Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[C:14](N)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:14]([CH3:16])([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)CC(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 46.2 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 30 g of tert-octylamine in 300 ml of 95° EtOH is refluxed for 16 hours. The solvent is evaporated off under vacuum to give 13 g of the expected product after crystallization from an iso ether/heptane mixture (40/60; v/v). M.p.=108° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:30][O-:31].[Na+]>CN(C)C=O.[Cu]I>[F:28][C:25]([F:26])([F:27])[CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:8]3=[N:9][C:10]=2[C:2]([O:31][CH3:30])=[CH:3][CH:4]=1)[OH:29]
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(OC)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 1-[9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.425 mmol), sodium methoxide (28% methanol solution, 3 mL), copper (I) iodide (121 mg, 0.635 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (96.6 mg, 0.229 mmol, 54%).
Reaction SMILES: C(O[C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:9]([O:8][CH2:7][C:6](=[O:12])[C:5]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.3 %

Procedure:
One gram of 17α,21-diacetoxy-4-pregnene-3,20-dione is heated analogously to Example 1 in "Dowtherm" for 80 minutes to 285° C., worked up, separated, and combined. Recrystallization from hexane/ethyl acetate yields 700 mg of 21-acetoxy-4,16-pregnadiene-3,20-dione (83% of theory), m.p. 146°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:11]([NH2:19])[NH:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@H:28]([NH2:30])[CH3:29]>CN1C(=O)CCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@H:28]([NH:30][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[C:11]([NH2:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1)[CH3:29]
Reactant: C[C@H](N)c1ccc(F)cc1F
Reactant: CSc1nc(Cl)cc(C2=C3N=CC=CN3NC2N)n1
Solvent: CN1CCCC1=O
Product: CSc1nc(N[C@@H](C)c2ccc(F)cc2F)cc(-c2c(N)nn3cccnc23)n1
Temperature: 220 °C
Yield: 19.4 %

Procedure:
3-(6-Chloro-2-(methylthio)pyrimidin-4-yl)-1,2-dihydropyrazolo[1,5-a]pyrimidin-2-amine (4b) (500 mg, 1.70 mmoles) was dissolved in 5 mL of NMP along with (S)-1-(2,4 difluorophenyl)-ethylamine (988 mg, 5.0 mmoles, added as the free base). The reaction mixture was heated in the microwave three times at 220° C., for 15 minutes each. The reaction progress was monitored by LC/MS. Upon completion, the reaction was quenched by addition of 1N HCl to the vigorously stirred material until a thick oily material separated. This crude mixture was centrifuged and the thick oil separated. The oily mass was transferred to a round-bottomed flask and methanol was added. Solvents were removed under reduced pressure and the resulting solid was suspended in acetonitrile, warmed to 50° C. and vigorously stirred. Then it was cooled and the resulting precipitate was suction-filtered. The filtrate was reduced to an oil under reduced pressure and then re-dissolved in a minimum amount of methanol and purified via HPLC on C18 silica with acetonitrile/water/TFA as the eluent. After lyophilizing the desired fractions a beige solid was obtained (136 mg, 19.4% yield).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][CH:9]([N:11]([CH2:13][C@@H:14]2[C@@H:21]3[C@@H:17]([O:18][C:19]([CH3:23])([CH3:22])[O:20]3)[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C=O)C>[N:34]([CH2:6][CH:7]1[CH2:8][CH:9]([N:11]([CH2:13][C@@H:14]2[C@H:21]3[O:20][C:19]([CH3:22])([CH3:23])[O:18][C@H:17]3[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:10]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methyl methane sulfonate (150 mg, 0.31 mmol) in DMF (3 ml) was added NaN3 (81 mg, 1.24 mmol). The mixture was heated at 70° C. for 3 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound (90 mg, Yield 67%). ESI-MS (m/z): 430.2[M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:4]=1[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[CH:21]([O-])([O-])[O:22][CH2:23][CH3:24]>>[CH2:1]([C:3]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:4]=1[C:5]([C:7](=[CH:21][O:22][CH2:23][CH3:24])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1CC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC

Procedure:
Employing ethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylacetate (8 g) and ethyl orthoformate (6.1 g), the procedure of Reference Example 20 is repeated to give ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=CC=1>>[CH3:23][C:20]1([CH3:22])[C:19]([CH3:24])([CH3:25])[O:18][B:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:16][CH:15]=2)[O:21]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (200 mg, 0.59 mmol). Crude product was purified by flash chromatography using EtOAc/hexanes as eluent (2:98 to 15:85) to give the title compound as a colourless oil (239 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.25-4.22 (m, 2H), 2.78 (t, J=12.5 Hz, 2H), 2.67-2.61 (m, 1H), 1.82-1.78 (m, 2H), 1.67-1.57 (m, 2H), 1.48 (s, 9H), 1.32 (s, 12H); MS ESI 410.1 [M+Na]+, calcd for [C11H34BNO4+Na]+410.25.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4](N(C)C)[C:5]([Cl:11])([Cl:10])[C:6]([F:9])([F:8])[F:7].S(=O)(=O)(O)O>>[Cl:10][C:5]([Cl:11])([C:6]([F:9])([F:8])[F:7])[CH:4]=[O:3]
Reactant: CN(C)C(O[Si](C)(C)C)C(Cl)(Cl)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=CC(Cl)(Cl)C(F)(F)F

Procedure:
This compound may be prepared by reacting a dimethylformamide solution of 1,1,1-trichloro-2,2,2-trifluoromethane with chlorotrimethylsilane in the presence of zinc, forming 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dime thylpropylamine. The 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dimethyl propylamine is reacted with sulfuric acid to form 2,2-dichloro-3,3,3-trifluoropropionaldehyde. The 2,2-dichloro-3,3,3-trifluoropropionaldehyde is then reacted with sulfur tetrafluoride to produce 2,2-dichloro-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH3:35])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1.[C:38](=O)=O>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH2:35][CH3:38])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Reactant: O=C=O
Solvent: CO
Product: CCNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(OC(F)(F)F)cc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (111 mg, 0.204 mmol from Example 98) was purified using chiral SFC to afford 29.5 mg of peak A (Example 98A) and 37.7 mg of peak B (Example 98B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 12 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=3.4 min, tR (peak B) 8.2 min. The absolute stereochemistry of individual enantiomers (Examples 98A and 98B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 98).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]Br)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:19]([NH2:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22].C([O-])(=O)C.[Na+]>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]([NH2:28])=[O:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(N2CCN(CCBr)CC2)cc1
Reactant: NC(=O)c1ccccc1N
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccccc1NCCN1CCN(c2ccc(O)cc2)CC1
Yield: 40 %

Procedure:
A mixture of 61 g 1-(p-hydroxyphenyl)-4-(2-bromoethyl)piperazine dihydrobromide, 18.5 g anthranilamide, 33.5 g sodium acetate, and 250 ml water was refluxed 16 hours, cooled, filtered and the solid washed with water and isopropanol. The solid was suspended in water and made alkalline with Na2CO3. The solid was filtered, suspended in 75% ethanol and added dilute HCl until acidic. The solution was cooled and the solid filtered and recrystallized from 1200 ml water to give 18.5 g product, m.285°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15](C1ON=C(C3C=CC=CC=3)C=1C(F)(F)F)=[O:16])[CH2:7][CH2:6]2.[C:32]1([C:38]2[O:42][N:41]=[C:40](C(O)=O)[C:39]=2[C:46]([F:49])([F:48])[F:47])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15]([C:40]1[C:39]([C:46]([F:47])([F:49])[F:48])=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:42][N:41]=1)=[O:16])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Product: COc1ccc2c(c1)CCC(NC(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 43A employing 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Step D of Intermediate 5). 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=8.80 Hz), 7.85 (1H, d, J=5.28 Hz), 7.70 (2H, d, J=7.48 Hz), 7.52-7.62 (3H, m), 6.88 (1H, dd, J=8.80, 2.42 Hz), 6.74 (1H, d, J=2.20 Hz), 4.78 (1H, ddd, J=13.53, 4.95, 4.84 Hz), 3.89 (3H, s), 3.29 (1H, ddd, J=17.11, 12.93, 4.29 Hz), 2.93-3.08 (2H, m), 1.97-2.10 (1H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])[CH:11]=[C:10]([CH3:21])[CH:9]=1)(=O)=O.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][N:26]2[C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]3[C:22]2=[O:32])[N:13]=[C:12]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])[CH:11]=1
Reactant: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: ClCCl
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)nc(-n2c(C)ccc2C)c1
Temperature: 40 °C
Reaction time: 20 h
Yield: 63.3 %

Procedure:
To a stirred solution of 250 mg (0.906 mmol) of 6-(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 59, Step A) in 0.70 mL of dry N,N-dimethylformide was added 336 mg (1.81 mmol) of potassium phthalimide and 67 mg (0.18 mmol) of tetrabutylammonium iodide. The mixture was stirred at room temperature for 2 h and at 40° C. for 20 h. The reaction was diluted with 50 mL of dichloromethane, washed with 30 mL of saturated aqueous sodium bicarbonate and 30 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. To remove the contaminating phthalimide, the residue was dissolved in 40 mL of diethyl ether and washed 2×20 mL of 2.5 N aqueous sodium hydroxide, followed by saturated aqueous sodium chloride. The organic phase was dried (sodium sulfate), decanted, and concentrated. Flash column chromatography on 26 g of silica gel, eluting with 200 mL of 7% of ethyl acetate/hexane and 500 mL of 30% of ethyl acetate/hexane furnished 206 mg (63% yield) of 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phthalimidoethyl)pyridine as an amber syrup.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:32])[CH:15]([NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[OH:16].Cl.[CH3:34]O>CO>[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:32])[CH:15]([NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[O:16][CH3:34]
Reactant: CO
Reactant: N=C(N)NCCCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Agent: Cl
Product: COC(NC(=O)CCCCCCCCNC(=N)N)C(=O)NCCCCNCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 160 mg (0.31 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2-(9-guanidinononanamido)-2-hydroxyethanamide trihydrochloride in 3.2 ml of anhydrous methanol was added 0.32 ml of 2N hydrogen chloride-methanol. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting white powder was purified in a manner as that in Example 7, using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to yield 107 mg (65% yield) of a white powder of N-[4-(3-aminopropyl)aminobutyl]-2-(9-guanidinonoanamido)-2-methoxyethanamide trihydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)C.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([CH2:19][CH2:18][CH:17]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1ccc(C(=O)NN)cc1
Reactant: O=CCCc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(C(=O)NN=CCCc2ccccc2)cc1

Procedure:
4-ethyl-benzoic acid hydrazide (10 g, 60.9 mmoles) was dissolved in 32 mL of methanol. Acetic acid (1 mL) was added, the mixture was brought to reflux, and hydrocinnamaldehyde (5.77 g, 67 mmoles) was then slowly added. The reaction mixture was refluxed for 10 h and monitored by TLC. The precipitates were collected via filtration and washed with hexanes. 4-Ethyl-benzoic acid (3-phenyl-propylidene)-hydrazide was obtained as a white solid (9.34 g, 54.7% yield). Rf=0.36 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.72-7.24 (m, 10H), 2.87 (t, J=15.2 Hz, 2H), 2.79-2.57 (m, 4H), 1.24 (t, J=8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:16]([CH3:18])[CH3:17])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(Cl)Cl.[NH4+].[Cl-].[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:28][CH2:27][CH3:31])([N:16]([CH3:17])[CH3:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCC1(N(C)C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A little iodine was added to a mixture of 17.7 g (6 eq) magnesium and 50 ml dry ether, followed over a period of 1 h by 100 g (6 eq) bromobutane dissolved in 100 ml dry ether. This reaction mixture was stirred for 1 h at room temperature. The Grignard reagent produced in the preceding step was added over a period of 20 min to a solution of 30 g (1 eq) 1-benzyl-4-(dimethylamino)piperidine-4-carbonitrile dissolved in 210 ml dry THF and the reaction mixture obtained was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, filtered over celite, extracted with ethyl acetate (3×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
Reaction SMILES: FC([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)F.[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:48]=[CH2:49])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:46][CH3:47])=[CH:27][C:26]=1[CH2:25][CH2:24]3)(C(C)(C)C)([CH3:11])[CH3:10]>>[C:18]([C@H:19]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:48]=[CH2:49])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([C:41]([F:44])([F:43])[F:42])([O:45][Si:5]([CH3:6])([CH3:7])[CH3:8])[C:41]([F:42])([F:44])[F:43])[CH2:34][C@:18]12[CH2:17][O:16][SiH:9]([CH3:10])[CH3:11])[C:31]1[CH:30]=[CH:29][C:28]([O:46][CH3:47])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCC(=O)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Reactant: C[Si](C)(C)C(F)(F)F
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCC(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 131 mg of alcohol 16b yields 162 mg of trimethylsilyl ether 17b as a yellow, viscous mass (GC-MS: m/z theor.: 734, pract.: 734). The latter is, without performing the reaction with tetrabutylammonium fluoride-trihydrate, used in the next stage.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C@@H:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:23])=[O:22]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 36 h
Yield: 59.2 %

Procedure:
(S)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (10.25 g, 58.5 mmol) was dissolved DCM (20 ml). Triethylamine (12.23 ml, 87.7 mmol) was added and the solution was cooled to 0° C. under nitrogen. Methanesulfonylchloride (5.0 ml, 64.3 mmol) was diluted with DCM (5 ml) and added drop wise to the reaction mixture keeping the temperature under 10° C. After addition, the reaction mixture was allowed to warm up to RT and stirring was continued for 36 h. Next, the reaction mixture was diluted with DCM (150 ml) and washed several times with NaHCO3-solution and water, the organic layer dried with Na2SO4, filtered and evaporated affording 8.78 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.06 (d, 3H), 1.38 (s, 9H), 3.16 (s, 3H), 3.75 (m, 1H), 4.04 (m, 2H), 6.93 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>C1COCC1.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>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: FC(F)(F)c1cnn2c(-c3cccc(Br)c3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4nccs4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
A mixture of 7-(3-bromophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2 g, 0.58 mmol), 2-tributylstannylthiazole (0.44 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.06 mmol) in THF (2 ml) was degassed with a stream of N2 for 10 min and stirred at 65° C. for 12 h. After allowing to cool to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) and triturated with Et2O to give 64 mg (32%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.42 (1H, d, J 3.2 Hz), 7.65 (1H, t, J 7.9 Hz), 7.94 (1H, d, J 3.2 Hz), 8.04 (1H, dq, J 7.9, 1.0 Hz), 8.06 (1H, dq, J 7.9, 1.0 Hz), 8.71 (1H, s), 8.76 (1H, t, J 1.6 Hz), 8.86 (1H, s); MS (ES+) m/z 348 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Solvent: CCO
Product: COc1ccc(Cn2cc(N)cn2)cc1
Reaction time: 18 h

Procedure:
1-(4-Methoxy-benzyl)-4-nitro-1H-pyrazole (240 mg, 1.03 mmol) was stirred in ethanol (10 mL) and the flask was evacuated and then flushed with nitrogen. Platinum, sulfided, 5 wt. % on carbon, reduced, dry (10 mg, catalytic amount) was added and after two vacuum/H2 cycles to replace the nitrogen inside with hydrogen, the mixture was shaken for 18 hours under ordinary hydrogen pressure (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield a red oil, which was used without further purification, 168 mg, 81%.