Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(S(O[C:14]2[C:25]3=[C:26]4[N:21]([CH2:22][CH2:23][CH2:24]3)[CH:20]=[C:19]([C:27]([OH:29])=[O:28])[C:18](=[O:30])[C:17]4=[CH:16][CH:15]=2)(=O)=O)=CC=1)([O-])=O.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[N:31]1([C:14]2[C:25]3=[C:26]4[N:21]([CH2:22][CH2:23][CH2:24]3)[CH:20]=[C:19]([C:27]([OH:29])=[O:28])[C:18](=[O:30])[C:17]4=[CH:16][CH:15]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1cn2c3c(c(OS(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc3c1=O)CCC2
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 14.4 %

Procedure:
20.0 g of 8-(p-nitrobenzenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 17 hours while stirring. Treatment in an analogous manner as in Example 15 gave 2.1 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH:36]3[CH2:38][CH2:37]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:32]2[CH:31]=[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)[CH:35]=[CH:34][N:33]=2)[CH2:37][CH2:38]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M267) (286 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (198 mg, 87%).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]C)=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].N1([C:24]2[N:29]=[CH:28][C:27]([C:30](OC)=O)=[CH:26][CH:25]=2)CCOCC1>>[CH3:5][O:4][C:1]1[CH:30]=[C:27]([CH2:26][CH2:25][C:24]2[CH:9]=[C:8]([NH:13][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])=[N:13][CH:12]=3)=[O:16])[NH:7][N:29]=2)[CH:28]=[CH:3][CH:2]=1
Reactant: C=CCOC(=O)Nc1ccc(C(=O)OC)cn1
Reactant: COC(=O)c1ccc(N2CCOCC2)nc1
Product: C=CCOC(=O)Nc1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 37 %

Procedure:
Methyl 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylate, used as starting material was prepared in an analogous manner to the synthesis of methyl 6-morpholin-4-ylpyridine-3-carboxylate in Example 32, but starting with 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylic acid carboxylate (880 mg, 3.96 mmol) to give the title compound (0.35 g, 37%); 1H NMR (400.132 MHz, CDCl3) 3.93 (s, 3H), 4.75 (dt, 2H), 5.32 (dq, 1H), 5.41 (dq, 1H), 6.09-5.99 (m, 1H), 8.07 (d, 1H), 8.30 (dd, 1H), 8.97 (d, 1H), 9.45 (brs, 1H); MH+237.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](O)/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20](O)=O)[C@H:12]2O[O:24][C@@H:10]1[CH2:11]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:24][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC

Procedure:
To a 12×75 mm tube containing [1-14C] PGH2 (2 μg, 0.01 μCi or 0.05 μCi) and inhibitor (1 mM final assay concentration, in 10 μl of ethanol) in 225 μl of phosphate buffer (0.1M, pH 7.5), was added to an aliquot of guinea pig lung mocrosomes (25 μl, containing 400 μg protein) or an aliquot of human platelet microsomes (25 μl, containing ≅130 g protein). The solution was incubated in a 22° water bath for 2 min.; ether (1 ml) and citric acid (25 μMoles) were added, and the tube plunged into an acetone-dry ice bath. The ether extract was transferred to a 1.0 ml Reacti-vial, and the volume reduced under nitrogen to ≅50 μl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F

Procedure:
The product of Example 59, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.24 (s, 3H), 2.68 (br s, 2H), 3.42 (m, 1H), 3.61 (m, 4H), 6.30 (br s, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.02 (m, 2H), 7.27 (m, 5H), 7.46 (m, 1H), LC MS (m/e)=439 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]([CH3:21])[C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[CH:20][C:13]=12
Reactant: [H][H]
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2[nH]ccc12
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccc(N)cc1F)c1ccnc2[nH]ccc12

Procedure:
9 mg of 10% palladium-on-carbon are added to a solution of 28 mg (0.08 mmol) of N-(2-fluoro-4-nitrophenyl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine in 10 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through kieselguhr and the kieselguhr is washed with ethanol. Concentration under reduced pressure gives the target product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[CH3:18]I.[H-].[Na+]>COCCOC>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([CH3:18])[C:6]=2[CH:11]=1
Reactant: CI
Reactant: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1C(=O)Oc2cc(N3CCCCC3)c(Cl)cc21

Procedure:
A solution of 2.5 g (10 mmoles) of 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one and 2.1 g (15 mmoles) of methyl iodide in 15 ml of absolute 1,2-dimethoxyethane is added dropwise in the course of 20 minutes to a suspension, boiling under nitrogen, of 530 mg (11 mmoles) of 50% strength sodium hydride-oil dispersion in 15 ml of absolute 1,2-dimethoxyethane. The mixture is then boiled under reflux for a further 3 hours, the solvent is removed in vacuo and the residue is cautiously acidified with dilute hydrochloric acid and extracted three times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Recrystallisation from ether/petroleum ether yields 5 -chloro-3-methyl-6-(piperidin-1-yl)-benzofuran-2(3H)-one having a melting point of 112°-113°.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH2:9][CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:5]=2[N:4]([CH2:16][C:17]([N:19]2[CH2:25][CH:24]3[CH2:26][CH2:27][CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:18])[C:3]1=[O:28].[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH:21]12[CH2:22][CH2:23][CH:24]([CH2:26][CH2:27]1)[CH2:25][N:19]([C:17]([CH2:16][N:4]1[C:5]3[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:6]=3[C:7]([CH2:9][CH3:10])=[N:8][CH:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)=[O:38])[C:3]1=[O:28])=[O:18])[CH2:20]2
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Solvent: C1CCOC1
Product: CCC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one (310 mg) and 3-methylphenyl isocyanate (113 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to dryness. The residue was triturated in diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl 2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (360 mg, 86.2% yield) as a crystalline powder.
Reaction SMILES: Cl.CCO[CH:5](OCC)[CH2:6][Cl:7].[CH2:11]([O:13][C:14]([NH:16][NH2:17])=[O:15])[CH3:12]>O>[CH2:11]([O:13][C:14](=[O:15])[NH:16][N:17]=[CH:5][CH2:6][Cl:7])[CH3:12]
Reactant: CCOC(CCl)OCC
Reactant: CCOC(=O)NN
Agent: Cl
Solvent: O
Product: CCOC(=O)NN=CCCl
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
60 ml water and 0.8 ml of concentrated hydrochloric acid were heated to 90° C. in a three times tubulated round bottom flask of 250 ml contents equipped with a stirrer, thermometer and reflux condenser. The reaction mass was then reacted with 15.2 g of chloroacetaldehydediethylacetal and was subjected to stirring for 15 minutes at 90° to 100° C. The mass was then cooled to 30° C. and a solution of 12.5 g of hydrazinoformic acid ethylester in 40 ml water was added within a period of 10 minutes. There formed a white crystal slurry. After further stirring for 15 minutes the mass was subjected to suction. The separated crystals were washed with 30 ml icewater and were dried in vacuum at room temperture until the weight remained constant. There were obtained white crystals.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([C:17](OC)=[O:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Reaction time: 0.25 h

Procedure:
Methyl 4-(benzylthio)-5-nitrothiophene-3-carboxylate (5 g, 16.2 mmol) in dichloromethane (150 mL) at −40° C. was reacted with diisobutylaluminum hydride (1 M in dichloromethane, 36 mL, 2.2 equivalents) added dropwise. The reaction was stirred for 15 minutes after complete addition, quenched with 10% aqueous sodium potassium tartrate solution and stirred at 25° C. for 1 hour. The organic layer was separated, filtered through Celite® (diatomaceous earth) and the filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel with a Biotage-40s column eluting with 2:98 methanol/dichloromethane to give [4-(benzylthio)-5-nitrothien-3-yl]methanol as an oil, (4.32 g, 95%). 1H NMR (300 MHz, CDCl3) ppm 4.21 (s, 2 H), 4.39 (s, 2 H), 7.11 (m, 3 H), 7.23 (m, 2 H) 7.40 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:23]([CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
A mixture of 2.00 g (10.5 mmol) of the phenol prepared above, 1.60g (11.6 mmol) of anhydrous K2CO3, 1.304 ml (11.8 mmol) of ethyl bromoacetate, and 40 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 75 ml of water. The organic phase is washed with 50 ml of 5% aqueous NaOH, twice with saturated NaCl, dried (MgSO4), filtered, and the solvent removed to leave 2.186 g of a slightly yellow solid. This is recrystallized from hexane-EtOAc to give 2.01 g of 6-(4-carboethoxymethoxyphenyl)-4,5-dihydro3(2H)-pyridazinone as a white, crystalline solid, m.p. 127°-129° C. Yield 69%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[CH:24]=[CH:23]1.C>CO>[C:8]([C:24]1[C:25]2[C:30](=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[NH:22][CH:23]=1)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC(=O)N(C)C
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 90 °C
Yield: 39.2 %

Procedure:
Phosphorus oxychloride (27.5 ml) was added dropwise during 20 minutes to stirred N,N-dimethyldodecanamide (84.9 g) at room temperature. The temperature of the mixture rose during the addition to 50° C. The mixture was stirred and heated at 90° C. for 15 minutes and then methyl indole-6-carboxylate (33.4 g) was added portionwise to the stirred mixture during 10 minutes, the temperature of the mixture being maintained at 90° C. during the addition. The mixture was then stirred for 2 hours at 90° C. and was then poured onto ice. The aqueous mixture was extracted with chloroform (3×300 ml) and the extract was dried over magnesium sulphate and was evaporated to give a red brown oil. The oil was dissolved in boiling methanol (100 ml), the solution was treated with charcoal and the solution was filtered and cooled (0° C.) to give methyl 3-(n-dodecanoyl)indole-6-carboxylate (26.7 g), in the form of a buff solid, m.p. 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Si](C)(C)C.[Cl:20]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To a solution of (E)-methyl 4-amino-6-chloro-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (176 mg, 0.581 mmol) in DMF (2.3 mL) was added N-chlorosuccinimide (116 mg, 0.872 mmol). The reaction mixture was stirred at 60° C. After 4 h, the observed conversion was ˜50%. At this point, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (SiO2, hexane/EtOAc gradient) to afford the title compound (75 mg, 0.283 mmol, 48.7% yield) as an orange solid: mp 128-130° C.; 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=14.1 Hz, 1H), 6.45 (d, J=14.1 Hz, 1H), 4.73 (s, 2H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.17; ESIMS m/z 265 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)cc2C1=O

Procedure:
The compound of example 41 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3-cyanophenyl isocyanate. The compound of example 41 was used directly without isolation for the preparation of compound of example 42.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH2:15]>CN(C)C=O.[Cu]>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:9])=[O:15])=[CH:4][C:3]=1[C:11]([F:12])([F:14])[F:13]
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: [Cu]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Yield: 71 %

Procedure:
Activated copper (45 g) was added to a solution of 2-bromo-5-nitro-benzotrifluoride (50 g) in 100 ml of dimethylformamide and the mixture refluxed for 5 hours. The cooled mixture was poured into excess water and the resulting brown precipitate collected by filtration, washed with water and dried. Chromatography over silica gel gave 25 g (71% yield) of ##STR6## 2,2'-bis(trifluoromethyl)-4,4'-dinitro-1,1'-biphenyl, recrystallized as shiny yellow prisms from ether, m.p. 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:19]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenoxybenzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-phenoxyphenyl)-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 205-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.[NH2:13][C@H:14]([C:18]([O-:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[K+].S1(CCCC1)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)[O-]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 10 parts of 3,4-dichlorobenzotrifluoride, 23 parts of potassium valinate and 60 parts of sulfolane was heated and maintained at about 160° C. for about 48 hours, with mixing. The mixture was then cooled to room temperature, diluted with water, acidified with hydrochloric acid to a pH of 1.0. The aqueous layer was extracted with diethyl ether. The ether layers were washed with water, then dried and concentrated by evaporation to yield 10.4 parts of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (85% purity); a yield of about 75% based on the dichlorobenzotrifluoride starting material.
Reaction SMILES: [CH:1]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](#[N:13])[CH3:12].[H-].[Na+]>C1COCC1>[CH:1]1([C:6](=[O:8])[CH2:12][C:11]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Yield: 90 %

Procedure:
A solution of ethyl cyclopentanecarboxylate (prepared by esterification of commercially available cyclopentantecarboxylic acid, 30 g, 0.21 mol) and acetonitrile (10.1 g, 0.25 mol) in dry THF (80 mL) was added dropwise to a suspension of NaH (12.5 g, 0.31 mol) in dry THF (80 mL) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The aqueous layer was separated, adjusted to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 3-cyclopentyl-3-oxopropanenitrile (26 g, 90% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ4.06 (s, 2 H), 2.92 (m, 1 H), 1.41-1.77 (m, 8 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.Cl.[NH2:13][OH:14]>C(O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc(CCCl)cc1
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccc(CCCl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
4-(2-Chloroethyl)benzaldehyde (1.70 g, 10.08 mmol) was dissolved in ethanol (35 ml), hydroxylamine hydrochloride (1.05 g, 15.11 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. Ethanol was evaporated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.75 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO>[CH3:18][O:17][C:15]([CH2:14][CH:9]1[CH2:10][CH2:11][CH:12]([OH:13])[C:8]1([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23])=[O:16]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Product: CCC#CCC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 5.5 g quantity of 5-t-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (2-a)) and 1.5 g of lithium aluminum hydride are dissolved in 200 ml of methanol, and the solution is refluxed in a nitrogen atmosphere for one hour. The same procedure as in Example 1 is thereafter followed, giving 3-methoxycarbonylmethyl-2-t-butoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a), R1 =t-butyl, R2 =CH3) in a yield of 93.4%, b.p. 80°-86° C./0.02 mm Hg.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:56][O:57][C:58](=[O:64])[C:59]([NH2:63])([CH3:62])[CH2:60][CH3:61]>CN(C=O)C>[CH3:56][O:57][C:58](=[O:64])[C:59]([CH3:62])([NH:63][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH2:60][CH3:61]
Reactant: O=C(O)c1ccc2ccccc2c1OCCOc1ccccc1
Reactant: CCC(C)(N)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)OC
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 487 mg 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid in 6 ml abs. DMF under inert atmosphere 216 mg 1-hydroxybenzotriazole, 306 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 293 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 252 mg of 2-amino-2-methyl-butyric acid methyl ester hydrochloride, followed by 293 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by chromatography on silica (ethyl acetate/heptane) to yield 419 mg of 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid methyl ester.