>CN(C=O)C.N1CCCCC1.CN(C)C=O>[CH2:32]1[C@H:34]([C:38]([OH:41])=[O:40])[NH:30][C@H:31]1[C:35]([OH:37])=[O:36]
Reactant: CC(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: O=C(O)[C@H]1C[C@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was synthesized by solid-phase methodology on a SyRo II multiple peptide synthesizer (MultiSynTech, Bochum) on a 0.03 mmol scale using Fmoc-L-Trp-trityl-polystyrene(1%)divinylbenzene resin (Fmoc-L-Trp-TCP; loading: 0.57 mmol/g; PepChem, Tübingen) as starting material. The α-amino groups of the proteinogenic amino acids Ala and Ser were protected by 9-fluorenylmethoxycarbonyl (Fmoc), the side chain hydroxy group of Ser by tert.-butyl. The non-proteinogenic amino acid Ada was used as Fmoc-Ada(Boc2)-OH (from example2). The Fmoc-protected amino acids were coupled in a 6-fold excess for 30 min in DMF. TBTU (1 eq) and NMM (1 eq) were used as activating reagents. Cleavage of the Fmoc group was carried out in piperidine/dimethylformamide (1:1v/v) for 2×10 min. Coupling of Boc-Ada(Boc2)-OH and Thr was performed manually in DMF within 1 h by using 0.048 mmol of the protected amino acid Boc-Ada(Boc2)-OH (1.65-fold excess) and a 6 fold excess in the case of Thr. Equimolar amounts of TBTU and NMM were used for activation. The peptide was cleaved from the resin with 750 ul of acetic acid/trifluoroethanol/dichloromethane (30:10:70) within 2 h. After washing five times with 150 ul of the same solvent mixture the filtrates were combined, diluted with 10 ml heptane and concentrated. This procedure was repeated twice in order to remove the acetic acid completely. The oily residue was dissolved in 5 ml 4 N hydrogen chloride in dioxane. To this solution 270 ul ethanedithiol were added and the mixture was stirred for 3 h at room temperature. Then the solvent was removed and the residue dissolved in heptane and concentrated again several times until the ethanedithiol was almost completely removed. The crude peptide was lyophilized from tert.-butanol/water (1:1) and purified by preparative HPLC to yield 2.6 mg T-Ada-SAW as colorless lyophilisate (purity by HPLC >98%). ESI-MS: m/z 644.3 M+
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)=[CH:13][C:6]2=[N:5][C:4]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O-])=[O:31])[CH2:25]1)=O.FC(F)(F)COP([CH2:45][C:46]([O:48][CH3:49])=[O:47])(=O)OCC(F)(F)F.C1CCN2C(=NCCC2)CC1.[Cl-].[Li+]>O1CCCC1>[CH:30]([CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[N:5]=[C:6]3[CH:13]=[C:12]([CH2:14][CH2:15][C:16]4[S:17][CH:18]=[C:19]([CH:21]([CH3:22])[CH3:23])[N:20]=4)[CH:11]=[CH:10][N:7]3[C:8](=[O:9])[C:3]=2/[CH:1]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])[CH2:25]1)=[O:31]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCCC(C(=O)[O-])C4)nc3c2)n1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/c1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{3-Formyl-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}-3-piperidylformate (94.0 mg, 0.207 mmol) and bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonoate (0.131 ml, 0.620 mmol) were dissolved in tetrahydrofuran (2 ml), added with DBU (0.085 ml, 0.620 mmol) and lithium chloride (26.3 mg, 0.620 mmol), and then the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([CH2:36]Cl)[CH:30]=[CH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O>O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([CH2:36][N:12]1[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]1)[CH:30]=[CH:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Sodium hydride (60%, oily, 0.36 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (1.81 g), 6-benzyloxy-2-chloromethylnaphthalene (2.54 g) and N,N-dimethylformamide (35 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and methyl 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carboxylate (3.20 g, yield: 80%) was obtained as colorless crystals from the fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 109–110° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccccc1)(C(=O)OCC)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
2-(1H-Pyrrole-2-carbonyl)-malonic acid diethyl ester (0.79 mmol, 0.21 g) in DME (3 ml) was treated with lithium bis-trimethylsilylamide (0.79 mmol, 133 mg). The resulting solution was held at room temperature for 30 minutes, then treated with benzyl bromide (0.79 mmol, 0.10 ml). The resulting solution was held at room temperature overnight, then diluted with ethyl acetate (30 ml), and washed with saturated ammonium chloride (10 ml), followed by brine (20 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 0.23 g (84%) of 2-benzyl-2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. 1H NMR (CDCl3) δ10.01 (1H, s), 7.25-7.17 (4H, m), 7.14 (1H, dt, J=2.7, 1.3), 7.03-6.98 (1H, m), 6.86 (1H, ddd, J=3.8, 2.4, 1.3), 6.29-6.25 (1H, m), 4.22 (4H, q, J=7.1), 3.47 (2H, s), 3.39 (2H, s), 1.25 (6H, t, J=1.7).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:26]([C@@H:8]([C@@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)[C@@H](Cc1ccccc1)[C@@H](O)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a cold (−78° C.) solution of diisopropyl-(R)-(+)-malate (9.4 mL; 45.82 mmol; 1.00 eq.) in anhydrous THF (17 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (96.2 mL; 1.00 M; 96.2 mmol; 2.10 eq.) in THF. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Benzyl bromide (9.40 g; 55.0 mmol; 1.20 eq.) was added and the mixture stirred at RT for 16 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product as a colourless oil (9.76 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:15]>C(OCC)(=O)C.ClCCl.[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]12[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][CH:24]([CH2:26]3)[CH2:25]1)[CH2:27]2)=[O:15]
Reactant: COC(=O)/C=C/c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 24 h
Yield: 104 %

Procedure:
5% Rhodium on carbon (0.40 g) was added to a solution of (2E)-3-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-2-propenoic acid, methyl ester (Example 6a, 2.2 g) in ethyl acetate/dichloromethane (4:1) (160 ml) and the mixture hydrogenated at 3 bar for 24 h. The catalyst was removed by filtration and the filtrate concentrated to give the subtitled compound as an oil (2.3 g).
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1>O1CCOCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:21][CH:22]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 143.3 %

Procedure:
tert-Butyl ethyl malonate (41.3 ml, 211 mmol) was added drop-wise to a suspension of sodium hydride (19.33 g, 483 mmol) in dioxane (1000 mL) at 0° C. The reaction was stirred at 0° C. for 1 hr and then allowed to warm to ambient temperature. 3,6-dichloropyridazine (30 g, 201 mmol) was then added portion wise at 25° C. The reaction was stirred at reflux for 2 hrs and then solvent was removed via rotary evaporation. The resulting residue was dissolved in EtOAc (400 mL), and the organic phase was washed with saturated NaHCO3 (400 mL), dried over MgSO4, filtered, and concentrated to dryness via rotary evaporation. This reaction was repeated. The combined crude residues from both batches was purified via MPLC (Hex:EtOAc, 8:2) to provide the title compound, 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate (86.5 g, 288 mmol, 71.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.23 (m, 3 H) 1.36-1.52 (m, 9 H) 4.20 (m, J=10.71, 7.22, 7.22, 3.85, 3.85 Hz, 2 H) 5.29 (s, 1 H) 7.85 (d, J=8.84 Hz, 1 H) 7.99 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 301.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[O:6]C1C=CC([N+]([O-])=O)=CC=1)[C:2]#[CH:3].[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH2:28])[CH2:22]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH:28][C:5]([NH:4][CH2:1][C:2]#[CH:3])=[O:6])[CH2:22]1
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A solution of Intermediate 22 (0.024 g) in dichloromethane (1 ml) was stirred with Intermediate 20 (0.033 g) and N,N-diisopropylethylamine (0.022 ml) for 3 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo, and the residue was dissolved in dichloromethane (5 ml), and the solution shaken with polystyrene methyl isocyanate resin (Argonaut technologies, 0.256 g, 1.43 mmol/g) for 16 h. The solution Was drained from the resin and the resin washed with dichloromethane (8 ml); the combined filtrate and washings were concentrated in vacuo to give the title compound as a pale yellow gum (0.02 g).
Reaction SMILES: [C:1](NC1CCC(=O)CC1)(=O)C.Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21]N.CS(O)(=O)=O.[C:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[C:38]([F:46])[CH:39]=[C:40]([F:45])[CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)(=[O:30])[CH3:29]>C(O)C>[C:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[C:38]([F:46])[CH:39]=[C:40]([F:45])[CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)(=[O:30])[CH3:29].[CH2:35]([NH:36][CH:37]1[CH2:38][C:39]2[C:16]3[C:15](=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=3)[NH:21][C:40]=2[CH2:41][CH2:42]1)[CH:43]([CH3:44])[CH3:1]
Reactant: NNc1ccc(F)cc1F
Reactant: CC(=O)NC1CCC(=O)CC1
Agent: CC(=O)NC1CCc2[nH]c3c(F)cc(F)cc3c2C1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: CC(C)CNC1CCc2[nH]c3c(F)cc(F)cc3c2C1

Procedure:
A solution of 15.5 g. of 4-acetamidocyclohexanone, 18 g. of 2,4-difluorophenylhydrazine hydrochloride and 10 g. of methanesulfonic acid in 200 ml. of absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residual oil was triturated with water and the resulting solid was collected by filtration, triturated with ether, and recrystallized by dissolving in methanol, adding toluene, and evaporating the methanol to give 8.5 g. of 3-(acetamido)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole, m.p. 179°-183° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:26][CH2:27][CH2:28][NH2:29])[C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:15])(=O)C.C(SCC(CCCN)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)(=O)C>>[NH2:29][CH2:28][CH2:27][CH2:26][CH:13]([CH2:12][SH:11])[C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](NC(=O)C(CS)CCCN)C(=O)O

Procedure:
By substituting Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-lysine trifluoroacetate for the Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine in the procedure of Example 31, Nα -(5-amino-2-mercaptomethylpentanoyl)-L-lysine is obtained.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CN1C(=O)N(C)CCC1.[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([OH:29])=[O:28].IC>C1COCC1>[CH3:1][C:23]1([C:27]([OH:29])=[O:28])[CH2:24][CH2:25][CH2:26][O:22]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C1CCCO1
Agent: [Li]CCCC
Solvent: CI
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of N,N-diisopropylamine (15 ml, 106 mmol) in THF (40 ml) at 0° C. was added n-BuLi (99 mmol, 1.6 M/Hex). After stirring the mixture for 30 min. DMPU (12 ml, 99 mmol) and tetrahydro-2-furoic acid (4.2 ml, 44 mmol) were added at 0° C. After 1 hr at 0° C., iodomethane (5.4 ml, 88 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was partitioned between ethyl acetate and 1N HCl. The aqueous layer was extracted with ethyl acetate (2×500 ml) and chloroform (500 ml). The extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with methylene chloride/methanol/acetic acid=97:3:0.5 to afford the desired product as an oil (2.5 g).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[Cl:14])=[O:4].O[Li].O.[CH3:18][CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.C([O-])(O)=O.[Na+]>C1COCC1.CO.O.CN(C=O)C>[Cl:14][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([N:24]3[CH2:25][CH2:26][N:21]([CH:19]([CH3:20])[CH3:18])[CH2:22][CH2:23]3)=[O:4])[CH:6]=2)[NH:10][CH:9]=1
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1ccc2[nH]cc(Cl)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]cc(Cl)c3c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
A mixture of 1.05 g (5 mmol) 3-Chloro-1H-indole-5-carboxylic acid methyl ester and 1.05 g (25 mmol) LiOH.H2O in THF, methanol, water was stirred at 50° C. for 4 h. The mixture was evaporated to dryness and the corresponding acid was used without further purification in the subsequent step. 0.77 g (6 mmol) 1-(2-propyl)-piperazine, 2.4g (7.5 mmol) TBTU, 2.5 g (25 mmol) NEt3 and 20 mL DMF was added and the mixture was stirred at room temperature for 4 h. 1N NaHCO3 was added and the mixture was extracted with DCM. The combined organic layers were dried with MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica eluting with a gradient formed from heptane, ethyl acetate, methanol and NEt3. The combined product fractions were evaporated to yield 0.67 g (44%) of the title compound as light brown solid. MS(m/e): 306.3 (MH+).
Reaction SMILES: [O:1]=O.[C:3]([O:6][CH:7]([CH:12]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1)C(Cl)(Cl)Cl)(=O)C.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Na]>CO.Cl>[CH:12]1([C:7]([O:6][CH3:3])=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: O=O
Reactant: CC(=O)OC(C1C=CCCCCCCCCC1)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Na]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: CO
Product: COC(=O)C1C=CCCCCCCCCC1
Yield: 56 %

Procedure:
A stream of dry oxygen was passed through a stirred solution (heated at 30°-35° C.) of 1-(2-cyclododecen-1-yl)-2,2,2-trichloroethyl acetate (12 g; 35 m. moles) in methanol (10 ml) and a solution of cupric chloride dihydrate (0.19 g; 1.1 m. moles) and 1,10-phenanthroline hydrate (0.56 g; 2.85 m. moles) in methanol (45 ml) in which sodium (1.39 g; 6.0 m. moles) had been dissolved was added portionwise over a period of 225 minutes. The mixture was then diluted with dilute hydrochloric acid (100 ml), extracted with ether (3×50 ml) and the combined ether extracts were washed with aqueous sodium carbonate solution (50 ml) and water (50 ml). The dried (MgSO4) extract was evaporated and the crude product (4.7 g) distilled to give methyl 2-cyclododecene-1-carboxylate (3.9 g; 56%), b.p. 90°-110° C./0.1 mm. G.L.C. analysis indicated a purity of 85%.
Reaction SMILES: [Br-:1].[K+].BrBr.[C:5]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])(=[O:7])[CH3:6]>O>[C:5]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([Br:1])[C:10]=1[CH:11]=[O:12])(=[O:7])[CH3:6]
Reactant: [Br-]
Reactant: COc1cccc(C=O)c1OC(C)=O
Agent: BrBr
Agent: [K+]
Solvent: O
Product: COc1ccc(Br)c(C=O)c1OC(C)=O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of potassium bromide (40 g) in H2O (250 mL) was added bromine (6.8 mL). To the dark red solution was added aldehyde 10 (20.2 g). The turbid orange solution was stirred overnight, filtered, rinsed with ethyl acetate, recrystallized from ethyl acetate/hexane to afford yellow crystals (22.4 g, 79%): m.p. 121.6-123.4° C., lit18 m.p. 119-120° C.; EIMS m/z 274 (M+, 81Br), 272 (M+, 79Br), 232, 230, 186, 184, 43; 1H NMR δ 10.26 (1H, s, CHO), 7.51 (1H, d, J=9.0 Hz, H4), 7.05 (1H, d, J=9.0 Hz H2, H4), 3.85 (3H, s, OCH3), 2.38 (3H, s, COCH3); 13C—NMR (75.5 MHZ) δ 190.38, 168.71, 151.78, 140.37, 131.41, 126.49, 117.69, 116.35, 56.40, 20.44. Anal. Calcd. For C10H9O4Br: C, 43.98; H, 3.32. Found: C, 44.46; H, 3.55.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O.C(O)C>C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:5]3=[N:4][C:3]=2[C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
0.225 g (0.74 mM) 4-(3-bromoimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde is dissolved in 5 mL of toluene. To this mixture is added 4-fluorphenyl boronic acid (1.5 eq) followed by tetrakis triphenylphosphine palladium (0) 10% by wt, K2CO3 (3 eq) and ethanol water mixture (4 mL). The reaction mixture is heated at 90° C. for 4-6 h. The reaction is cooled to room temperature and 20 mL of water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by flash column chromatography to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCCCC(=O)O1
Reactant: Nc1c(F)c(F)cc(F)c1S
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 25.5 %

Procedure:
A solution of adipic acid (10.0 g, 68 mmol) in acetic anhydride (50 ml) was heated to reflux for 3 hours. An excess of acetic anhydride was then distilled off in vacuo leaving adipic anhydride (7.4 g). 2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in NMP (1 ml) under a nitrogen stream. To the resultant solution was gradually added adipic anhydride (143 mg, 1.1 mmol) and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 5-(4,5,7-trifluorobenzothiazol-2-yl)pentanoic acid (81 mg, 26%).