Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=2)[C:19]#[N:20])=[N:12][C:11]2[C:10](=[O:23])[N:9]([CH2:24][CH3:25])[C:8]3=[N:26][C@H:27]([CH:29]([CH3:31])[CH3:30])[CH2:28][N:7]3[C:6]1=2.CO.[NH4+]=[S:40].O>CCOC(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=2)[C:19](=[S:40])[NH2:20])=[N:12][C:11]2[C:10](=[O:23])[N:9]([CH2:24][CH3:25])[C:8]3=[N:26][C@H:27]([CH:29]([CH3:31])[CH3:30])[CH2:28][N:7]3[C:6]1=2
Reactant: CCN1C(=O)c2nc(-c3ccc(F)c(C#N)c3)n(Cc3ccc(F)cc3F)c2N2C[C@@H](C(C)C)N=C12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1C(=O)c2nc(-c3ccc(F)c(C(N)=S)c3)n(Cc3ccc(F)cc3F)c2N2C[C@@H](C(C)C)N=C12
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A 10 mL microwave vial was charged with (R)-5-(1-(2,4-difluorobenzyl)-5-ethyl-7-isopropyl-4-oxo-4,5,7,8-tetrahydro-1H-imidazo[2,1-b]purin-2-yl)-2-fluorobenzonitrile (50) (275 mg, 0.558 mmol), MeOH (5 mL), and ammonium sulfide solution in water (20 wt %, 600 μL, 1.67 mmol). The reaction mixture was stirred in a microwave at 85° C. for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue obtained was diluted with EtOAc (200 mL) and brine (250 mL) and the layers separated. The aqueous phase was extracted with EtOAc (200 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using CombiFlash chromatography (silica gel, 96:4, CH2Cl2/MeOH) to provide (R)-5-(1-(2,4-difluorobenzyl)-5-ethyl-7-isopropyl-4-oxo-4,5,7,8-tetrahydro-1H-imidazo[2,1-b]purin-2-yl)-2-fluorobenzothioamide (118 mg, 40%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([C:24](=[CH:27]NC2C=CC=CC=2)[C:25]#[N:26])=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:27][C:24]=1[C:22](=[O:23])[C:21]1[CH:35]=[CH:36][CH:37]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(OCCN2CCOCC2)c1
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylaminoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2-3% MeOH/CH2/Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[CH3:36][CH:37]1[CH:42]([NH2:43])[CH:41]2[CH2:44][CH2:45][N:38]1[CH2:39][CH2:40]2.[OH-].[Na+]>C1COCC1>[CH3:36][CH:37]1[CH:42]([NH:43][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[CH:41]2[CH2:44][CH2:45][N:38]1[CH2:39][CH2:40]2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC1C(N)C2CCN1CC2
Agent: Cl
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1C(NC(=O)c2ccc(Oc3ccccc3)cc2)C2CCN1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
TEA (0.32 mL, 2.3 mmol, 1 eq) is added to a solution of 4-phenoxybenzoic acid (0.50 g, 2.3 mmol, 1 eq) in 15mL THF. Diphenylchlorophosphate (0.44 mL, 2.3 mmol, leq) is added and the mixture is stirred at room temperature. After 0.5 h, a suspension of 2-methylquinuclidin-3-amine dihydrochloride from Step N (0.49 g, 2.3 mmol, 1 eq) and TEA (1.30 mL, 9.2 mmol, 4 eq) in THF is added and the resulting mixture is stirred overnight at room temperature. 1N NaOH is added and the aqueous layer is extracted with CHCl3. The combined organic layers are dried over MgSO4, filtered and concentrated to provide 0.64 g (82%) of N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-4-phenoxybenzamide. MS (ESI) for C21H24N2O2 m/z 337.3 (M+H)+ . The fumaric acid salt of the product is made and crystallized from IPA to give the product as a white solid. Reverse phase HPLC (ZORBAX Eclipse XDB-C8, 4.6 mm×15cm, 75:5:20 H2O/CH3CN/IPA) reveals an 85:15 trans/cis mixture of isomers.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][CH2:29][CH2:30]Cl)[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:26][O:28][CH2:29][CH3:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-chloroethyl ethyl ether (0.056 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (19 mg, yield 11%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])(=[O:5])[CH3:4]>CO.C(Cl)Cl>[OH:5][CH:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])[CH3:4]
Reactant: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)O)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
Sodium tetrahydroborate (82 mg, 2.16 mmol) was added to a solution of methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (650 mg, 1.96 mmol) in methanol (20 mL) and DCM (10 mL) at −10° C. After 15 min of stirring at −10° C., the reaction mixture was quenched with water (25 mL). The volatiles were removed and the aqueous layer extracted twice with DCM. The combined organics phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with diethylether and the solid collected by filtration to give methyl 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (500 mg, 76%) as a brown solid, which used for the next step without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 65 %

Procedure:
To a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (0.86 g) in dimethylsulfoxide (8 ml) was added pivaloyloxymethyl iodide (0.67 g). This reaction mixture was stirred for 100 min. at room temperature, and then added to a mixture of water (86 ml) and ethyl acetate (86 ml) with stirring. The ethyl acetate layer was separated, washed twice with water, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure. Petroleum ether was added to the residue. Filtration of resulting crystals and drying thereof under reduced pressure gave the title compound (0.67 g) in crude form. This crude product was purified by chromatography on a reverse phase column (LiChroprep® RP-8) with a mobile phase consisting of water-acetonitrile-acetic acid (650:350:5), and the fractions containing the product were freeze-dried. The product thus obtained was contaminated with 2-cephem isomer.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][NH:21][C:22]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH:34](=O)[CH3:35].S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>C(OCC)C.CO>[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:34][CH3:35])[C:22]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCOCC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCOCC
Solvent: CO
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(=O)O)CCOCC1
Temperature: 40 °C
Yield: 62.9 %

Procedure:
1M HCl in diethyl ether (1.4 ml) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid (0.66 g, 1.43 mmol), acetaldehyde (1.6 ml, 28.6 mmol) and anhydrous magnesium sulfate (0.34 g, 2.83 mmol) in methanol (10 ml). Sodium cyanoborohydride (0.36 g, 5.71 mmol) was added and the resulting mixture heated at 40° C. for 4 hours. The reaction mixture was then filtered and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated. The resulting gum was triturated with diethyl ether to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]tetrahydro-2H-pyran-4-carboxylic acid as a white solid (440 mg, 63%); 1H NMR Spectrum: (DMSO-d6) δ 0.79 (t, 3H), 1.71-1.84 (m, 2H), 2.07-2.11 (d, 2H), 2.67-2.76 (q, 2H), 3.23-3.33 (t, 2H), 3.80-3.88 (m, 2H), 3.89-3.95 (m, 5H), 7.16 (s, 1H), 7.22-7.29 (m, 1H), 7.43-7.49 (m, 1H), 7.52-7.57 (dd, 1H), 8.38 (s, 1H), 8.41 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2].C([O-])([C:37](Cl)([F:39])[F:38])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH:37]([F:39])[F:38])=[CH:31][CH:32]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(OC(F)F)cc4)nn3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of (S)-3-{4-[2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.25 g, 0.54 mmol) in DMF (10 mL) is added sodium chloro difluoro acetate (0.142 g, 1.09 mmol) and cesium carbonate (0.354 g, 1.09 mmol) at 0° C. and the reaction mixture is heated at 80° C. for 4 hours. The reaction mixture is diluted with ice cold water (50 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel (combiflash purifier 40 g redisep column) and is eluted with 45% EtOAc in hexane to give the title compound as a colorless semi solid (0.15 g, 55.5%). LCMS m/z 506 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (307 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (549 mg) and HOBT (439 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (420 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (3.7 g) was added. The reaction mixture was heated at reflux overnight. The organic solvent was evaporated off in vacuo and purified by column chromatography to give ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D164) (240 mg) as white solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)=[N:4][N:3]=[N:2]1>Cl.O1CCOCC1>[NH:4]1[C:5]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(c2nnn[nH]2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
The title compound from Step A above (197 mg, 0.77 mmol) was dissolved in 4 M HCl in dioxane (3.0 mL) and stirred at RT for 1 h. The product was concentrated under reduced pressure and dried under high vacuum to give the title compound (i-32) (116 mg, 98%). ESI-MS calculated for C6H11N5: Exact Mass: 153.13. Found 154.12.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClC1C=CC=CC=1Cl.CO>[Cl:1][C:2]1[C:3]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2nc3c(Cl)c(Cl)cnc3[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2nc3c(Nc4ccccc4)c(Cl)cnc3[nH]2)cc1
Temperature: 180 °C
Yield: 77 %

Procedure:
6,7-Dichloro-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (0.73 g, 2.4 mmol), aniline (0.70 ml) and a catalytical amount of p-toluenesulfonic acid monohydrate were dissolved in o-dichlorobenzene (4.0 ml) and heated to 180° C. for 5 h. Ethyl acetate and methanol were added, the mixture stirred and the solid filtered off to afford the title compound (0.68 g, 77%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[C:40]([C:39]1[CH:42]=[C:35]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:36]=[N:37][CH:38]=1)#[N:41]
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 192.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.09 min, m/z=474.3 [M+H]+, m/z=472.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.42-3.52 (m, 2H) 3.52-3.62 (m, 2H) 4.68 (br. s, 1H) 7.70 (d, J=8.56 Hz, 2H) 7.88-7.98 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.00 (dd, J=8.44, 2.08 Hz, 2H) 10.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[O:7]1.O.[NH2:22][NH2:23]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:7])[NH:23][N:22]=1
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1N
Reactant: NN
Solvent: O
Product: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1N
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A stirred mixture of the above 3-(3-amino-4-methoxybenzylidene)-3H-isobenzofuran-1-one (1.336 g, 0.005 mol), industrial methylated spirit (20 ml) and hydrazine monohydrate (0.25 g, 0.005 mol) was heated under reflux for 1.5 hours then cooled to ambient temperature. The resulting solid was collected by filtration, washed with water (5 ml), and dried in vacuo to give 4-(3-amino-4-methoxybenzyl)-2H-phthalazin-1-one (1.15 g) as a beige solid, m.pt. 211.5–214.5° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.75 (s, 3H) (—OCH3), 4.15 (s, 2H) (ArCH2—), 4.75 (s, 2H) (—NH2) 6.5–6.6 (m, 2H) (2×ArH), 6.7–6.75 (m, 1H) (ArH) 7.8–8.0 (m, 3H)(3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+. 282, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][O:30]C3CCCCO3)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][OH:30])[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(CN2CCC(CCCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 11.5 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>C(O)CCC>[CH3:12][C@@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:18]1
Reactant: C[C@H]1CNCCN1
Reactant: Clc1ccc2ccccc2n1
Solvent: CCCCO
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1

Procedure:
A solution of 1.554 g (9.5 mmol) of 2-chloroquinoline and 1 g (9.984 mmol) of (S)-2-methylpiperazine in 10 ml of n-butanol is stirred for three hours at 130° C. Then the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=20:1:0.1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Na+].[Br-:21].O.OOS([O-])=O.[K+]>CC(C)=O>[Br:21][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([CH:7]2[CH2:8][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:6]2)[CH:15]=1
Reactant: [Br-]
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.1 %

Procedure:
To the title compound of Step A (2.75 g, 10.1 mmol) and NaBr (4.2 g, 41 mmol) in acetone (50 mL)/H2O (50 mL) at 0° C. was added Oxone (6.2 g, 10.1 mmol) portionwise over 1 h. After 3 h, the ice bath was removed and the reaction allowed to warm to rt. Then 5 wt % Na2S2O5 (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 3.95 g (>98%) of the title compound. 1H NMR (CDCl3): 7.35 (dd, J=8.7, 3.8, 2.5 Hz, 1H), 7.25 (dd, J=5.5, 2.7 Hz, 1H), 6.77 (dd, J=8.7, 4.5 Hz, 1H), 4.13-4.06 (m, 1H), 3.94-3.82 (m, 4H), 3.75-3.57 (m, 2H), 3.51-3.41 (m, 1H), 2.37-2.05 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH:32]1[CH2:34][O:33]1>>[OH:33][C@@H:32]([CH:24]1[CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1)[CH2:34][N:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: O=S(=O)(c1ccc(O)cc1)[C@H]1CCNC1
Reactant: c1ccc2c(c1)CC(C1CO1)C2
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)[C@H]1CCN(C[C@@H](O)C2Cc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=388.3 (M+H+) was prepared from (S)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and (RS)-2-indan-2-yl-oxirane.