Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([CH2:9][N+:10]([O-])=O)[CH2:3][C:4](OCC)=O.C1(C)C=CC=CC=1.C([OH:28])C>[Ni]>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3](=[O:28])[CH2:4][NH:10][CH2:9]1
Reactant: CCOC(=O)CC(C)(C[N+](=O)[O-])c1ccccn1
Reactant: CCO
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC1(c2ccccn2)CNCC1=O

Procedure:
A solution of 5.9 g of the compound obtained in Step 2 in 150 ml of ethanol was hydrogenated for 12 hours in the presence of 0.6 g of Raney nickel (10% w/w) under a hydrogen gas pressure of 60 psi. After the reaction was completed, the reaction solution was filtered with Celite® 545 and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added 150 ml of toluene, and the resulting mixture was heated to reflux for 2 hours. The reaction product solution was concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and methanol of 9:1 to obtain 3.35 g of the title compound as a white solid.
Reaction SMILES: CNN.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(Cl)Cl>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][NH2:17])[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methyl hydrazine (0.23 mL, 4.40 mmol) was added dropwise over 5 minutes to a solution of (S)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.43 g, 4.3 mmol) in DCM (12 mL). The mixture was stirred at ambient temperature for 1 hour then evaporated. The resultant residue was suspended in diethyl ether (10 mL) and the solid was filtered. The filtrate was concentrated to provide the title compound as a colourless oil (0.86 g, 99%). 1H NMR (CDCl3, 400 MHz) 4.24-4.26 (m, 1H), 3.60-3.66 (m, 1H), 3.44-3.54 (m, 1H), 3.30-3.42 (m, 2H), 2.03-2.12 (m, 1H), 1.84-1.96 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].I[CH2:9][C:10]([CH2:12]I)=[CH2:11]>C1C=CC=CC=1>[CH3:3][O:2][P:1]([CH2:9][C:10](=[CH2:11])[CH2:12][P:1]([O:2][CH3:3])([O:4][CH3:5])=[O:6])([O:4][CH3:5])=[O:6]
Reactant: C=C(CI)CI
Reactant: COP(OC)OC
Solvent: c1ccccc1
Product: C=C(CP(=O)(OC)OC)CP(=O)(OC)OC
Yield: 92 %

Procedure:
400 ml of trimethyl phosphite was placed into a 2-1 flask equipped with an addition funnel, a gas inlet tube, and a Vigreux column with distilling head. The phosphite was heated at reflux, then a solution of 131 g (0.425 Mole) of 2-iodomethyl-3-iodopropene [see J.Amer.Chem.Soc., 89, 4688 (1967)] in 200 ml of benzene was added dropwise over a period of 2 h, followed by an additional 100 ml of trimethyl phosphite within 30 min. The reaction was run under nitrogen, and approx. 150 ml of distillate was allowed to collect. Distillation of the reaction mixture afforded 106 g (92%) of the title compound, b.p. 125°-7°/0.08 Torr;
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15]>O>[Cl:1][S:2]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][C:7](=[O:15])[CH2:8]2)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30° C. during the addition. After the addition, the reaction mixture was stirred at room temperature for 1.5 hours, heated to 68° C. for 1 hour, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulfonyl-2-oxindole (50% yield) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([N:32]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8, 38 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]bromo-N-[2-(dimethylamino)ethyl]benzamide (2-10) as a colorless foam. 1H NMR (500 MHz, CDCl3) δ 7.55 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.04 (d, J=15.4 Hz, 1H), 5.92 (m, 1H), 5.12 (d, J=15.4 Hz, 1H), 3.37 (m, 2H), 2.05 (m, 4 H), 1.83 (m, 6H), 0.65 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15](OCC)C.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:15][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:2]([NH2:1])[CH:3]=1
Reactant: CCOCC
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-Amino-4-trifluoromethyl-benzoic acid were dissolved using 50 ml of diethyl ether and 25 ml of methanol. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.3 g of the title compound, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)CS(=O)(=O)/C=C/c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 80% yield. m.p. 178-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:16])[CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].N1C=CC=CC=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Reaction time: 18 h

Procedure:
4-((6-Chloro-2-pyridinyl)oxy)-3-chlorobenzeneamine (7.1 grams; 0.028 mole) and propionyl chloride (2.6 grams; .028 mole) were contacted in the presence of 40 ml. of dry pyridine and the resulting reaction mixture allowed to stand at ambient temperatures for a period of about 18 hours. The reaction mixture was then poured into 250 ml. of cold water and allowed to stand for about 15 minutes. The resulting product precipitate was recovered by filtration and taken up in boiling benzene and the resulting solution dried, treated with Norite and filtered. Hexane was then added to the filtrate which was then cooled to precipitate the desired N-(3-chloro-4-((6-chloro-2-pyridinyl)oxy)phenyl)propionamide compound as a white crystalline solid having a melting point of 166°-168° C. The product was found to have carbon, hydrogen, nitrogen and chlorine contents of 55.0, 3.9, 9.0 and 22.5, respectively, as compared with the theoretical contents of 54.0, 3.9, 9.0 and 22.8, respectively, calculated for the named structure.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@H:4]([OH:9])[CH2:5][N:6]=[N+:7]=[N-:8].[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C.C(N(CC)CC)C>C(#N)C>[N:6]([CH2:5][C@@H:4]([OH:9])[C@@H:3]([NH:2][C:20]1[C:21](=[O:25])[C:22](=[O:23])[C:19]=1[O:18][CH3:17])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)CC1CCCCC1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The HCl salt of (2R,3S)-3-amino-1-azido-4-cyclohexylbutan-2-ol (˜74 mg, 0.30 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (70 mg, 0.49 mmol) were dissolved in acetonitrile (3 mL). Triethylamine (84 μL, 0.60 mmol) was added. The reaction was stirred at rt for 4 h. The solvent was evaporated and the crude material was redissolved in CH2Cl2. The solution was washed with 2% aq HCl, followed by brine, and dried over Na2SO4. The solution was filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with hexanes/EtOAc. 3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (63 mg) was isolated as a solid; MS m/z 323.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([OH:12])=O.[CH3:16][O:17][CH:18]([O:27][CH3:28])[CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][CH:18]([O:27][CH3:28])[O:17][CH3:16])=[O:12]
Reactant: O=C(O)CCOCCc1cccc(Br)c1
Reactant: COC(CNC1CCCCC1)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 3-(3-bromophenethoxy)propanoic acid (3.3 g, prepared as in Preparation 3, Step ii), Procedure B) in acetonitrile (60 mL) was added TEA (20.21 mL) and N-(2,2-dimethoxyethyl)cyclohexanamine (2.26 g). T3P (1.56M in THF, 15.39 mL) was then added portionwise. The reaction was stirred overnight, and then worked up by the addition of saturated sodium hydrogen carbonate, which was extracted twice with ethyl acetate. The pooled organics were washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford a brown oil, which was purified on silica (5% Ethyl acetate/isohexane to 20% Ethyl acetate/isohexane). The solvent was evaporated to afford an orange oil (4.5 g). MS [M+H-MeOH]+=410/412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.40-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.20-7.12 (m, 2H), 4.54 (t, J=5.0 Hz, 0.5H), 4.39 (t, J=5.4 Hz, 0.5H), 4.08-3.98 (m, 1H), 3.73-3.59 (m, 4H), 3.39-3.36 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H), 2.83-2.78 (m, 2H), 2.67-2.61 (m, 2H), 1.82-1.74 (m, 2H), 1.70-1.55 (m, 3H), 1.55-1.42 (m, 2H), 1.38-1.26 (m, 2H), 1.19-1.04 (m, 1H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[C:26]#[N:27])=[CH:21][CH:20]=4)=[C:14]([CH2:32][CH2:33][CH3:34])[N:13]4[N:35]=[CH:36][N:37]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]#[N:27])=[CH:21][CH:20]=3)=[C:14]([CH2:32][CH2:33][CH3:34])[N:13]3[N:35]=[CH:36][N:37]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile (0.69 g), 3N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), sodium borohydride (0.076 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.41 g, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].[H-].[Na+]>CN(C)C=O>[CH3:12][C:4]1[N:3]=[C:2]([N:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-2-methylquinazoline (1.4 g, 7.84 mmol) and (4-nitro-phenyl)-methylamine (1.09 g, 7.16 mmol) in 20 mL of dimethylformamide cooled to 0° C. was added sodium hydride (0.6 g, 60 oil suspension, 15 mmol). The reaction mixture was stirred at 0° C. for 1 h and quenched by adding 200 uL of water. It was diluted with 150 mL of ethyl acetate, washed with water (100 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexanes) to give the title compound (1.41 g, 4.78 mmol, 67%). 1H NMR (CDCl3): 8.14 (m, 2H), 7.91 (m, 1H), 7.71 (ddd, J=8.4, 6.6, 1.8, 1H), 7.19-7.32 (m, 2H), 7.05 (m, 2H), 3.76 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].Br[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41].CS(C)=O.[I-].[K+]>[Cu].ClCCl>[F:2][C:1]([F:3])([C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:18])([F:17])[C:19]([F:21])([F:20])[C:22]([F:24])([F:23])[C:25]([F:27])([F:26])[C:28]([F:31])([F:30])[F:29]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(C)c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
A solution of C10F21I(4.2 g, 6.5 mmol) was added dropwise over 10 min to a stirred mixture of 2-bromo-ρ-xylene (1 g, 5.4 mmol), copper powder (1.9 g, 29.7 mmol), DMSO (80 mL) at 130° C. The reaction mixture was subsequently stirred for a further 2 d at this temperature. After cooling to room temperature, it was poured into a beaker containing dichloromethane (50 mL) and saturated potassium iodide solution (50 mL). After filtering, the organic layer was separated, washed with water (3×30 mL) and dried over MgSO4. Recrystallization from hexane gave the product 15 as a white solid (2.7 g, 82%): 1H NMR (300 MHz, CDCl3): 7.31 (1H, s), 7.24 (1H, d, J=8.1 Hz)), 7.17 (1H, d, J=8.1 Hz)), 2.46 (3H, t, J=3.0 Hz)), 2.39 (3H, s); 19F NMR (282 MHz, CDCl3): −81.4, −106.7, −121.1, −121.8, −122.0, −122.9, −126.3; HR-MS (EI) calcd. for C18H9F21 (M+): 624.0363, found: 624.0353.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[F:1][C:2]1[C:3]([CH2:3][CH2:2][CH2:12][CH2:11][N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:20])[CH2:22][CH2:23]2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Product: CCOC(=O)c1cccc(F)c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Step (c) of Example 75 was repeated, except that the compound prepared in step (a) of Example 81 was used and 4-(t-butoxycarbonyl)piperazine was used instead of 4-(3,3-diphenyl-1-propyl)piperazine. Thus, ethyl 3-fluoro-[4-[4-(t-butoxycarbonyl)piperazin-1-yl]butyl]-benzoate was prepared.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10]([S:11][CH2:12][CH3:13])=[C:9]([C:14]([NH2:16])=[O:15])[CH:8]=[N:7][N:6]2[CH:17]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>CN1C(=O)CCC1>[CH2:12]([S:11][C:10]1[C:5]2[N:6]([CH:17]=[C:3]([C:1]3[NH:20][N:19]=[N:18][N:2]=3)[CH:4]=2)[N:7]=[CH:8][C:9]=1[C:14]([NH2:16])=[O:15])[CH3:13]
Reactant: CCSc1c(C(N)=O)cnn2cc(C#N)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12

Procedure:
A solution of 6-cyano-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (140 mg, 0.568 mmol) and azidotributyltin (0.187 mL, 0.682 mmol) in NMP (2.0 mL) was heated to 180° C. for 60 minutes under microwave oven (CEM). The reaction mixture was taken to the next step without purification. MS (ES+) m/z: 290.08 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FCCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (3 ml, 17.5 mmol) was added to a solution of 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.5 mmol) in methylene chloride (12 ml). The reaction mixture was stirred at ambient temperature for 40 minutes, before the solvent was evaporated under high vacuum. The residue was azeotroped with toluene to give 1-(2-fluoroethyl)-piperazine diTFA salt (377 mg, 96%). NMR Spectrum: (DMSOd6) 3.06 (s, 4H); 3.17 (m, 2H); 3.25 (m, 4H); 4.67 (dt, 2H); 9.03 (br s, 1H). MS-EI: 133 [MH]+
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([C:10]([F:13])([F:12])[F:11])=[C:2]([NH2:14])[CH:7]=1
Reactant: N
Reactant: Fc1cc(F)c(C(F)(F)F)cc1F
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
225 g of 2,4,5-trifluorobenzotrifluoride in 600 ml of tetrahydrofuran were initially introduced into an autoclave and it was pressurized using 100 ml of liquid ammonia. The mixture was heated at 140° C. for 8 hours with stirring at 400 rpm and then cooled to 20° C. After releasing the pressure of the unused ammonia, the batch was distilled. 37 g of 4,5-difluoro-2-aminobenzotrifluoride were obtained in the forerun. The main amount distilled at 78° C./18 mbar and is, according to NMR spectroscopic findings, 2,5-difluoro-4-amino-benzotrifluoride (nD20 : 1.4560) having a yield of 154 g.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[C:4]([CH2:23][CH:24]([CH3:26])[CH3:25])=[N:3]1.C1(C)C=CC(S(=O)([S:35][CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)=O)=CC=1>>[OH:39][CH2:38][CH2:37][CH2:36][S:35][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[C:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)SCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(Cc3cccc4ccccc34)sc12
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc12

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)thieno[2,3-d]-pyridazin-4(5H)-one (385 mg) prepared as described in Example 7 above and S-{3-[(1,1-dimethylethyl)dimethylsilyl]oxypropyl} paratoluenethiosulfonate (600 mg) (J. Med. Chem., 1995, 38, 2557) following the method of Example 3. Yield 370 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1ccc(C)c(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 32.8 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,5-dimethylbenzoyl chloride (0.143 mmol), the title compound (14 mg, yield 33%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[SH:15][C:16]1[S:17][CH2:18][CH2:19][N:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([N:20]1[CH2:19][CH2:18][S:17][C:16]1=[S:15])=[O:14])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)NCC(=O)NCC(=O)O
Reactant: SC1=NCCS1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)NCC(=O)NCC(=O)N1CCSC1=S

Procedure:
The synthesis of MA-GG-TT was similar to the synthesis of MA-GFLG-TT in Example 1. N-methacryloylglycylglycine (MA-GG-OH) was coupled with 2-mercaptothiazoline in DCM mediated by EDCI in presence of catalytic amount of DMAP. After reaction, the product was purified by recrystallization from MeOH solution.