Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][OH:15].[C:21]1([S+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][O:15][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1.[C:34]1([S+:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)([O-])C(F)(F)CO
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Under ice cooling, 2.0 g (12 mmol) of the 4-vinylbenzoyl chloride in methylene chloride was added dropwise to a mixture of 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate in Synthesis Example 1-13, 1.21 g (12 mmol) of triethylamine, 0.24 g (2 mmol) of N,N-dimethylaminopyridine, and 20 g of methylene chloride. The resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, which was washed with dilute aqueous ammonia and then with water. Thereafter, methyl isobutyl ketone was distilled off in vacuum. Diisopropyl ether was added to the residue. By decantation, the target compound, triphenylsulfonium 1,1-difluoro-2-(4-vinyl-benzoyloxy)-ethane-1-sulfonate was obtained. Colorless oil, 5.1 g (yield 86%). The compound has the following structure.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]=1[CH3:23])=[O:8].N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.Cl>[C:30]1([S:36]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:11]=2[CH3:23])=[O:8])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the carboxamide (0.304 mmol) of step 1 above in dichloromethane (5 mL) in a 25 ml round bottom flask was added pyridine (0.304 mmol) and benzenesulfonyl chloride (0.304 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with hydrochloric acid (2N) and extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layers were then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown oil. The oil was further purified by silica gel chromatography using 5% ethyl acetate in hexanes as the mobile phase to yield ′3-[(phenylsulfonyl)amino]-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)thiophene-2-carboxamide as a white to yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=1.[C:16]([Mg]Br)#[CH:17]>CCCCCC.C(OCC)(=O)C>[C:16]([CH:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:10]=1)[OH:15])#[CH:17]
Reactant: C#C[Mg]Br
Reactant: O=Cc1nc(COC2CCCCO2)cs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CC(O)c1nc(COC2CCCCO2)cs1

Procedure:
The product was prepared starting with the product of Stage B and ethynyl magnesium bromide using the procedure of Example 1 to obtain the desired product with a Rf=0.11 (hexane-ethyl acetate (7-3)).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](=[O:15])C(Cl)(Cl)Cl.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:20]([OH:22])=[O:21]>>[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH:26][C:10]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=1)=[O:15])[C:20]([OH:22])=[O:21].[NH2:26][C:25]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[NH:16][C:10]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=1)=[O:15]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(=O)O)cc1N
Product: Cn1cc([N+](=O)[O-])cc1C(=O)Nc1cc(C(=O)O)ccc1N
Product: Cn1cc([N+](=O)[O-])cc1C(=O)Nc1ccc(C(=O)O)cc1N

Procedure:
As a further alternative, the compound of the formula (14) can also be synthesized as will be described next. For example, 1-methyl-4-nitro-2-pyrrolecarboxylic acid is reacted, by using the process disclosed in Tetrahedron, 34, 2389-2391(1978), with thionyl chloride into 1-methyl-4-nitro-2-pyrrolecarboxylic acid chloride, which is then reacted with a 3,4-diaminobenzoic acid to obtain 3-amino-4-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid or 4-amino-3-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid as the exemplified compound. Here, the reaction product can also be a mixture of both the benzoic acids. Methylene chloride, chloroform, DMF or the like can be used as a solvent. Other solvents are also usable as long as they do not take part in the reactions. Heating of the thus-obtained amide compound with trilfluoroacetic acid with any solvent, which do not participate in the reaction, provides 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid. Further, 1-methyl-4-nitro-2-trichloroacetylpyrrole which is a known compound disclosed in Heterocycles, 27, 1945-1952(1988) is likewise reacted with 3,4-diaminobenzoic acid to obtain 3-amino-4-(1-methyl-4-nitro-2-pyrrolecarboxamido)-benzoic acid or 4-amino-3-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid. Here, the reaction product can also be a mixture of both the benzoic acids. The reaction product can also be converted into 1H-2-(1-methyl-4-nitropyrrole-2-yl)benzimidazole-5-carboxylic acid likewise. The reaction can also be conducted similarly by using as a starting material an equivalent carboxylic acid other than 1-methylpyrrole-2-carboxylic acid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:37]2[N:44]=[C:45]([C:47]([OH:49])=O)[CH:46]=[C:36]2[N:35]=1.[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:50]([NH:57][C:47]([C:45]1[CH:46]=[C:36]2[N:35]=[C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:37]2[N:44]=1)=[O:49])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.430 g, 0.973 mmol) was added to a suspension of 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.250 g, 0.811 mmol) and benzylamine (0.106 mL, 0.973 mmol) in tetrahydrofuran (10 mL) containing triethylamine (0.339 ml, 2.43 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and crude the product was purified by column chromatography on silica gel to give 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.280 g, 86%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>O1CCCC1>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([CH:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[OH:11])=[CH:14][CH:13]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: O=Cc1cc2ccncc2[nH]1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cc3ccncc3[nH]2)cc1
Reaction time: 3 h
Yield: 77 %

Procedure:
1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (180 mg, 1.23 mmol) was dissolved in tetrahydrofuran (6 mL) under a nitrogen atmosphere. p-Tolylmagnesium bromide in tetrahydrofuran (2.48 mL, 2.48 mmol) was added dropwise. After stirring for 3 h, the reaction mixture was quenched by pouring into a 2:1 solution of saturated ammonium chloride and water, then extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water and then brine, dried over sodium sulfate, and concentrated to provide the crude material. Purification by Biotage chromatography (silica, 0 to 18% methanol in methylene chloride) to provide (4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (226 mg, 77%) as an off-white solid: mp 78-82° C.; 1H NMR (500 MHz, CD3OD) δ2.32 (3H, s), 5.95 (1H, s), 6.36 (1H, s), 7.17 (2H, d, J=7.9 Hz), 7.34 (2H, d, 8.0 Hz), 7.51 (1H, m), 8.00 (1H, d, J=5.6 Hz), 8.59 (1H, s); ESI MS m/z 239 [C15H14N2+H]+; HPLC (Method A) >99% (AUC), tR=15.1 min.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.5 %

Procedure:
2 g (8.0 mmle) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethyl carbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dirmthylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoYl-3-t-butyl-5-(methyl-sulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-:9].[Al+3].[Cl-:11].[Cl-].Cl[CH:14]([Si:17]([Cl:20])([Cl:19])[Cl:18])[CH2:15]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:15]([C:2]1[CH:7]=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[Cl:11])[CH2:14][Si:17]([Cl:20])([Cl:19])[Cl:18]
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Product: Clc1ccc(Cl)c(C(C[Si](Cl)(Cl)Cl)c2cc(Cl)ccc2Cl)c1
Reaction time: 1 h
Yield: 287.3 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 17.35 g (118 mmol) of 1,4-dichlorobenzene and 0.47 g (3.5 mmol) of aluminum chloride were alkylated with 5.45 g (23.5 mmol) of (1,2-dichloroethyl)trichlorosilane for 20 min at 120° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane was distilled, the reaction products were vacuum distilled to give 4.56 g of [2,2-bis(2,5-dichlorophenyl)ethyl]trichlorosilane (bp; 161-163° C./0.5 torr, yield; 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](N2C=CN=C2)=[O:10])=[C:4]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:10])[N:28]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:16]2([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[OH:24]
Reactant: O=C(c1ccc(Br)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a solution of N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide (4.0 g, 9.9 mmol) in THF (20 mL) was added 2,2,2-trifluoroethylamine (1.1 g, 10.9 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow foam was partitioned between n-butyl chloride (15 mL) and aqueous 10% citric acid (15 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration to give 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H); 7.50 (br d, 2H, J=8.79 Hz); 7.34 (br d, 2H, J=8.79 Hz); 7.22 (m, 2H); 6.97 (dd, J=1.46 and 7.57 Hz, 1H); 4.35 (dq, 1H, J=8.78 and 16 Hz); 3.53 (dq, 1H, J=8.55 and 17 Hz); 3.22 (s, 1H). MS (Electrospray): m/z M+Na, Br=79, 457.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].[CH3:23][N:24]1[C:28](S(C)(=O)=O)=[N:27][N:26]=[C:25]1[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][C:28]3[N:24]([CH3:23])[C:25]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:26][N:27]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
1-[5-(3-chlorophenyl)isoxazol-3-yl]ethanol (63.4 mg, 0.28 mmol), DMF and sodium hydride (60% dispersion in oil, 15.1 mg, 0.38 mmol) were mixed under inert atmosphere and stirred at r.t for 1 h, followed by addition of 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (45 mg, 0.19 mmol). After stirring at 80° C. for 24 h, the mixture was cooled to r.t., diluted with EtOAc and washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified via column chromatography on silica using 5% methanol in EtOAc to isolate the title compound (11.7 mg). 1H-NMR: 8.81 (bs, 2H), 7.77 (s, 1H), 7.67 (m, 3H), 7.42 (m, 2H), 6.73 (s, 1H), 6.36 (q, 1H), 3.62 (s, 3H), 1.94 (d, 3H).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7]C(C([O-])=O)=[CH:5][CH:4]=1.[K+].CN(C=O)C.[C:18](Cl)(=O)[C:19]([Cl:21])=[O:20].C(Cl)[Cl:25]>>[ClH:21].[Cl:25][CH2:2][C:3]1[N:8]=[CH:7][C:18]([C:19]([Cl:21])=[O:20])=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1ccc(CO)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of potassium 6-(hydroxymethyl)pyridine-3-carboxylate (96 mg; 0.50 mmol; 1.0 eq.) in DCM (1 mL) was added DMF (0.07 mg; 0.02 eq., 0.01 mmol). The mixture was chilled at 0° C. Then oxalyl chloride (317 mg; 2.5 mmol; 5.0 eq.) was added dropwise and the resulting mixture was stirred 4 h at rt. Evaporation of the solvent gave a black line powder without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: Clc1nccc2ccc(Br)cc12
Product: CCCN(CCC)c1nccc2ccc(Br)cc12
Yield: 62 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline from step 1 (500 mg, 2.1 mmol) and dipropylamine (2.8 mL, 21 mmol) was heated at 150° C. in a sealed tube for 2 d. The reaction mixture was cooled, and the solvent was removed under reduced pressure to provide 7-bromo-N,N-dipropylisoquinolin-1-amine (400 mg): 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (d, J=6 Hz, 1H), 7.75–7.64 (m, 2H), 6.87 (d, J=6 Hz, 1H), 3.42 (q, J=7 Hz, 4H), 1.65 (q, J=7 Hz, 4H), 0.94 (t, J=7 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[C:20]([NH:7][C:6]1[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Reaction time: 1 h

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with 1 mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188°-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetyl bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268°-72° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.[NH3:37]>ClCCl.CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH2:37])=[O:28])=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cccn4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-pyrazole as described in Example 49 and isolated as white solid (0.075 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.55-8.58 (m, 1H), 7.91 (d, J=4 Hz, 1H) 7.65-7.73 (m, 4H), 7.29-7.31 (m, 1H), 7.34 (d, J=8 Hz, 2H), 7.40 (d, J=4 Hz, 1H), 6.86 (d, J=2 Hz, 1H), 6.47 (d, J=2 Hz, 1H), 6.09-6.14 (m, 1H), 5.37 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=456.2; Rt=1.19 min; HRMS (M+H)+=456.16.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.86 g, 46.6 mmol) in dry DMF (5 mL) under nitrogen and cooled to 0° C. was added a solution of benzimidazole (5.0 g, 42.2 mmol) in DMF (15 mL) and the reaction mixture was allowed to stir for 30 min at room temperature. The reaction mixture was cooled to 0° C. and a solution of 4-bromobenzyl bromide (10.6 g, 42.4 mmol) in DMF (10 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4) and evaporated. The crude product was triturated with ethyl ether and recovered by filtration. Yield: 70%. LCMS (ESI+) 387.2 and 389.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)=[O:16]
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2Br)CC1

Procedure:
A solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (500 mg, 1.77 mmol), Boc-piperazine (329 mg, 1.77 mmol), EDC (418 mg, 2.12 mmol), HOBt (286 mg, 2.12 mmol) and TEA (530 mg, 5.31 mmol) in 20 mL of DCM was stirred at room temperature overnight. The solvent was removed under reduce pressure and the crude was purified via prep-TLC to afford tert-butyl 4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.225 mmol) to afford the desired product (37 mg, 51%) as a yellow solid. 1H NMR (500 MHz, DMSO) δ 10.65 (d, J=7.9 Hz, 1H), 8.93 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.03 (dd, J=8.7, 2.1 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.61-7.54 (m, 2H), 4.20-4.11 (m, 1H), 2.66 (s, 3H), 2.28 (t, J=7.3 Hz, 2H), 2.22-2.15 (m, 2H), 2.15 (s, 6H), 1.84 (d, J=12.5 Hz, 2H), 1.51-1.31 (m, 5H), 1.21-1.09 (m, 2H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC>99% (AUC), tR=11.13 min.