Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+].CCOC(C)=O>C(Cl)(Cl)(Cl)Cl>[Br:30][C:13]1[NH:14][C:15]2[C:11]([C:12]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:10][CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution (0.14 M) of tert-butyl-3-cyclohexyl-1H-indole-6-carboxylate in CCl4 was added NBS (1.1 eq.) portionwise over a period of 1 h at RT. The resulting mixture was stirred 2 h at RT, then a saturated aqueous solution of sodium thiosulfate was added and the reaction mixture vigorously stirred for 1 h. EtOAc was then added and the organic layer was separated and washed with a saturated aqueous solution of sodium thiosulfate (3×) then dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (Flashmaster Personal, petroleum ether:EtOAc, 20:1) to give the title compound (68%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.33-1.39 (m, 3H), 1.54 (s, 9H), 1.65-1.99 (m, 7H), 2.73-2.81 (m, 1H), 7.52 (d, J 7.6, 1H), 7.70 (d, J 77.6, 1H), 7.83 (s, 1H), 11.92 (br s, 1H); MS (ES+) m/z 379 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 67 %

Procedure:
A mixture of 6-hydroxy-2,3-dihydroinden-1-one (8.1) (available from Aldrich) (5.0 g, 34 mmol), 1-(bromomethyl)benzene (available from Aldrich) (4.4 mL, 37 mmol) and cesium carbonate (25 g, 78 mmol) in DMF (40 mL) was stirred at room temperature for 23 hours. The resulting mixture was diluted with EtOAc (400 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give product 8.2 in 67% yield.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C([O-])(=O)C.[Na+].[C:24]([O:27][C:28](=O)C)(=[O:26])[CH3:25]>O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:28]([O:27][C:24](=[O:26])[CH3:25])[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:7])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(OC(C)=O)c2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 24 g of 2-Benzylidene-malonic acid diethyl ester in 60 ml of acetic acid anhydride, 7.5 g sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(OCC)(=O)C>C1COCC1>[NH2:7][CH2:8][CH2:9][S:10]([C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)=[O:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCSc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCS(=O)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C

Procedure:
A solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 39 above) (150 mg, 0.35 mmol) in THF (approximately 15 mL) was treated with mCPBA (Acros, 97 mg, 0.42 mmol, 75%) at 0° C. The reaction mixture was allowed to stir and warm up to room temperature overnight. The mixture was poured into ethyl acetate and washed successively with aqueous saturated Na2S2O3 and aqueous saturated K2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by HPLC (silica gel, 40% ethyl acetate in hexanes). The resulting intermediate was precipitated out of THF with excess of pentane. This material was then dissolved at 0° C. in 50% TFA in CH2Cl2 solution (10 mL) that contained H2O (0.5 mL) and stirred for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and extracted with aqueous ammonium hydroxide. The organic layer was dried over Na2SO4, filtered and concentrated to an orange solid. This solid was dissolved in THF and precipitated with excess of pentane to give 5-(2-amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as an orange solid. (Yield 75 mg, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([C:13]#[N:14])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCOC(C)=O>[C:13]([C:5]1[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[N:7][C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)[N:4]=1)#[N:14]
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2cccc(F)c2)ccc1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
A mixture of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (200 mg), 3-fluorophenylboronic acid (243 mg), tetrakistriphenylphosphine palladium (20.1 mg) and Na2CO3(246 mg) indioxane (10 ml) and water (2 ml) was stirred at 90° C. for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N′-[3-cyano-6-(3-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg) as white powder.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[CH:6]=1.[OH-].[Na+]>CO.O>[Cl:14][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:15])=[O:2])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of (3-Chloro-5-nitro-phenyl)-acetic acid methyl ester (327, 920 mg, 4.0 mmol) in 20 mL of MeOH was added a solution of NaOH (EM, 1.6 g, 40 mmol) in 10 mL of H2O. The mixture was stirred for 2 h. MeOH was removed under reduced pressure, and the mixture was diluted with water, brought to pH 2 with con. HCl. The mixture was extracted 3× with EtOAc (50 mL). The organic layers were washed twice with a brine solution (50 mL), dried over Na2SO4. Removal of the solvent gave 810 mg (94%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.17-8.14 (m, 2H), 7.84 (br s, 1H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[CH3:12][NH2:13]>C(Cl)(Cl)Cl>[CH3:12][NH:13][S:7]([C:6]1[CH:5]=[C:4]([Cl:11])[S:3][C:2]=1[Cl:1])(=[O:9])=[O:8]
Reactant: CN
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc(Cl)sc1Cl

Procedure:
3500 ml. of absolute chloroform are placed in a 4 liter volume flask and 533 g. of 2,5-dichlorothiophene-3-sulfonic acid chloride are dissolved therein. Dry methylamine is passed in at 20° with stirring until the solution gives a basic reaction with moistened indicator paper. The solution is stirred for an additional 11/2 hours at room temperature, then extracted several times with 0.5 N HCl in a separating funnel, dried with anhydrous sodium sulfate, and finally concentrated by evaporation in vacuo. The oil thus obtained is placed in a low temperature container, where it crystallizes. The product thus obtained is purified by recrystallization from 1500 ml. of carbon tetrachloride, is dried in a vacuum drying cabinet at 40° and 2,5-dichlorothiophene-3-sulfonic acid methylamide having a melting point of 59°-61° is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)[N:28]=2)=[CH:19]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: N[C@H]1CC[C@H](O)CC1
Product: O[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1

Procedure:
Using the procedure of example 1, trans-4-amino-cyclohexanol (200 mg) was reacted with compound 1f (100 mg) to provide compound 18 (18 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, J=8.0 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.26 (dd, J=8.0 Hz, 4.8. Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 3.91 (m, 1H), 3.65 (m, 1H), 2.17 (m, 2H), 2.05 (m, 2H), 1.45 (m, 4H). MS (ESI) m/z: 310 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([SH:16])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:16][C:12]2[N:11]=[C:10]([NH2:9])[CH:15]=[CH:14][N:13]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: Nc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccnc(Sc2cnc(N)s2)n1
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A mixture of 2-amino-5-bromothiazole hydrochloride (2.2 g), 4-amino-2-mercaptopyrimidine (2.2 g) and potassium carbonate (6.5 g) in N,N-dimethylformamide (100 ml) was heated at 90° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The solution was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give solid. The solid was triturated with ethanol to give 2-amino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.25 g, yield: 55.6%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12]C(OC(C)(C)C)=O)=[O:5].C1(C)C=CC=CC=1>O1CCOCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH2:12])=[O:5]
Reactant: COC(=O)[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4.0 M solution of hydrochloric acid in 1,4-dioxane (20 mL) was added to a solution of (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid methyl ester (1.28 g, 4.97 mmol) in 1,4-dioxane (15 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, then toluene (40 mL) was added and the volatiles were removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-amino-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)(=[O:26])=[O:25])[CH2:19][CH2:18]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[S:24]([NH:23][CH:20]1[CH2:21][CH2:22][N:17]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:18][CH2:19]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(NS(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-(piperidin-4-yl)naphthalene-2-sulphonamide hydrochloride salt to give 4-(2-naphthalenesulphonamido)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperidine in 28% yield;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.Cl.[F:10][C:11]([F:22])([F:21])[C:12]1[N:16]2[CH2:17][CH2:18][NH:19][CH2:20][C:15]2=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:19]2[CH2:18][CH2:17][N:16]3[C:12]([C:11]([F:22])([F:10])[F:21])=[N:13][N:14]=[C:15]3[CH2:20]2)[CH:3]=1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: Fc1cc(Br)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(c1cc(Br)ccn1)C2
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-fluoropyridine (0.216 mL, 2.1 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.399 g, 1.75 mmol) and potassium carbonate (0.482 g, 3.49 mmol) in anhydrous DMF (7.0 mL) was heated at 100° C. for 16 h. Reaction mixture was cooled, diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C11H10BrF3N5: 348.0. (M+H+); Found: 348.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].Cl>FC(F)(F)CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)ccc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCC(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 180 °C
Yield: 44 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.13 g, 0.25 mmol) and 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.077 g, 0.25 mmol) in 2,2,2-trifluoroethanol (1.5 mL) was added HCl (0.13 mL, 4M in dioxane, 0.50 mmol). The reaction was heated at 180° C. for 40 min in the microwave. The reaction mixture was quenched with sodium methoxide (0.5M in MeOH) and concentrated. Purification by flash chromatography, and recrystallization with EtOH provided the title compound (0.082 g, 0.11 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ 1.19-1.30 (m, 2H), 1.39 (t, J=6.6 Hz, 3H), 1.43-1.53 (m, 1H), 1.57-1.68 (m, 2H), 1.74 (d, J=13.9 Hz, 2H), 2.53-2.64 (m, 2H), 2.92 (s, 3H), 3.07-3.18 (m, 2H), 3.66 (d, J=11.4 Hz, 2H), 3.76 (s, 3H), 4.23 (d, J=6.2 Hz, 2H), 6.43-6.53 (m, 2H), 6.63 (s, 1H), 6.86-6.97 (m, 1H), 7.15 (t, J=7.6 Hz, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.32-7.43 (m, 3H), 7.66 (d, J=9.2 Hz, 1H), 7.71 (d, J=11.5 Hz, 1H), 8.01 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.39 (s, 1H), 9.33 (br. s., 1H), 9.71 (s, 1H). MS (ESI) m/z=782 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12](C(OC)=O)[C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:5][CH:4]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: COC(=O)C1C(=O)N(Cc2ccc(OC)cc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)CC2=O)cc1

Procedure:
Crude product A3 was dissolved in acetonitrile (50 mL) and water (50 mL) and stirred for 4 h at 80° C. The acetonitrile was evaporated off and the solids were filtered off, washed with water and taken up in DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product A4 (1.57 g) was obtained as a white solid. Overall yields (A2 to A4) are 70%. 1H NMR (400 MHz, CDCl3, 300K): δ=1.23 (2H, m), 1.41 (9H, s), 1.76 (2H, m), 3.13 (2H, m), 3.26 (2H, s), 3.37 (2H, m), 3.39 (2H, s), 3.81 (3H, s), 4.58 (2H, s), 6.87 (2H, d, J=8.6 Hz), 7.22 (d, J=8.6 Hz). 13C NMR (100 MHz, CDCl3, 300K): δ=28.8, 30.0, 46.3, 47.1, 49.8, 51.7, 55.7, 80.2, 114.6, 128.4, 130.5, 154.9, 159.8, 166.4, 206.8. MS (ES) C22H30N2O5 requires: 402. found: 425.2 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: C1CNCCNC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCCNCC2)nc1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1,4-diazepan-1-yl)nicotinamide. MS (Q1) 408 (M)+.
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])=[CH:7][CH:6]=1)=O.[CH3:26][OH:27]>C(OCC)(=O)C>[CH3:26][O:27][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]([S:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CO
Reactant: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(Sc1ccccc1C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1 g (30.2 mmol) of 2-(4-methoxycarbonylphenylthio)2-tert.butoxycarbonylcyclohexanone is dissolved, together with 0.37 g (3.3 mmol) of potassium tert. butylate, in 100 ml of methanol of reagent purity and the solutions is left to stand for 2 hours at room temperature. It is then diluted with 500 ml of ethyl acetate and the organic phase is washed with water and a saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation. After drying in a high vacuum 11.3 g of an oily product are obtained, which is sufficiently pure to be used for further reactions.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH2:33]Br)[CH:26]=1>CC(C)=O>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH2:33][O:1][C:2]2[CH:3]=[C:4]([C:8]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH:26]=1
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: BrCC#Cc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(OC)(c1cccc(OCC#Cc2cccnc2)c1)c1nccs1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.25 g), potassium carbonate (0.28 g), 3-(3-pyridyl)prop2-yn-1-yl bromide hydrobromide (0.28 g) and acetone (5 ml) was stirred and heated to reflux for 17 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with hexane/ethyl acetate (1:1 v/v) to give 2-[1-[3-(3-(3-pyridyl)prop-2-yn-1-yloxy)phenyl]-1-methoxypropyl]thiazole as an oil (0.217 g, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[C:21]([C:25]([O:27]C)=[O:26])=[CH:22][S:23][CH:24]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]([CH3:34])[CH3:35])[CH:30]=[CH:29][C:16]=2[C:17]2[O:26][C:25](=[O:27])[C:21]3[C:20](=[CH:24][S:23][CH:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(-c2nc3cscc3c(=O)o2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(dimethylamino)benzoylamino]thiophene-3-carboxylate (2.3 g, 4.6 mmol) in MeOH (100 mL) and THF (50 mL) was treated with a solution of 1 N aqueous NaOH (10 mL) at 60° C. for 24 h. The mixture was concentrated to dryness, mixed with brine (25 mL) and glacial acetic acid (0.65 mL), then extracted with CHCl3 (2×100 mL). The extracts were dried over MgSO4, cooled to 0° C. and treated with Et3N (1 g) followed by a 2 M CH2Cl2 solution of oxalyl chloride (3.5 mL). The mixture was stirred overnight, concentrated to dryness, and treated sequentially with potassium carbonate (11 g), THF (20 mL), water (20 mL), and di-tert-butyl dicarbonate (8 g). The mixture was stirred overnight, diluted with more THF (50 mL) and treated with NaCl (20 g). The organic layer was separated, dried over MgSO4, and concentrated to an oil which was purified by silica chromatography using 15% EtOAc in hexanes to give 2 g of product as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
In a manner similar to Preparation 1, react 1-methylpiperazine with 1-fluoro-4-nitrobenzene to obtain the title compound.