Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[N:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[N:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C2(C)OCCO2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2csc(CO)n2)OCCO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (1.30 g, 4.12 mmol) in dry THF (10 mL) was treated at 0° C. with TBAF (6.2 mL of a 1M solution in THF, 6.20 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1->1:3 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.20. LC-MS-conditions 02: tR=0.59 min; [M+H]+=202.48.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:34])[CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[O:14])=[C:11]([NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[N:10]=1)#[N:2].Cl>CO>[NH2:26][CH2:25][CH2:24][CH2:23][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[CH2:16][NH:15][C:13](=[O:14])[C:12]1[CH:35]=[CH:36][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[N:10][C:11]=1[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)N1CCCC1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(C(=O)NCC2CCCN2C(=O)CCCN)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl 4-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (71 mg, 0.11 mmol) in MeOH (5.0 mL) was added HCl (1.0 mL, 4 mmol, 4 M in dioxane). The reaction mixture was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude was purified on RP-HPLC using a mixture of acetonitrile (0.1% TFA) and water (0.1% TFA) to give N-((1-(4-aminobutanoyl)pyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide as a pale yellow solid (57.1 mg, 68%). LRMS (M+H+) m/z 529.2.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][Si](C)(C)C)[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:15]([C:11]1[CH:10]=[C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:21]3[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[O:27])[CH2:22]3)[CH2:4][CH2:3]2)[CH:14]=[CH:13][CH:12]=1)#[CH:16]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: C[Si](C)(C)C#Cc1cccc(C2(O)CCC(=O)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-trimethylsilanylethynyl-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4 followed by a TBAF work-up using the procedure described in Step D of Example 40.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[F:31][C:32]([F:36])([F:35])[CH2:33]I.Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 505.2 %

Procedure:
To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.
Reaction SMILES: [C:1]([CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:21][CH2:22]O>>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH:4]([CH3:5])[C:1]([O:3][CH2:21][CH3:22])=[O:2])=[N:7][NH:8]1
Reactant: CC(C(=O)O)c1n[nH]c(=O)c2ccccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)c1n[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(1-carboxyethyl)-1(2H)-phthalazinone (1.5 g, 6.9 mmol) in EtOH (50 mL) was added thionyl chloride (1.10 mL, 15.1 mmol). The mixture was stirred at 80° C. for 4 hours, cooled to 0° C., and quenched with 1M NaHCO3 (40 mL). The aq layer was extracted with EtOAc (2×50 mL), dried (Na2SO4), filtered, and concentrated to give the title compound: MS (ESI+) M/Z 247 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cc(F)cc(OCC(C)C)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 55 %

Procedure:
Add 1-bromo-2-methyl-propane (0.05 g, 0.35 mmol) to (2R,3S,5R)-5-[(1S,2S)-2-acetylamino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.46 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and heat in a 60° C. oil bath for 2.5 hours. Cool to room temperature and dilute with ethyl acetate. Wash (0.1N citric acid, 10% potassium carbonate, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate. Purify on 12 g silica gel column eluting with 100:0 to 40:60 hexanes:ethyl acetate to give 0.072 g (54.5%) of the title compound as a white foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([NH:26][CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([O:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1
Reactant: NCCO
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(Nc2nc(NCCO)nc(NC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,5-triazine with ethanolamine according to the procedure of Example 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[F:9][C:10]([F:23])([F:22])[C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[NH2:14]>N1C=CC=CC=1>[F:9][C:10]([F:22])([F:23])[C:11]1[CH:12]=[C:13]([NH:14][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 3-chloropropanesulfonyl chloride (5.0 g) and 3,5-bis(trifluoromethyl)aniline (6.47 g) in pyridine (50 ml) was stirred at room temperature for 16 hr. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 95:5-60:40) to give the title compound (7.20 g, yield 69%) as a pale-brown solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]3[C:11](I)=[N:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:18][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:10]=[C:11]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CCCn3ccnc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.086 g, 0.233 mmol) in ethylene glycol dimethyl ether (4 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.104 g, 0.256 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.059 g, 0.56 mmol) in water (2 mL). The reaction mixture was stirred for 24 h at 80° C. The organic solvent was removed under reduced pressure and dichloromethane (25 mL) was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 10 g ISCO column. The column afforded 0.06 g (49%) of pure N2-(4-{4-amino-1-[3-(1H-1-imidazolyl)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.443 (s, 1H), 8.278 (s, 1H), 8.1324-8.1121 (d, 1H, J=8.12 Hz), 7.744-7.699 (m, 2H), 7.6-7.579 (d, 1H, J=8.4 Hz), 7.365-7.283 (m, 5H), 7.172-7.135 (m, 1H), 6.939 (s, 1H), 4.36-4.326 (m, 2H), 4.079-4.019 (m, 5H), 3.964 (s, 3H), 2.324-2.309 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.25 min (100%), MH+ 522.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C(N(CC)CC)C>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C

Procedure:
To a 20 ml, microwave tube was added 2-bromo-5-nitropyridine (0.20 g, 0.98 mmol), potassium vinyltrifluoroborate (145 mg, 1.1 mmol), PdCl2(dppf)-CH2Cl2 complex (40 mg, 0.049 mmol), and a stir bar. The tube was sealed, and ethanol (6 mL) and triethylamine (0.41 mL, 3.0 mmol) was added via syringe. The mixture was purged three times with nitrogen and then heated to 120° C. for 30 minutes. LC at that point showed mostly product. The reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 151 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][OH:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:16][CH2:17][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with Cs2CO3 (17.2 g, 52.8 mmol) and 2-bromoethanol (3.90 g, 31.7 mol) and heated to about 50° C. under nitrogen for 12 h. DMF was distilled out completely and the residue was dissolved in DCM and washed with water and brine. Organic layer was dried over Na2SO4, evaporated and purified by column chromatography (silica) to afford 5.5 g (90%) of the title compound as pale yellow solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33]Cl)[CH3:29]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:28][CH3:29])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCN(CC)CCCCl
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCCCN(CC)CC)ccc-2c(C(=O)OCC)c1N
Yield: 42 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 3-diethylamino-propyl chloride the title compound of m.p. 125-127° C. is obtained in 42% yield.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3O)C2
Yield: 65668736 %

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 46 (0.26 μg, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 47 (0.14 g, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][C:7]1=[O:13].[CH3:17][NH:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:19][NH:18][CH3:17])[CH2:8][C:7]1=[O:13]
Reactant: O=C1CCN(Cc2cccc(Cl)c2)C(=O)C1
Reactant: CNN
Solvent: CCO
Product: CNN=C1CCN(Cc2cccc(Cl)c2)C(=O)C1

Procedure:
1-(3-Chlorobenzyl)piperidine-2,4-dione (1.2 g) was dissolved in ethanol (25 ml), and methylhydrazine (0.5 ml) was added. The mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:1) to give 1-(3-chlorobenzyl)-4-(methylhydrazono)piperidin-2-one (1.05 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([O:14][CH2:15][CH2:16][NH2:17])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH:11]([O:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)OCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)OCCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 80.9 %

Procedure:
2 g of para-fluoronitrobenzene was added to a solution of 20 ml of N-methylpyrrolidinone (NMP), 1.75 g of 2-aminoethyl isopropyl ether and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was poured into a water+ice mixture. A yellow precipitate formed and was filtered off. The precipitate was reslurried in water and then dried over P2O5.2.57 g of N-(2-isopropoxyethyl)-4-nitro-1-aminobenzene (7) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:18](=[O:19])[C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:13])[CH3:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
0.4 mmol 6-chloro-1-isoindolinone (CAS: 58083-59-3) was dissolved in 3 nml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example B1 and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature, then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated. Chromatography (silica gel; ethyl acetate/heptane) gave the title compound as a slightly yellowish solid. Yield=55%. MS (m/e): 408.2 [M+H]+, 100%).
Reaction SMILES: [CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[CH3:38])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(OS(=O)(=O)C(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(C2[C:27](C3N=CN(C4C=CC=CC=4)C=3)=[C:26](C(F)(F)F)[O:25]N=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:26](=[O:25])[CH3:27])=[C:11]([C:13]([F:14])([F:15])[F:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2cc(C(F)(F)F)on2)c1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Product: CC(=O)c1c(-c2cccc(F)c2)noc1C(F)(F)F
Yield: 51 %

Procedure:
As described for Example 1e, 3-(3-fluoro-phenyl)-5-trifluoromethyl-isoxazole (20 g, 86.5 mmol), instead of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, was converted to the title compound (12.2 g, 51%) which was obtained as a light yellow oil. MS: m/e=272.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35](N)=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[OH-:38].[K+].O.Cl>CO>[Cl:1][C:2]1[C:3]([C:35]([OH:36])=[O:38])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=3)[C:6]=2[CH:34]=1
Reactant: [OH-]
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(=O)O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol (10 mL) was stirred at 100° C. for 1 day. The mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 36 mg (25%) of the title compound as white solids: mp 145-150° C.; MS (ESI) m/z 541 (M+H)+; 1H-NMR (DMSO-d6) δ 8.10 (1H, s), 7.76 (2H, d, J=7.9 Hz), 7.36-7.47 (6H, m), 7.10 (1H, s) 3.28 (2H, m), 2.69-2.81 (4H, m), 2.34 (3H, s), 1.24 (3H, t, J=7.5 Hz); IR (KBr) αmax : 3450, 1701, 1517, 1340, 1163, 1091, 900 cm−1.