Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28]C)=[O:27])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.C(Cl)(Cl)[Cl:35]>CCOCC>[ClH:35].[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cl
Product: O=C(O)COCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
A mixture of 2.56 g of methyl 2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetate, 6.6 ml of 2N sodium hydroxide aqueous solution and 25 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH 2 with 10% hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated to give yellowish brown liquid, which was solidified with a mixture of chloroform and ether to give 2.7 g of pale yellow amorphous solid, mp 75°-80° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:17][CH:16]=2)(=O)=O)=CC=1.[F-:35].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.C1COCC1>O>[F:35][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:17][CH:16]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-(4-(4-p-toluenesulfonyloxybutyl)phenyl)ethoxy)quinazoline (0.3 g, 0.63 mmol) is added to a solution of potassium fluoride/kryptofix 222 in 5 ml THF (1:1 ratio, 3.15 mmol each). After stirring at room temperature for 15 minutes the solution is then refluxed for 20 minutes. It is then cooled and water is added to it. The solution is then extracted in dichloromethane and washed with water and dried. The crude product is purified by silica gel flash chromatography (ethyl acetate/hexanes) to afford the product.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([Cl:24])[Cl:23])[C@H:19]1[C:25](Cl)=[O:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([Cl:23])[Cl:24])[C@H:19]1[C:25]([O:10][CH:6]1[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:26]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Reactant: C=CCC1=C(C)CC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)CC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 84.5 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (310 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 379 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 18). Yield 77% nD24 1.5112
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45]2[C:50]([NH2:51])=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:57])=[O:56])[CH:53]=[CH:54][C:46]=23)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([NH:44][C:45]2[C:50]([NH:51][C:7](=[O:9])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:56])=[O:57])[CH:53]=[CH:54][C:46]=23)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: O=C(O)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 45.1 %

Procedure:
Cyclopentylacetic acid (0.532 ml, 4.24 mmol), diisopropylethylamine (1.5 ml, 8.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g, 4.70 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.00 mmol) in CH2Cl2 (60 ml) at 25° C. The reaction mixture was stirred for 9 h at 25° C., then was partitioned between 1.0 M HCl (125 ml) and CH2Cl2 (125 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 40%) as an off-white solid. LCMS (Method G, ESI): RT=1.15 min, m+H=582.5. This material was used in the next step below without additional characterization.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1.CI.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1
Reactant: Cc1[nH]c(=O)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cc1c(Br)cc(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 327c (10.0 g, 37.5 mmol), CH3I (5.3 g, 37.5 mmol), and K2CO3 (7.8 g, 56.2 mmol). The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and the resulting white solid was collected to afford 327d (8.2 g, 78%) as a white solid. MS-ESI: [M+H]+ 280.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1

Procedure:
A solution, kept under nitrogen, of 6.1 g (26.5 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate, 10.5 g (39.8 mmol) of triphenylphosphine and 4.76 ml (39.8 mmol) of 3-(dimethylamino)-1-propanol in 200 ml of THF is cooled in an ice bath, and 8.21 ml (39.8 mmol) of diisopropyl azodicarboxylate are subsequently slowly added dropwise with stirring. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo. The residue is partitioned between dichloromethane and saturated aqueous potassium hydrogensulfate solution. The aqueous phase is separated off, adjusted to a pH of 12 using saturated aqueous sodium hydroxide solution and extracted twice with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: methyl 3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate as colourless crystals; m.p. 66° C.; ESI 316 (M+H); HPLC: 2.18 min (method B).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH2:16])[CH:7]=1)=[O:5])[CH3:2].[N:17]([O-])=O.[Na+].O.O.[Cl:23][Sn]Cl>Cl>[ClH:23].[NH:16]([C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH2:17]
Reactant: CCOC(=O)c1cc(N)cc2ccccc12
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(NN)cc2ccccc12
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 3-aminonaphthalene-1-carboxylic acid ethyl ester (2 g, 9.3 mmol) in conc. HCl (2 mL) was added dropwise an aqueous solution of NaNO2 (0.63 g, 9.3 mmol) at 0° C. The resulted mixture was stirred for 1 h and then treated dropwise with a solution of SnCl2.2H2O (4.2 g, 18.6 mmol) in conc. HCl (10 mL) at 0° C. The reaction mixture was stirred for 2 h at RT. precipitate was collected and washed with EtOH and Et2O to yield ethyl 3-hydrazinonaphthalene-1-carboxylate hydrochloride as a white solid (1.5 g), which was used for the next reaction without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([O:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(OC(C1(NC(=O)C2C=CC(C(O)C)=C(OCCC3C=C(C)C=CC=3)C=2)CC2C(=CC=CC=2)C1)=O)C.C(N(S(F)(F)[F:78])CC)C>C(Cl)Cl>[F:78][CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:35])=[CH:17][C:18]=1[O:25][CH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH3:23]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(C(C)O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: CCOC(=O)C1(NC(=O)c2ccc(C(C)O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Solvent: ClCCl
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2C(C)F)c1

Procedure:
The mixture of 2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid methyl ester and 2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid ethyl ester obtained in example 9 (50 mg) was dissolved in DCM, and diethylaminosulfur trifluoride (33 mg, 0.204 mmol) was added in two portions (second portion after 3.5 h). After complete conversion as detected by HPLC, the mixture was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution and the aqueous phase extracted with EA. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred with a HEP/diethyl ether mixture, filtered, and dried in vacuo. The obtained ester was hydrolyzed in analogy to example 2 to give 12 mg of the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:52]1([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[O:63])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH:15]([CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:62]([OH:63])[CH2:61][CH2:60][CH2:59][CH2:58][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C(CCCS(=O)(=O)c1ccccc1)N1C(=O)OCC1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CCS(=O)(=O)c1ccccc1)C(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 141 %

Procedure:
A solution containing (-)-4-benzyl-3-(4-phenylsulfonylbutanoyl)oxazolidin-2-one (2 g, 5.16 mmol) in anhydrous CH2Cl2 (20 mL) is cooled to 0° C. Di-n-butylboron triflate (1 M in CH2Cl2, 6 mL, 6.03 mmol) is added by syringe over 15 minutes followed by the addition of triethylamine (0.68 g, 6.76 mmol). The clear yellow solution is then cooled to -78° C. Freshly distilled 5-phenylpentanal (0.92 g, 5.72 mmol) in anhydrous CH2Cl2 (2 mL) is added dropwise to the reaction mixture. After 30 min, the reaction mixture is warmed to 0° C. and maintained at this temperature for 1 hour. The reaction mixture is quenched by the slow addition of 3:1 MeOH/pH 7 phosphate buffer (30 mL) followed by 2:1 MeOH/30% H2O2 (30 mL) being careful to keep the temperature below 5° C. After the addition is complete, the reaction is maintained an additional hour at 0° C. then concentrated to half-volume in vacuo. The mixture is then diluted with diethyl ether (100 mL) and water (100 mL) and the layers are separated. The organic phase is washed with 5% NaHCO3 (3×50 mL), aqueous NaHSO3 (3×50 mL), water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product is combined with the crude material obtained from four additional reactions performed on identical scale and purified by silica gel chromatography (CH2Cl2 /diethyl ether, 19:1→9:1) to provide 4 g (35%) of (-)-4-benzyl-3-[3-hydroxy-7-phenyl-2-(2-phenylsulfonylethyl)-heptanoyl]-oxazolidin-2-one as a colorless, viscous oil which is homogeneous by TLC analysis [CH2Cl2 /diethyl ether, 19:1, Rf (oxazolidinone)=0.45, Rf (aldol product)=0.40]. [α]23D -20° (c 7.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.42-1.58 (m, 6H), 2.06 (m, 1H), 2.20 (m, 1H), 2.24 (d, J=4 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 2.69 (dd, J=13.3, 9.9 Hz, 1H), 3.24 (m, 3H), 3.86 (m, 1H), 3.98 (quint. J=4.2 Hz, 1H), 4.16 (m, 2H), 4.65 (m, 1H), 7.18-7.52 (m, 10H), 7.59 (m, 2H), 7.68 (m, 1H), 7.90 (m, 2H) ppm. Mass spectrum (FAB) m/z 550 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].[C:29](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:29][CH:18]1[CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]2[CH:26]=[C:10]([O:9][CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[CH:11]=[CH:12][C:13]=2[S:19]1(=[O:20])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CC(C)S3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 16.5 h
Yield: 73.5 %

Procedure:
Into a suspension of methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (0.7 ml) of potassium carbonate (137 mg), and the resulting mixture was stirred at 70° C. for 16.5 hours. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (147 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[N:22][CH:23]=1.Cl.CN(C)CCCN=C=NCC.N1CCCCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25](=[O:26])[NH:1][C:2]3[C:3]([C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH:21]=[N:22][CH:23]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cncc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A solution of 2-amino-5-chlorobenzophenone (230 mg, 1.00 mmol), 5-bromo-3-pyridineacetic acid (215 mg, 1.00 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (230 mg; 1.20 mmol) in DCM (2.5 mL) was stirred overnight at room temperature. Toluene (2.5 mL) and piperidine (0.2 mL) were then added and the resulting solution was heated to approximately 100° C., allowing the DCM to evaporate from the reaction mixture. After 2 h, the reaction was allowed to cool and stirring was continued at room temperature overnight. The precipitate that formed was filtered and washed with toluene. This crude product was dissolved in chloroform and extracted with water (4×), dried over potassium carbonate (K2CO3) and concentrated to afford the pure quinolinone product (285 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 12.4 (br.s, 1H), 8.45 (d, 1H, J=3.0 Hz), 8.21 (d, 1H, J=1.3 Hz), 7.86 (t, 1H, J=1.5 Hz), 7.64 (dd, 1H, J=8.9, 2.3 Hz, 1H), 7.46 (d, 1H, J=8.6 Hz), 7.44-7.31 (m, 3H), 7.28-7.21 (m, 2H), 6.94 (d, 1H, J=2.0 Hz). MS: 413.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:22]
Reactant: CCOCCON=C(C(=O)OCC)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOCCON=C(C(=O)OCC)c1csc(NC=O)n1
Yield: 68.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-etoxyethoxyimino)acetate (syn isomer, 11.5 g.), acetic anhydride (8.2 g.) and formic acid (3.7 g.) were treated in a similar manner to that of Example A-(4) to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 8.6 g.).
Reaction SMILES: [Li][C:2]([CH3:5])([CH3:4])C.Br[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([Si:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15](Br)=[CH:14][CH:13]=3.Cl[Si:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[NH4+].[Cl-]>C1COCC1>[C:28]1([Si:21]([C:4]2[CH:2]=[CH:5][CH:8]=[CH:7][CH:19]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:7]2[CH:8]=[CH:9][C:10]3[N:11]([Si:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([Si:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:14][CH:13]=4)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)(C)C
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3c(c2)c2cc([Si](c4ccccc4)(c4ccccc4)c4ccccc4)ccc2n3[Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
tert-BuLi (1.7 M in pentane, 58 ml, 99 mmol) is added slowly to a cold solution (−78° C.) of 3,6-dibromo-9-triphenylsilylcarbazole (90% purity, see i), 13 g, 22 mmol) in dry THF (1000 ml). After stirring at −78° C. for two hours, ClSiPh3 (34 g, 115 mmol) in dry THF is added. The mixture is stirred overnight, and saturated NH4Cl solution is added. The resulting salt is filtered off, and the organic phase is separated from the aqueous phase. The aqueous phase is extracted with CH2Cl2. The organic phase is washed twice with water. The combined organic phases are dried over Na2SO4. After column chromatography (SiO2; 5:1 cyclohexane:CH2Cl2), the pure product is obtained (Rf˜0.3, 11 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (0.5 g, 3.07 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (0.77 g, 3.22 mmol) in EtOH (15 mL) was added Et3N (0.62 g, 6.13 mmol) and the mixture was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the product as colourless oil (0.23 g, 21%).
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:3].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:4])[CH3:3]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: CC(=O)SC1CCNC/C1=C\c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-benzylidene-piperidine hydrochloride and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (713 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (256 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:17) as the eluent to afford the title compound (531 mg, yield: 68%) as a yellow oil.
Reaction SMILES: C([N:3](CC)CC)C.[O:8]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OC)=O.N>C1COCC1>[O:8]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:3])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (5.6 g) was added at 0° C. under N2 to a stirred solution of 3-phenoxybenzoic acid (10.7 g, Aldrich) in THF (75 ml), followed by the addition of methyl chloroformate (4.7 g) at less than 5° C. After additions were complete, the mixture was stirred at 0° C. for 30 minutes. 0.88 Ammonia (30 ml) was added and the mixture stirred at room temperature for 20 hours, then evaporated in vacuo and the residue taken up in ethyl acetate (100 ml) and water (100 ml). The aqueous phase was separated, extracted with ethyl acetate and the combined ethyl acetate solutions washed with 5% w/v aqu. Na2CO3 (2×50 ml), 2N aqu. HCl (50 ml) and water (100 ml), dried over Na2SO4 and evaporated in vacuo to give the desired product as a colourless solid which was recrystallised from ethyl acetate/60-80 pet. ether (1:2 v/v), mp 125°-127° C. (6.5 g). The 200 MHz 1H NMR was consistent with the proposed structure.