Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:15]#[N:16])(=[O:4])[CH3:3].[CH2:17]([OH:19])[CH3:18]>C(OCC)C>[ClH:14].[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:15](=[NH:16])[O:19][CH2:17][CH3:18])(=[O:4])[CH3:3]
Reactant: CC(=O)N1c2ccc(Cl)cc2CC1C#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(Cl)ccc2N1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
HCl (as a 2 M solution) was added slowly to intermediate (9) until gas evolution was noted. Then stopped adding the prepared HCl (2N in diethylether), and suspended HCl in diethylether (150 ml) and then ethanol (0.042 mole) was added. The mixture was cooled to 0° C. and HCl (gas) was added over an hour, with an oil precipitating out. The reaction was diluted to 1 l with diethylether. More oil precipitates, and no solid formed after sitting for 1 hour. The diethylether was decanted off. The residue was diluted (diethylether, 500 ml). The solid begins to form, and the mixture was stirred for 2 hours. The sample was filtered, rinsing with diethylether. The sample was placed under vacuum, yielding 6.41 g of ethyl 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 10).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:18][C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[C:37]([C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br)#[N:38]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:18]([CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[C:37]#[N:38])[C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#Cc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2C#N)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of [3-(5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl)-cyclohexyl]-carbamic acid benzyl ester (45 mg, 0.10 mmol) in DMF (2 mL) was added NaH (5 mg, 0.12 mmol 60% in mineral oil) at 0° C. After hydrogen evolution had ceased, 2-cyanobenzylbromide (31 mg, 0.16 mmol) was added and the reaction was stirred at room temperature for 2 h. The flask was cooled with an ice-bath, and the reaction was quenched by addition of saturated aqueous NH4Cl. The mixture was extracted with CH2Cl2 and the organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH to give {3-[3-(2-cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl]-cyclohexyl}-carbamic acid benzyl ester (55 mg, 97% yield). 1H-NMR (CDCl3): δ 8.58 (m, 2H), 7.75 (m, 1H), 7.48 (m, 1H), 7.35 (m, 6H), 7.17 (d, 1H, J=7.6 Hz), 6.26 (m, 1H), 5.96 (m, 1H), 5.08 (s, 2H), 3.91 (s, 3H), 3.69 (m, 1H), 2.93 (m, 1H), 2.08 (m, 1H), 1.98 (m, 1H), 1.83 (m, 2H), 1.76 (m, 1H), 1.59 (m, 1H), 1.51 (m, 1H), 1.33 (m, 1H). MS: calculated for C32H30N6O3+H 547.3; found: 547.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.C(O[N:19]1[CH2:24][CH2:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]1=C=O)(C)(C)C.[Cl-].[Li+].[C:37](=[O:40])([O-])[O-:38].[Na+].[Na+]>O1CCCC1.CO>[C:5]([O:38][C:37]([N:19]1[CH2:24][CH2:23][C:22]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)=[CH:21][CH2:20]1)=[O:40])([CH3:10])([CH3:6])[CH3:4]
Reactant: OB(O)c1cncc2ccccc12
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)ON1CCC(OS(=O)(=O)C(F)(F)F)=CC1=C=O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2cncc3ccccc23)CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 2.5 gm (14.5 mMol) isoquinolin-4-ylboronic acid, 3.43 gm (10.3 mMol) 1-tert-butoxy-carbonyl-4-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydropyridine, 1.3 gm (30.9 mMol) lithium chloride, 0.04 gm (0.05 mMol) [1,1′-bis (diphenylphosphino)-1-ferrocene]-palladium II chloride, and 2 mL 2M aqueous sodium carbonate in about 20 mL tetrahydrofuran containing a few drops of methanol was stirred at reflux for about 4 hours. The reaction was cooled to room temperature and then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 3:2 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.216 gm (57%) 1-tert-butoxycarbonyl-4-(isoquinolin-4-yl)-1,2,5,6-tetrahydropyridine as a light yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N:25](CC)CC)C>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH:6]([N:25]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:7])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CN
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)C(N)N=Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
To a 2 L flask, equipped with an overhead stirrer, was added 101.1 g of glycine ethyl ester hydrochloride salt (1.05 eq), 82.1 g magnesium sulfate (1.0 eq), 0.5 L acetonitrile, 72.7 g benzaldehyde (1.0 eq), and 138.7 g triethylamine (2 eq). The reaction mixture was stirred at 20-25° C. for ˜4 h. The solid was filtered off, and washed with 2×0.1 L acetonitrile. The crude product (filtrate) was ready for use in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c2c1OCC21CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 156, 176 mg, 1 mmol) in dry DMF (4 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyridine (158 mg, 1 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (270 mg) as an orange solid that was used in the next step as crude material without further purification.
Reaction SMILES: C1(C)C=CC(S(OCCCC[CH:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)(=O)=O)=CC=1.[F-:35].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[CH2:63]1[CH2:67]O[CH2:65][CH2:64]1>O>[F:35][CH2:65][CH2:64][CH2:63][CH2:67][C:31]1[CH:30]=[CH:29][C:28]([CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:33][CH:32]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC(COc2ncnc3ccccc23)c2ccccc2)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Product: FCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-(4-(4-p-toluenesulfonyloxybutylphenyl 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: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][C:19]1([C:24]#[N:25])[CH2:22][C:21](=O)[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:21]1[CH2:22][C:19]([CH3:18])([C:24]#[N:25])[CH2:20]1)#[N:8]
Reactant: CC1(C#N)CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C#N)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (52.9 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (8.98 mL, 0.0555 mol) in tetrahydrofuran (90 mL, 1 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was added a solution of 1-methyl-3-oxocyclobutanecarbonitrile (5.50 g, 0.0504 mol) in tetrahydrofuran (40 mL, 0.6 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (3.12 g, 46.84%). LCMS calculated for C8H9N2(M+H)+: 133.1; Found: 133.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:32]>>[ClH:32].[N:11]1([C:3]2[CH:4]=[CH:5][C:10]3[C:1](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:2]=2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(3-isoquinolyl)piperazine-1-carboxylate (201 mg, 0.64 mmol) was added a 1:1 mixture of DCM and trifluoroacetic acid, the resulting mixture was stirred at room temperature for one hour. The volatiles were removed under reduced pressure, the residue was dissolved in THF and evaporated again. The residue was dissolved in THF and 4N HCl in 1,4-dioxane was added to precipitate the hydrochloride salt which was collected by filtration and dried under reduced pressure. 123 mg of a solid were obtained (0.49 mmol, 77%). MS (APCI) m/z=214.1 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=O.[CH2:13]([NH:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Ca+2].[Cl-]>CCOCC>[CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[N+:20]([O-:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ONCc1ccccc1
Reactant: CC(C=O)COC1CCCCO1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C=[N+]([O-])Cc1ccccc1)COC1CCCCO1
Yield: 62.9 %

Procedure:
An etheral solution (1 ml) of 2-methyl-3-tetrahydropyranyloxypropanal (37.9 mg; 0.20 mmol) was added dropwise to a suspension of benzylhydroxylamine (28.7 mg; 0.23 mmol) and powdery calcium chloride (22.2 mg; 0.20 mmol) in ether (0.5 ml) at 0° C., and the resultant mixture was stirred for 1.5 hours. The reaction mixture was purified by TLC using ethyl acetate to give N-(2-methyl-3-tetrahydropyranyloxypropylidene)-benzylamine-N-oxide (34.9 mg; yield, 57%).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:35]4[CH:34]=[CH:31][CH:30]=[C:29]([N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:36]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCN(c2cccc(CN)c2)CC1
Solvent: Oc1ccccc1
Solvent: CO
Product: CN1CCN(c2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.189 g, 0.585 mmol), 3-(4-methyl-piperazin-1-yl)-benzylamine (0.100 g, 0.487 mmol) and phenol (1.0 g) was stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to r.t. and MeOH (10 mL) was added. After 30 minutes the precipitate was filtered off and washed with MeOH (50 mL). The crude product was purified by flash chromathography using a mixture of EtOAc, MeOH and TEA as eluent to give the product as an off white solid. Yield: 0.079 g (30%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.60 (d, 2H, J=7.92 Hz), 7.44 (s, 1H), 7.40 (d, 2H, J=7.92 Hz), 7.22 (m, 1H), 6.92 (bs, 1H), 6.85 (d, 1H, J=7.92 Hz), 6.79 (d, 1H, J=7.46 Hz), 5.15 (s, 2H), 3.19 (m, 4H), 2.53 (m, 4H), 2.32 (s, 3H). MS (ESI+) 450.95 (M+1H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([CH3:34])=[CH:4][N:3]=1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:36][OH:37])[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([CH3:34])=[CH:4][N:3]=1
Reactant: Cc1cnc(F)cc1C(=O)CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(F)cc1C(CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C)=NO

Procedure:
In analogy to example 74, step 7, from 4′-[3-(2-fluoro-5-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.7:1) as a colorless oil, MS (ESI+): m/z=469.1924 ([M+H]+).
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][C:17]=1[F:18].[NH4+].[Cl-]>C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: C[C@@H]1NC(C)(C)COC1=O
Reactant: Fc1ccc([Mg]Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
A solution of morpholin-2-one 15 (410 mg, 2.86 mmol) in anhydrous THF (2.9 mL, 1M) was cooled to −78° C. and treated with 3,4-difluorophenylmagnesium bromide (1.2 equiv., 3.43 mmol, 6.90 mL, 0.5 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. under an inert atmosphere for 1.5 h, saturated aqueous solution of NH4Cl was added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and extracted with ether (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. Purification of the residue by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH—NH4OH (90:9:1) as the eluent gave 190 mg (25%) of 4m as a yellow solid: [α]22D +18.2° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.45-7.39 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.10 (m, 1H), 3.82 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 122.40, 122.31 116.74, 116.51, 115.8, 115.6, 96.5, 69.6, 53.4, 49.8, 27.3, 22.8, 16.5; LCMS (ESI) m/z 258.6, [(M+H)+, M=C13H17F2NO2].
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH2:22])=[N:19][CH:20]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:5](=[O:7])[CH2:4][CH2:3][C:2]([F:1])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:19][CH:20]=1
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Reactant: NCc1ccc(Cl)cn1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC(F)(F)C(F)(F)F)NCc1ccc(Cl)cn1

Procedure:
To a solution of 4,4,5,5,5-pentafluoropentanoic acid (6.44 g, 33.5 mmol) and the intermediate from Step E (5.0 g, 27.9 mmol) in DCM (100 mL) was added EDC (7.49 g, 39.1 mmol) followed by DIEA (24.4 mL, 140 mmol). After stirring the reaction at room temperature for 2 hours, it was diluted with DCM (100 mL), and washed with water (2×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil. m/z=316.8 (M+H).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:19])[O:15][C:14]3=[O:27])=[CH:9][CH:8]=2)[NH:3]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])[O:15][C:14]3=[O:27])=[CH:11][CH:12]=2)[NH:3]1
Reactant: COC(=O)CCNC(=O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1

Procedure:
1.12 g of methyl 3-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonylamino}propionate [obtainable according to Example 4] are stirred at room temperature for 3 h in 13.5 ml of water and 30 ml of methanol with the addition of 1.35 g of potassium carbonate. The reaction solution is then given the customary workup. 3-{3-[4-(5-Oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonylamino)propionic acid is obtained, m.p. 221°-223°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:20][C:19]3[C:18](=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]2[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC>CN(C=O)C.C(OCC)(=O)C.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>[N:39]1[CH:40]=[CH:41][C:36]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:20][C:19]4[C:18](=[O:21])[C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[NH:11][C:10]=4[CH:9]3[C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)=[N:6][CH:7]=2)=[CH:37][CH:38]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(Br)cn1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(-c3ccncc3)cn1)C2
Temperature: 140 °C

Procedure:
A stirred mixture of 1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (46 mg, 0.1 mmol) (prepared as in Example 53), (PPh3)4Pd (3.5 mg, 3.0 μmol) and 4-tri-n-butylstannylpyridine (37 mg, 0.1 mmol) in dry DMF (2.0 ml) was heated at 140° C. for 12 h. More catalyst (3.5 mg) was added and the mixture was refluxed for 4 h and then cooled. The solution was diluted with ethyl acetate and filtered through filter paper. The organic phase was washed with brine and water, then dried over Na2SO4. A small amount of silica gel was added into the solution and dried in vacuo. Purification by flash column (silica gel, neat acetonitrile followed by 10% ammonium hydroxide in water:actonitrile=1:10, v/v) yielded the product as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[F:53][C:54]1[CH:55]=[C:56]2[C:60](=[CH:61][CH:62]=1)[CH2:59][NH:58][CH2:57]2>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:58]1[CH2:57][C:56]2[C:60](=[CH:61][CH:62]=[C:54]([F:53])[CH:55]=2)[CH2:59]1)=[O:6]
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Reactant: Fc1ccc2c(c1)CNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc(C(=O)N3Cc4ccc(F)cc4C3)c(Cl)c2)CC1
Reaction time: 16 h
Yield: 70 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D33) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline hydrochloride (D8) (0.10 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E63) as a white solid (0.09 g). MS electrospray (+ion) 417/419 (MH+). 1H NMR δ (DMSO-d6): 9.80 (1H, s), 7.22-6.81 (6H, m), 4.70-4.39 (3H, m), 4.25 (3H, m), 3.24 (2H, m), 2.88 (2H, m), 2.10-1.70 (4H, m), 1.06 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)=[CH:5][C:4]=1[C:21]([O:23][CH3:24])=[O:22].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6](=[CH:5][C:4]=1[C:21]([O:23][CH3:24])=[O:22])[NH:7][CH:8]=[CH:9][C:14]2=[O:15]
Reactant: COC(=O)c1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1OC
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2[nH]ccc(=O)c2cc1OC
Temperature: 260 °C
Reaction time: 0.08 h
Yield: 58.2 %

Procedure:
5-(4-Methoxy-3-methoxycarbonylanilinomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (28.9 g) was added portionwise to a mixture (200 ml) of biphenyl and diphenyl ether (‘Dowtherm A’) that had been warmed to 260° C. The solution was stirred at that temperature for 5 minutes. The resultant mixture was cooled to ambient temperature and added to a mixture of petroleum ether (250 ml) and diethyl ether (250 ml). The precipitate was collected by filtration and washed with petroleum ether. The material so obtained was purified by column chromatography on silica using increasingly polar solvent mixtures of methylene chloride and methanol (from 10:0 to 17:3) as eluent. There was thus obtained a 7:3 mixture (11.7 g) of 6-methoxy-7-methoxycarbonyl-1,4-dihydroquinolin-4-one and 6-methoxy-5-methoxycarbonyl-1,4-dihydroquinolin-4-one; 1H NMR: (DMSOd6) 3.85 (s, 3H), 3.88 (s, 3H), 6.05 (d, 1H), 7.61 (s, 1H), 7.87 (s, 1H), 7.94 (d, 1H) and 3.75 (s, 3H), 3.82 (s, 3H), 5.92 (d, 1H), 7.55 (d, 1H), 7.63 (d, 1H), 7.88 (m, 1H); Mass Spectrum: M+H+ 234.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O>O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][C:15]1[NH:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Reactant: c1cc[nH]c1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(Cc2ccc[nH]2)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzylalcohol and 5.0 ml of pyrrole in 3.0 ml of dioxane was heated for 5 h at 100° C. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated and the residue was purified in a silicagel column using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent. Yield 0.42 g (33%), m.p. 115°-118° C.