Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[C:33](F)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:40])=[O:39])[CH:37]=1>CS(C)=O>[Cl:31][C:32]1[C:33]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:39])=[O:40])[CH:37]=1
Reactant: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
2-Chloro-5-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 52, 140 mg, 0.4 mmol) was dissolved in DMSO (1 mL) and potassium carbonate (110 mg, 0.8 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 203 mg, 0.44 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (50 mL) and water (40 mL). The ethyl acetate was separated and dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 80:20 to 20:80 to give the title compound (231 mg, 0.30 mmol, 73%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].O.C[C:15]([N:17](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]#[N:17])=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)Oc1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(=O)Oc1ccc(C#N)cc1C
Temperature: 100 °C
Yield: 99 %

Procedure:
A solution of 4-bromo-2-methylphenyl acetate (6.9 g, 30 mol) in 75 mL of anhydrous dimethyl acetamide was treated with zinc cyanide (3 g, 25.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The reaction mixture was heated at 100° C. for 2 hours, cooled to room temperature, and treated with 300 mL of cold water. The resulting precipitate was filtered, washed with water, and air dried. Chromatography on SiO2 (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[C:14](OC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>C(OCC)(=O)C>[CH3:18][C:16]1[C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH2:7][C:2]=2[NH:1][C:14](=[O:19])[CH:15]=1
Reactant: NC1=CC(=O)CC(c2ccsc2)C1
Reactant: COC(=O)CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Temperature: 170 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of 1-amino-5-(thiophen-3-yl)cyclohexen-3-one (4.75 g) and methyl acetoacetate (10 g) was stirred at 170° C. for 18 hours and cooled, and to the mixture was added ethyl acetate. Precipitated crystals were filtered and washed with ethyl acetate to give 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (1.4 g) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:20])CCCCCCC>C(Cl)Cl>[C:1]1([CH2:7][S:8]([NH2:20])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCCCCCCCN
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
The synthesis of the sulfonamide containing carboxylic acid precursor corresponding to the autoinducer analog 10 was accomplished by the two step sequence described below. Accordingly, a solution of α-toluenesulfonyl chloride (10 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of octylamine (20 mmol) in CH2Cl2 (20 mL) at 0° C. The resulting mixture was subsequently stirred at room temperature for 30 min and was then extracted with H2O (3×24 mL) The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo to provide the corresponding α-toluenesulfonamide (262 mg, 93%) as a colorless solid. Subsequent oxidative degration of the phenyl moiety within this compound via the procedure of Sharpless, et. al. [e.g., cat. RuCl3 hydrate, NaIO4, H2O/CH3CN/CCl4 (vide supra)] furnished the α-sulfonamidoacetic acid corresponding to homoserine lactone 10. Accordingly, a mixture of the above α-toluenesulfonamide (1.00 mmol), CCl4 (2 mL), CH3CN (2 mL), H2O (3 mL) and NaIO4 (14.50 mmol) was vigorously stirred at room temperature and RuCl3 hydrate (5 mg) was added. The reaction mixture was vigorously stirred for a further 2 h at room temperature and then CH2Cl2 (10 mL) was added and the phases were separated. The upper aqueous phase was extracted with three portions of CH2Cl2 and the combined organic phases were dried (MgSO4) and the solvents were removed in vacuo. Recrystallization of the residue from EtOH provided the α-sulfonamidoacetic acid (181 mg, 72%) as a colorless solid.
Reaction SMILES: S(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(C)(=O)=O.[C:45]1([SH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][C@H:7]2[CH2:6][S:51][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of (2S,4S)-2-mesyloxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (9.6 g, 15.2 mmol) in THF (190 ml), thiophenol (2.34 ml, 22.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (3.4 ml, 22.8 mmol) were successively added dropwise in a nitrogen stream under cooling with ice. The reaction solution was stirred at room temperature for 15 minutes and the solvent was distilled off. To the residue, ethyl acetate was added. The organic layer was washed with 1N aqueous potassium hydrogensulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1) to give (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-phenylthiomethyl-4-tritylthiopyrrolidine (9.24 mg, yield: 94%) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=O)[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10].O.ON1C2C=CC=CC=2N=N1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:22])[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10]
Reactant: CN1CCNCC1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)N3CCN(C)CC3)oc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-[2-(3,5-Dichloro-4-pyridyl)-1-oxoethyl]-7-methoxybenzofuran-2-carboxylic acid (Compound M, 5.8 g) obtained in Reference Example 3 was dissolved in DMF (700 ml), and 1-hydroxybenzotriazole monohydrate (8.4 g), N-ethyl-N′-3-dimethylaminopropylcarbodiimide monohydrochloride (11.6 g) and 1-methylpiperazine (6.8 ml) were added thereto, and the mixture was stirred at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol 80:1 to 20:1) and then recrystallized from ethanol to give Compound 13 (5.5 g, 79%) as colorless crystals.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[F:18])(=O)C>O1CCOCC1.O>[C:14]([C:10]1[C:9]([F:18])=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][OH:6])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OCc1cccc(C(C)(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cccc(CO)c1F
Temperature: 50 °C
Reaction time: 7 h
Yield: 97.3 %

Procedure:
67 g of 8% strength aqueous sodium hydroxide solution are added to a solution of 25 g (0.11 mole) of 3-tert-butyl-2-fluorobenzyl acetate in 100 ml of dioxane and the mixture is stirred for 7 hours at 50° C., diluted with 100 ml of water and extracted three times with dichloromethane. Drying and evaporation give 19.5 g (97%) of 3-tert-butyl-2-fluorobenzyl alcohol.
Reaction SMILES: C1(C(OCCC)CO)C=CC=CC=1.[CH2:14]([O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][OH:21])[CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>C1CCCCC1>[CH2:14]([O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=[O:21])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC(CO)c1ccccc1
Agent: CCCOC(CO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCCCOC(C=O)c1ccccc1
Yield: 68 %

Procedure:
The procedure in Example 3 was repeated except that 180.25 g of 2-phenyl-2-propoxyethanol was replaced with 194 g of 2-butoxy-2-phenylethanol and 540 g of toluene was replaced with 580 g of cyclohexane, to obtain 130.5 g of 2-butoxy-2-phenylethanal (yield: 68%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH:19]1([CH2:25][CH2:26][CH2:27]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C)C=O>[O:6]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][CH2:27][CH2:26][CH2:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Reactant: BrCCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1CCC(CCCO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (200 mg, 8.33 mmol) in anhydrous dimethylformamide (20 mL) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6.6 mmol) in anhydrous dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 30 min. and then a solution of 3-(cyclohexyl)propyl bromide (1.67 g, 8.15 mmols) in anhydrous dimethylformamide was quickly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were back-washed with brine (50 mL) and the solvent was evaporated in vacuo. The residue was taken up with water (50 mL) and the pH was adjusted to pH 1.0 with 6M HCl aqueous solution. The acidic aqueous solution was extracted with diethyl ether (2×50 mL), then basified to pH 5.0-5.5 with 5M NaOH aqueous solution and extracted with diethyl ether (3×50 mL). The combined organic extracts at pH 5.0-5.5 were concentrated in vacuo to provide the crude title compound suitable for the next step without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH3:10])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:10]
Reactant: COc1ccccc1C(C)Oc1cncc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1C(C)Oc1cncc(N2CCNCC2)n1
Temperature: 90 °C
Yield: 67 %

Procedure:
A mixture of the product from step 1 above (0.93 g, 3.53 mmol) piperazine (0.88 g, 10.2 mmol) and K2CO3 (0.49 g, 3.53 mmol) in acetonitrile (7 mL) was heated in a sealed pyrex flask at 90° C. for 6.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina, covered with K2CO3, using CHCl3 as eluent. Solvent removal in vacuo gave 0.74 g (67%) of the title compound as a beige oil. HRMS m/z calcd for C17H22N4O2 (M)+ 314.1743, found 314.1733. Anal. (C17H22N4O2.0.5H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 65 %

Procedure:
(R)-(+)-1-(4-Bromophenyl)ethylamine (0.98 g), 2,2′-dibromodiethyl ether (1.36 g) and diisopropylethylamine (2.5 ml) were stirred in dimethylformamide (20 ml) under argon at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature, then partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted further with diethyl ether (50 ml) and the combined organic phases were washed with water (100 ml), dried (MgSO4), concentrated in vacuo, redissolved in toluene and purified by Bondelute® chromatography, eluting with 0–50% ethyl acetate/iso-hexane to give the product as a yellow oil (0.86 g).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].O.[NH2:21]N>CCO>[CH3:7][C:6]([C:5]1[NH:21][N:2]=[CH:3][CH:4]=1)([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccn[nH]1
Temperature: 50 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4 mmol) and hydrazine hydrate (1.0 g, 6.25 mmol) in EtOH was heated at 50° C. for 3 h. The mixture was concentrated, and the residue was diluted with H2O and EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the titled compound as a yellow solid. MS: (ES+) 232 (M+H.) Calc'd for C12H14N3O2—232.10.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]2=[O:17].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:66][N:67]1[CH2:73][CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:17])[CH:8]=1)=[CH:5][C:4]([O:18][CH3:19])=[CH:3][C:2]=2[N:70]1[CH2:71][CH2:72][CH2:73][N:67]([CH3:66])[CH2:68][CH2:69]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a 250 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5 g (4.59 mmol, 1.0 equiv.) of 8-Bromo-6-methoxy-4-oxo-4H-chromene acid ethyl ester (Reference Example 2c), 84 mg (0.092 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 2 g of 4 A molecular sieves. To this suspension is added 150 mL of dry toluene. To the stirred suspension is then added 628 mg, 684 μL, (5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05 g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 20% methanol in methylene chloride as eluent, yielded 1.0 g, (60%) of the desired product.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[C:7]#[N:8].[C:23]([NH:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([O:32][C:33](=O)[C:28]=12)=[O:31])(=[O:25])[CH3:24]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[N:5]1[C:33](=[O:32])[C:28]2[C:29](=[CH:35][CH:36]=[CH:37][C:27]=2[NH:26][C:23](=[O:25])[CH3:24])[C:30]1=[O:31])#[N:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(C(N)C#N)cc1OC1CCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 65 %

Procedure:
A mixture of 2-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethanenitrile acetate (3.5 g, 11.0 mmol) and 3-acetamidophthalic anhydride (2.3 g, 11.0 mmol) in glacial acetic acid (40 mL) was heated to reflux for 17 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in EtOAc and washed with water, brine and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 98:2) to give 3.1 g (62%) of N-{2-[cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as white solid; mp 124-126° C.; 1H NMR (CDCl3) δ 9.44 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.03-6.99 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.60-5.53 (dd, J=6.2 and 10.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s, 3H), 3.29-3.20 (dd, J=6.4 and 17 Hz, 1H), 2.72 (s, 3H0, 1.97-1.56 (m, 8H); 13C NMR (CDCl3) δ 169.58, 169.11, 167.18, 150.61, 147.98, 137.72, 136.28, 130.89, 128.66, 125.09, 119.80, 118.29, 116.78, 114.19, 111.90, 80.68, 56.02, 51.10, 32.73, 24.92, 24.03, 21.07. Analy. Calculated for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 66.89; H, 5.42; N, 9.26.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Yield: 54.1 %

Procedure:
A solution of 3-benzyl-7-chloro-2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3H-quinazolin-4-one (505 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) was stirred at room temperature for 18 h. The reaction was washed sequentially with 0.5 N HCl, water. 5% NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to yield the title compound as an orange oil (338 mg, 54%). MS(ES+) m/e 534 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8](=[O:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:12][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8]([CH3:12])([OH:11])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CCc2c(Br)cncc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCc2c(Br)cncc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
A brown suspension of 4-bromo-5H-cyclopenta[c]pyridin-7(6H)-one (intermediate A-4[B]) (424 mg, 2.0 mmol) in THF (5 mL) was cooled (−78° C.) and treated during 10 min with methylmagnesium bromide (2.1 mL, 3.0 mmol, 1.4 M in THF:toluene 1:3). The reaction was allowed to warm up to RT over 3 h then stirred for 1.5 h at RT. The mixture was poured on aq. sat. NH4Cl-solution and extracted with EtOAc (3×). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (4%)) gave the title compound (180 mg, 40%) as dark green viscous oil. MS: 228.0 (M+H+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]([N:1]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[N:7][C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
A solution of 0.22 g (0.5 mmol) of [6-amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 7) in 5.0 ml of DMF was treated with 0.43 ml=0.309 g (3.1 mmol) of Et3N and 0.006 g (0.05 mmol) of DMAP. To the stirred solution was added 0.08 ml=0.12 g (1.0 mmol) of methanesulfonyl chloride drop by drop and the reaction mixture was subsequently warmed up to 50° C. After 5 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.13 g (44%) of the title compound as yellow solid. MS: 589.1 (MH+).