Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:34])[C:31]([NH2:33])=[O:32].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:29][N:30]([CH3:34])[C:31](=[O:32])[NH:33][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)Nc2ccc3cn(C)nc3c2)ccn1
Temperature: 110 °C
Yield: 71.3 %

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (110 mg, 0.25 mmol, prepared as detailed infra in Example 4A) and 1,1-dimethylurea (114 mg, 1.3 mmol) were suspended in dioxane (3 mL) under a nitrogen atmosphere and treated consecutively with DMF (1 mL), cesium carbonate (98 mg, 0.3 mmol), Pd2 dba3 (5 mg, 0.005 mmol) and Xantphos (9 mg, 0.015 mmol). The reaction mixture was flushed with nitrogen and heated for 5 hours at 110° C. (bath temperature). On cooling the reaction was concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica get (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5) to give 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide (79 mg, 71%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.15 (1H, s), 8.80 (1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.82 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.22-7.32 (2H, m), 6.95 (1H, d), 6.68 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 2.91 (6H, s); m/z (ES+) 444 [M+H]+, 223; Mp. 184° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethylaniline (48 μl, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (14 mg, 21%). 1H NMR (CDCl3): 9.70 (dd, J=0.8, 2.0 Hz, 1H), 8.74–8.70 (m, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 7.75 (s, 1H), 7.43–7.38 (m, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 2.38 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31][CH3:32])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31][CH3:32])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenoxy]acetate (64 mg, 0.14 mmol, 1.0 eq) in THF (3 mL) was added an aqueous solution of LiOH (2M aqueous solution, 2 mL, 4 mmol). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo give the title compound as a white solid (32 mg, 53%).
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9].ClCCl.ClC1C=CC=CC=1>ClC(Cl)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=N[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Dinitrogen trioxide gas (1.5 g) was introduced into a solution of the thus prepared 3-isopentyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (4.68 g, 11.38 mmol) in a mixture of dichloroethane (50 ml), dichloromethane (10 ml), and monochlorobenzene (10 ml) with thorough stirring at 10°-18° C., and stirring was continued for further one hour at the same temperature. The reaction mixture was vacuum-concentrated at 28° C. or below and purified by column chromatography (packing silica gel; eluent: octane/isopropyl acetate 4:1) to obtain 3-isopentyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea (3.82 g, 8.68 mmol); yield 76.3%; m.p. 66°-68° C.; [α]D20 +65.3° (C 1.0, methanol).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].[S:8](=O)(=[O:11])([OH:10])[O-:9].[NH4+].N>O>[S:1]([O:5][S:8]([O-:11])(=[O:10])=[O:9])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=S(=O)([O-])O
Agent: N
Agent: [NH4+]
Solvent: O
Product: O=S(=O)([O-])OS(=O)(=O)[O-]

Procedure:
Halstead (J. Appl. Chem., 1970, 20:129-132) describes the decomposition of ammonium sulfate at 400° C. The first reaction converts ammonium sulfate to ammonium bisulfate and ammonia. In a second reaction, the ammonium bisulfate dehydrates to form a water molecule and ammonium pyrosulfate, (NH4)2S2O7. Further heating of the ammonium pyrosulfate to form sulfur dioxide and nitrogen, which are not desired products from ammonium sulfate, is also carried out.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[CH3:28][N:29]([CH3:30])[CH:25]([C:21]1[CH:20]=[C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:24]=[CH:23][CH:22]=1)[CH2:27][OH:26]
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(CO)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% dimethylamine in ethanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder from the mixture of isomers as gave ABD784. 1H NMR (300 MHz, CDCl3): δ 2.08 (6H, s), 3.40 (3H, m), 3.48 (1H, m), 3.62-3.64 (1H, m), 6.87-6.96 (3H, m), 7.04-7.12 (2H, m), 7.20-7.25 (1H, m), 7.33-7.40 (1H, m), 7.53 (2H, d, J=8 Hz) and 7.78 (2H, d, J=8 Hz). MS, m/z: Calcd, 432.132. Found, 432.56 (M).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.FC(F)(F)C(O)=O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
A mixture of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH2:41][C:42]([OH:44])=O)[C:37]([O:39][CH3:40])=[O:38])[NH:31]1)=[O:29])[CH3:26].CN1CCOCC1>CN(C)C=O>[CH3:40][O:39][C:37]([N:36]1[CH2:41][C:42](=[O:44])[N:31]2[CH:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:34][CH2:33][CH:32]2[CH2:35]1)=[O:38]
Reactant: CCOC(=O)C1CCC(CN(CC(=O)O)C(=O)OC)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Yield: 76.5 %

Procedure:
HATU (390 mg, 1.03 mmol) was added to solution of 5-[(carboxymethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (187 mg, 0.68 mmol) and 4-methylmorpholine (375 μL, 3.4 mmol) in dimethylformamide (30 mL). After 50 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (20 mL) which was washed with half saturated sodium chloride (2×10 mL), saturated sodium bicarbonate (2×10 mL) and dried over sodium sulfate. The aqueous phase also contained product. The water was removed under reduced pressure and the residue was azeotroped with toluene and then stirred with ethyl acetate (50 mL). The mixture was filtered and combined with the organic extracts. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (141 mg, 0.52 mmol, 76%). C12H18N2O5 calculated 270.1, observed [M+1]+ 271.1; rt=1.54 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[Cl:30][CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:30].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:31][C:32]3[N:33]=[C:34]([CH3:37])[S:35][CH:36]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1csc(C)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg, 1 mmol), 4-chloromethyl-2-methylthiazole hydrochloride (368 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 24 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in methanol (15 ml) and 1M sodium hydroxide (2 ml) was added and the mixture stirred for 30 minutes. Concentrated hydrochloric acid (0.5 ml) was added. The solvent was removed by evaporation. The residue was purified by reverse phase HPLC eluting with a gradient (0-70%) of methanol in water. Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions of pure product and the solvent was removed by evaporation. The residue was triturated with acetone, collected by filtration, washed with acetone and dried under vacuum at 55° C. to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (225 mg, 48%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])(=[O:32])=[O:31])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CS(C)=O>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:30]([C:26]1[N:25]=[C:24]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(c1cccc(Cl)n1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(S(=O)(=O)c4ccccc4F)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.6 g, 2 mmol), 2-chloro-6-(2-fluorophenylsulfonyl)pyridine (0.400 g, 1 mmol), 2M sodium carbonate (1 mL, 2 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (8 mL). The flask was heated in a pre-heated (95° C.) heat bath while stirring under inert atmosphere overnight. The mixture was cooled, diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to provide N-(6-(6-(2-fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428. Calculated exact mass for C20H14FN3O3S3: 427. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.20-8.36 (m, 2H), 8.08-8.19 (m, 2H), 7.95 (d, J=7.5 Hz, 1H), 7.79-7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.56 (m, 1H), 7.44 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[OH-:13].[Na+].O=O>O>[O:7]=[C:6]([OH:8])[C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:13])[OH:11])[OH:10])[OH:9]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: [OH-]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
50.0 g of gluconolactone is dissolved in 950 ml demineralised water. The pH is adjusted to 6.0 with 25 g of a 45% w/w sodium hydroxide solution. The solution is heated to 55° C. under nitrogen, until no more oxygen is detected. 6.35 g of the prepared Pb/Pt/C catalyst (ratio Pt/Pb 5/2) is added and the suspension is stirred at 1300 rpm for another 10 minutes under nitrogen. The reaction is started by switching from nitrogen to oxygen (maximum 10% oxygen in the mixture). The reaction is continued without further pH control. The reaction is stopped after 2.5 hours reaction time.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:15][CH:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=3)[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Clc1nc2ccccc2s1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1nc2ccccc2s1

Procedure:
N-(1,3-Benzothiazol-2-yl)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 2-chlorobenzothiazole (143 mg, 0.84 mmol) in a similar manner as described in Example 22 to give 11 mg (10%) of a yellow solid. 1H-NMR (CDCl3): δ 9.31 (s, 1H), 7.70-7.62 (m, 3H), 7.39 (t, 1H), 7.29-7.17 (m, 4H), 5.38-5.32 (m, 1H), 2.77-2.75 (m, 2H), 2.45-2.38 (m, 1H), 2.10-1.99 (m, 3H); MS m/z (M−1) 396, 398.
Reaction SMILES: [C:1](=[O:22])([O:18][CH:19](Cl)[CH3:20])[O:2][CH2:3][CH2:4][CH:5]([CH3:17])[CH:6]([O:13][N+:14]([O-:16])=[O:15])[CH:7]([O:9][N+:10]([O-:12])=[O:11])[CH3:8].[CH2:23]([C:27]1[N:28]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[N:53]([C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[N:52]=[N:51][N:50]=3)=[CH:39][CH:38]=2)[C:29]([C:33]([OH:35])=[O:34])=[C:30]([Cl:32])[N:31]=1)[CH2:24][CH2:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([C:27]1[N:28]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[N:53]([C:54]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:52]=[N:51][N:50]=3)=[CH:41][CH:42]=2)[C:29]([C:33]([O:35][CH:19]([O:18][C:1]([O:2][CH2:3][CH2:4][CH:5]([CH3:17])[C@@H:6]([O:13][N+:14]([O-:16])=[O:15])[C@H:7]([O:9][N+:10]([O-:12])=[O:11])[CH3:8])=[O:22])[CH3:20])=[O:34])=[C:30]([Cl:32])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(Cl)OC(=O)OCCC(C)C(O[N+](=O)[O-])C(C)O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R,5R))-3-methyl-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (1.01 g, 3.26 mmol) was added to a stirred solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 3, 3.32 g, 4.88 mmol) and Cs2CO3 (2.40 g, 7.33 mmol) in DMF (18 mL). The solution was stirred at room temperature overnight. The mixture was diluted with a solution of NaH2PO4 5% (40 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (4×20 mL) and brine. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, TLC method: n-Hexane/EtOAc 7:3, RE 0.45) affording the title compound that was used in the next step without any further characterization.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][C:24]=1[C:41]([F:44])([F:43])[F:42])[NH2:22].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:18][N:22]=[C:21]([C:23]4[CH:40]=[CH:39][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:31]5)=[CH:25][C:24]=4[C:41]([F:44])([F:42])[F:43])[N:20]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(C(F)(F)F)c2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
A mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.030 g, 0.104 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.039 g, 0.104 mmol), BOP-Cl (0.035 g, 0.136 mmol), and triethylamine (0.044 mL, 0.313 mmol) in N,N-dimethylformamide (1 mL) was shaken on platform shaker at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a mixture of 20% mixture of ethyl acetate in hexane to give tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.010 g, 0.017 mmol, 16% yield) as a white solid. The compound had an HPLC ret. time=3.16 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=595.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1.C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:48]([C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:55])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.250 g, 0.415 mmol), in tetrahydrofuran (5 mL), were added, nicotinoyl chloride-hydrochloride (0.148 g, 0.83 mmol), triethyl amine (0.210 g, 2.07 mmol, 0.289 mL), and 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification. ES-MS (m/z) 708 [M+1]+.