Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1[CH:26]=[CH:25]N=C1.[Cl-].[NH4+]>CN(C)C=O>[CH2:25]([O:12][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)=[O:13])[CH3:26]
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2[nH]1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To the solution of 10.0 g (49.0 mmol) 5-hydroxyindole-2-carboxylic acid (commercially available) in 30 ml N,N-dimethylformamide, 7.7 g (51.1 mmol) tert-butyldimethylchlorosilane and 3.5 g (51.4 mmoL) imidazole was added. After 1 hour, the solution was poured on 10% aqueous ammonium chloride solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel with ethyl acetate:n-hexane (1:2 v/v) as eluant to give 15.3 g (98.5%) of the compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=C(O)C=C2C=1C(C)=C(CC1C=CC(Cl)=CC=1)C(C)=N2>CO>[Cl:8][C:6]1[CH:5]=[C:4]([OH:9])[C:3]2[C:17]([CH3:18])=[C:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)[C:20]([CH3:21])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(O)cc(Cl)c1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc2cc(O)cc(Cl)c2c(C)c1Cc1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: Cc1nc2cc(Cl)cc(O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-5-chlorophenol (0.46 g), 3-(4-chlorobenzyl)pentane-2,4-dione (0.72 g), and p-toluenesulfonic acid monohydrate (0.26 g) was heated at 160° C. for 2 hours. The mixture was cooled to room temperature, diluted with methanol (5.0 mL) and sonicated. The resulting precipitate was collected by filtration, washed with methanol and dried to afford a 50:50 mixture of title compound and 5-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-7-ol as an off-white solid, 0.67 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:10]([Cl:17])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:26])[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:17][C:10]1[N:9]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:3][C:4]=2[Cl:26])=[N:12][C:11]=1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)c1nc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.17 h
Yield: 78.2 %

Procedure:
A mixture of 2-[2-(4-bromo-2-chlorophenyl)-5-chloro-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (184 mg, 0.37 mmol), 3-methanesulfonyl-phenylboronic acid (90 mg, 0.45 mmol), K2CO3 (0.15 g, 1.1 mmol), Cl2 Pd(dppf)-DCM (15 mg, 5 mol %) and H2O (0.2 mL) in DME (2 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 70 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (165 mg, 78%) as a white solid. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.93 (m, 1H), 7.84 (m, 1H), 7.73 (d, 1H), 7.67 (m, 1H), 7.33-7.47 (m, 5H), 3.42 (br s, 1H), 3.06 (s, 3H), 1.68 (s, 6H); MS (ES): 591, 593, 595 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][NH:13][CH2:12]1.[CH3:30]I>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][N:13]([CH3:30])[CH2:12]1
Reactant: CI
Reactant: COc1cccc(OC)c1C1CNCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CN(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A cooled (0° C.) solution of 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-piperazin-2-one (106 mg; 0.25 mmol) in anh. THF (1.5 ml) was treated with a solution of CH3I (33 mg; 0.23 mmol) in anh. THF (0.5 ml). The resulting mixture was allowed to warm-up slowly to rt, and stirring at rt was then continued for 15 h. Brine was added, and the mixture was extracted with AcOEt (3×20 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=0.87 min.; [M+H]+: 425.02 g/mol.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:29]#[N:30])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:31])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:29]([C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:31])#[N:30]
Reactant: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(O)C2=O
Yield: 45.9 %

Procedure:
A mixture of 2-benzyloxy-5-cyano-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.16 g, 0.40 mmol, from Example D2) and 5% Pd/BaSO4 (0.05 g) in THF (75 mL) was shaken in an atmosphere of hydrogen at 50 psi at ambient temperature for 86 hours with an additional 0.05 g of 5% Pd/BaSO4 being added after 70 hours. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica using chloroform/methanol (10:1) to give 0.059 g of the title compound, mp >250° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 3792.8 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0658 g, 0.215 mmol) and (2-bromoethyl)benzene (0.050 mL, 0.366 mmol) in 1MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.051 4 g, 48.9%). EI-MS m/z 410 (M+) Rt (1.83 min).
Reaction SMILES: [C:1]1([C@@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 1,1-dimethylethyl [((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (7.5 g, 20.4 mmol), accessed via the method of 11B, and methyl iodide (14.4 g, 102.0 mmol, 5 eq) in 100 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (30.6 mL, 30.6 mmol, 1.5 eq). The reaction mixture was stirred 8 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (1:4)) to give the title compound (3.1 g, 8.1 mmol, 40%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 10H), 4.36-4.27 (m, 2H), 3.67-3.45 (m, 1H), 3.26-3.13 (m, 2H), 3.07-2.99 (m, 1H), 2.77-2.62 (m, 3H), 1.39-0.80 (m, 12H). ES-LCMS m/z 404.2 (M+Na).
Reaction SMILES: [CH3:1][C@H:2]([NH:10][CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH2:12]([Cl:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH3:1][C@H:2]([N:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:19]
Reactant: ClCc1ccccc1
Reactant: CN[C@@H](C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](Cc1ccccc1)N(C)Cc1ccccc1
Product: Cl
Yield: 82.5 %

Procedure:
Benzphetamine hydrochloride is prepared in typical fashion in toluene. After reaction of methamphetamine with benzyl chloride in the presence of sodium carbonate, the reaction mass contained 28.76 g (0.1202 mole) of the acid salt which was a yield of 82.5%. To the reaction mass were added 100 g of deionized water. The mixture was stirred to dissolve the salts and then transferred to a separatory funnel. The reaction flask was rinsed with 50 g of water and 65 g of toluene. The rinsings were added to the separatory funnel. The layers were separated into a 169.5 g water layer and a 104.2 g of organic layer. The water layer was extracted twice with 27 g portions of toluene. The organic layers were combined bringing the total amount of organic medium to 156.1 g. The combined toluene portions were then washed with 33 g of deionized water.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:14].[C:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])[CH3:16].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.O>[C:15]([NH:18]/[C:19](=[CH:6]/[C:5]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:2]([NH2:1])=[C:3]([Cl:14])[CH:4]=1)/[C:20]([OH:22])=[O:21])(=[O:17])[CH3:16]
Reactant: Nc1c(Cl)cc(C=O)cc1C(F)(F)F
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N/C(=C/c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 128 °C
Reaction time: 2 h

Procedure:
A mixture of 50.0 g (224 mmol) 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde, 39.3 g (335 mmol) N-acetylglycine, 27.5 g (335 mmol) sodium acetate and 200 ml acetic anhydride was stirred for 2 hours in an oil bath at an oil bath temperature of 128° C. After cooling to an oil bath temperature of 90° C. 100 ml of water were added dropwise and the resulting suspension was added to a mixture of 1000 ml of water and 500 ml of toluene. The precipitate formed was suction filtered, washed with 300 ml of toluene and 500 ml of water and dried overnight at 60° C. in the circulating air dryer.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2].[C:22](=[O:28])=[N:23]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[N:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:22]([NH2:23])=[O:28])[C:9](=[O:14])[CH:8]2[C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2C(N)=O

Procedure:
The title compound was prepared from 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole (Example 9C) according to the procedure of Example 2C, using 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole (70 mg, 0.23 mmol), N-chlorosulfonyl isocyanate (25 L, 0.29 mmol) and acetonitrile (1.5 mL). Reaction time: 4 hours. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in chloroform for 3 days. After removal of the solvent in vacuo, the product was purified by flash chromatography on silica gel using 2:1 ethyl acetate/hexane as eluant and trituration with ether. Yield: 30 mg (37%). M.p. 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]I)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:38])[NH:33][C:34](=[S:37])[NH:35][CH:36]=2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:37][C:34]3[NH:35][CH:36]=[C:31]([CH2:30][C:27]4[CH:28]=[N:29][C:24]([O:23][CH3:22])=[N:25][CH:26]=4)[C:32](=[O:38])[N:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 50 °C
Yield: 8.5 %

Procedure:
A mixture of 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (400 mg, 0.938 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (258 mg, 1.031 mmol) and K2CO3 (259 mg, 1.875 mmol) in DMF (3 mL) was heated with a microwave reactor at 50° C. for 15 min. Purification via reverse phase flash chromatography then afforded the title compound (44 mg, 0.080 mmol, 8.55% yield). LCMS: rt=3.76 min, [M+H+]=549
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (13.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (500 ml), and to the suspension was added potassium carbonate (9.5 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl bromoacetate (4.2 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml) and precipitated crystals were recovered by filtration. The thus obtained crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol), and the crude product was re-precipitated from chloroform-hexane and recovered by filtration to obtain the title compound (9.0 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[F:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78](Cl)=[O:79].FC1C=CC=C(F)C=1C(Cl)=O>>[F:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:79]
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Reactant: O=C(Cl)c1ccccc1F
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1)c1ccccc1F

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-fluorobenzoyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 620 (M+H)+; (ESI(−)) m/e 618 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.54 (s, 1H), 9.62 (s, 1H), 8.81 (d, 1H), 8.29 (d, 1H), 8.03 (s, 1H), 7.84 (d, 1H), 7.67 (td, 1H), 7.53-7.62 (m, 3H), 7.50 (d, 1H), 7.42-7.48 (m, 1H), 7.30-7.40 (m, 3H), 7.22 (t, 1H), 6.87 (d, 1H), 6.63 (d, 1H), 3.52-3.59 (m, 4H), 3.17 (d, 1H), 3.66-3.77 (m, 2H), 2.51-2.55 (m, 1H), 2.37-2.43 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: CC(C)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.5 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (100 mg, 0.36 mmol) was dissolved in DMF (2.5 mL) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 1-bromomethyl-4-isopropylbenzene (83.5 mg, 0.39 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 29 mg of the title compound 17 as a yellow oil. 1H NMR (CDCl3): δ 7.88-7.83 (m, 2H), 7.59-7.47 (m, 3H), 7.21-7.14 (m, 4H), 3.89-3.78 (m, 1H), 3.45 (s, 2H), 2.95-2.88 (m, 3H), 2.03-1.84 (m, 5H), 1.51-1.44 (m, m, 2H), 1.23 (d, 6H, J=7.01 Hz), 1.01-0.93 (m, 2H), 0.79-0.69 (m, 2H). LC: 100%. MS (EI): m/z 413 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:12][C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=1.C[O:15][CH:16]([O:19]C)[CH2:17]Br.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:12][C:4]([CH3:3])=[CH:5][C:6]=2[C:7]1=[O:13]
Reactant: COC(CBr)OC
Reactant: Cc1cc2c(=O)[nH]ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.32 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 2-Methyl-5H-furo[3,2-c]pyridin-4-one (0.57 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde dimethylacetal (2.3 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (2 ml) was added to an acetone solution (10 ml) of the residue, and the liquid was stirred at 70° C. for 10 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.56 g) as a white solid.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:20]>C1COCC1.CC(O)=O.O>[O:1]=[CH:2][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:20]
Reactant: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCC1OCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Yield: 85 %

Procedure:
5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.5 mmol) was dissolved in a mixture of THF (4 mL), AcOH (8 mL) and H2O (0.5 mL), heated at reflux for 16 h, then concentrated to dryness. The residue was dissolved in EtOAc, washed with sat aq NaHCO3, dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by MPLC eluting with CH2Cl2/MeOH (0-5% gradient) to give 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (200 mg, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C1(C)C=CC=CC=1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOP(=O)(CN)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOP(=O)(CN=Cc1ccccc1Cl)OCC
Reaction time: 0.5 h
Yield: 100 %

Procedure:
14 g. (0.1 mol) 2-chlorobenzaldehyde are added dropwise, at ambient temperature, to a solution of 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. toluene. When the addition has ended, stirring is continued for 30 minutes. The water formed during the reaction is removed by decantation. The toluene phase is washed with 50 ml. of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and then evaporated. This gives 29 g. (yield: 100%) diethyl N-(o-chlorobenzylidene)-aminomethylphosphonate in the form of a yellow oil giving a single spot in TLC (silica plate, eluant: ethyl acetate, Rf=0.45).