Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[O:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=4)[N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@@H:8]([OH:35])[C@H:7]1[OH:36])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:38].CO.O>CO.C(Cl)Cl>[CH3:38][O:33][C:32](=[O:34])[CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][NH:21][C:17]2[N:16]=[C:15]3[C:14]([N:13]=[CH:12][N:11]3[CH:9]3[CH:8]([OH:35])[CH:7]([OH:36])[CH:6]([C:4](=[O:5])[NH:3][CH2:2][CH3:1])[O:10]3)=[C:19]([NH2:20])[N:18]=2)=[CH:25][CH:26]=1
Reactant: CCNC(=O)[C@H]1OC(n2cnc3c(N)nc(NCCc4ccc(CCC(=O)O)cc4)nc32)[C@@H](O)[C@H]1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(NCCc4ccc(CCC(=O)OC)cc4)nc32)C(O)C1O
Reaction time: 0.5 h
Yield: 66 %

Procedure:
The methyl ester, JR2171, was synthesized by dissolving approximately 10.0 mg of 3-(4-{2-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-ylamino]-ethyl}-phenyl)-propionic acid (CGS21680) in 5 mL 10% MeOH/CH2Cl2 and adding TMS Diazomethane (2.0 M solution in hexanes) dropwise until a yellow color persisted. After stirring for 30 minutes the solvent was removed under reduced pressure. The crude compound was then purified by HPLC using a C18 column and a MeOH/H2O gradient, yielding 6.7 mg of compound (66% yield). Characterization by HRMS, APCI MS, 1H NMR, and 13C NMR were consistent with the putative structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(CCCCO)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4.5 g (0.022 mole) 4-(acetylamino)benzenebutanol in 25 ml pyridine, add 8.3 g (0.044 mole) tosyl chloride and chill in the refrigerator overnight. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 90:10). At the completion of the reaction, pour the reaction mixture onto 500 ml ice water and stir for 15 minutes. Extract the aqueous mixture with 3×300 ml ether. Wash the combined organic layers with 1N hydrochloric acid, then with water, dry over potassium carbonate, filter and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(OCC)(=O)C.O>[Cl:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]2[CH2:12][N:11]([C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CCN=C=O
Reactant: Clc1nc(Cl)c2c(n1)CCNC2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCc2nc(Cl)nc(Cl)c2C1
Temperature: 25 °C

Procedure:
2,4-Dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (2.0 g, 8.3 mmol) prepared according to Reference Example 1 was dissolved in ethyl acetate (20 mL), and the solution was mixed with triethylamine (1.4 mL) and ethyl isocyanate (0.89 mL), followed by stirring at room temperature for twelve hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to thereby yield 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl-N-ethylcarboxamide (2.3 g, in a quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)C.[Pd].[H][H]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
Reduction of 1-fluoro-3-nitro-4-methoxybenzene (34 g) in 400 ml of ethanol was carried out with 2 g of 10% palladium/carbon catalyst in hydrogen. The mixture was filtered, concentrated and used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[F:11][C:8]1[CH:9]=[N:10][C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([O:6][CH3:20])=[O:5]
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cnc1Oc1ccc(F)cc1
Yield: 66.6 %

Procedure:
A mixture of 2-chloro-5-fluoronicotinic acid (2.61 g, 14.9 mmol), 4-fluorophenol (2.02 g, 18 mmol), potassium carbonate (4.56 g, 33 mmol), copper bronze (211 mg, 3.3 mmol), and cuprous iodide (230 mg, 1.2 mmol) in N,N-dimethylforamide (40 mL) was heated under reflux in an oil bath for 6 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was partitioned between ethyl acetate (200 mL) and 2 N hydrochloric acid (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of solvent, the residual oil was dissolved in methanol (50 mL). To the solution were added conc. hydrochloric acid (1 mL) and the mixture was heated under reflux for 4 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (3/1) to afford 2.63 g (67%) of the title compound: 1H-NMR (CDCl3) δ 8.11 (1H, d, J=3.1 Hz), 8.02 (1H, dd, J=7.7, 3.1 Hz), 7.11–7.07 (4H, m), 3.96 (3H, s); MS (ESI) m/z 266 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20][NH2:21])=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[O:2]=[C:1]1[O:19][C:18]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:20][NH:21]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1-c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of a 20% toluenic phosgene solution are added dropwise to a solution of 240 mg of 3-(tert-butoxycarbonylamino)thiophene-2-carboxylic hydrazide in 5 ml of THF and the mixture is stirred at RT. After one hour, the mixture is admixed with 10 ml of water and, after brief digestion, extracted with ethyl acetate. After the ethyl acetate phase has been dried over sodium sulfate, the mixture is concentrated under reduced pressure and the remaining residue is used further without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])[CH2:40][CH2:39]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].SCCO>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[SH:17][C@@H:15]1[CH2:16][N:12]([C:10]([O:9][CH2:8][C:7]2[CH:57]=[CH:58][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[C@H:13]([CH2:37][N:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=3)=[O:45])[CH2:42][CH2:43]2)[CH2:14]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: OCCS
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a solution of (2S,4S)-1- (4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (2.76 g) in trifluoroacetic acid (15 ml) was added 2-mercaptoethanol (0.31 ml) under ice-cooling and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in toluene (20 ml) and the solution was evaporated in vacuo to give a syrup. The syrup was dissolved in ethyl acetate (60 ml) and washed successively with saturated aqueous sodium hydrogen carbonate (30 ml) and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methylpyrrolidine (0.93 g).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](C(C)(C)C)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:32]1[CH:37]=CC=C[CH:33]=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:33][CH2:32][CH3:37])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,1), 251(17), 250 (100), 163 (6), 121 (34), 114 (9), 107 (6), 90 (17), 78 (9), 77 (10), 71 (17).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:30])[NH:12][C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[C:14]=2[C:27]([NH2:29])=[O:28])[CH2:3][CH2:2]1.[H][H]>CO.[Pt]=O>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[C:13]([NH:12][C:11]([NH:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:30])[S:17][N:16]=2)=[CH:23][CH:22]=1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reaction time: 16.5 h
Yield: 46.5 %

Procedure:
A mixture of 5-(3-(3-morpholinopropyl)ureido)-3-(4-nitrophenyl)isothiazole-4-carboxamide (110 mg, 0.25 mmol) and platinum oxide (25 mg, 0.11 mmol) in 15 mL MeOH was hydrogenated under 60 PSI hydrogen. After 16.5 hours, the mixture was filtered and rotary evaporated to an off-white solid. Then an additional 16 mg of impure product from another reaction was combined and this material chromatographed eluting with gradient 5% to 15% MeOH in CHCl3 to give the title compound as an off-white solid (47 mg, 40%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1.C(N(CC)CC)C.Cl.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][C:32]=3[C:5]=2[CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(CCBr)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Yield: 2.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. 4-Chlorophenylhydrazine hydrochloride (9 g, 50 mmol), 5-(2-bromoethyl)-2-methylpyridine (10 g, 50 mmol), triethyl amine (21 ml, 150 mmol) and N-methyl-4-piperidone hydrochloride (7.5 g, 50 mmol) were taken in ethanol (100 ml) to obtain 390 mg of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after on purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[C:12](=[S:14])=[S:13].[Cl:15][C:16]([Cl:21])=[C:17]([Cl:20])[CH2:18]Cl>O>[CH3:1][CH:2]([NH:9][C:12](=[S:14])[S:13][CH2:18][C:17]([Cl:20])=[C:16]([Cl:21])[Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C=S
Reactant: CC(N)c1ccccc1
Reactant: ClCC(Cl)=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(NC(=S)SCC(Cl)=C(Cl)Cl)c1ccccc1
Temperature: 20 °C
Yield: 88.3 %

Procedure:
A two-phase mixture containing 6.0 g (0.0495 mol) dl-α-methylbenzylamine and 8.0 g (0.05 mol) 25% NaOH in 50 ml water was stirred rapidly at 0°-10° C. while 4.0 g (0.05 mol) carbon disulfide was added dropwise over 2-3 minutes. The mixture was stirred and allowed to warm to 20° C. over a one hour period. To this stirred slurry was added 9.0 g (0.05 mol) 1,1,2,3-tetrachloropropene in one portion. A yellow two phase mixture resulted and the temperature slowly rose to a maximum of 28° C. The mixture was heated gently to 45°-50° C. for three hours, then let cool and extracted with 300 ml ethyl ether. The ether solution was washed with two, 50 ml portions of water, treated with activated charcoal and MgSO4, filtered through Hy-flo and evaporated in vacuo below 40°/<1 torr to give 14.9 g (88%) of a light orange oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=O.COC(OC)[N:14]([CH3:16])C.C(=O)(O)O.[NH2:23][C:24](N)=[NH:25].C[O-].[Na+]>CO>[NH2:25][C:24]1[N:23]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]([C:16]#[N:14])=[CH:9][N:10]=1
Reactant: N#CCC(=O)c1ccco1
Reactant: N=C(N)N
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc(N)nc1-c1ccco1

Procedure:
From 2-furoylacetonitrile and N,N-dimethylformamide dimethyl acetal. Then treatment with guanidine carbonate and sodium methylate in methanol. EI-MS m/e (%): 186 (M+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]2=[N:19][NH:20][C:21]([OH:22])=[C:9]12.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39]([O:43][C:44](=O)[O:45]C(C)(C)C)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44]([O:22][C:21]1[C:9]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]=2[NH:19][N:20]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(n[nH]c2O)N1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(OC(=O)OC(C)(C)C)n[nH]c2N1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-3-hydroxy-6-propyl-2H-pyrazolo[3,4-b]pyridine (12.5 g) in THF (400 mL) was added triethylamine (4.5 g), dimethylaminopyridine (0.5 g) and di-t-butylcarbonate (9.6 g) and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (12 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]([CH2:20][O:21][CH2:22][CH3:23])=O)[CH3:14].[CH2:25]([O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[CH3:26]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:33])=[C:30]([CH3:31])[NH:32][C:18]=1[CH2:20][O:21][CH2:22][CH3:23])=[O:24])[CH3:14]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOCC(=O)CC(=O)OCC
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2ccccc2C(F)(F)F)C(C(=O)OCC)=C(C)N1
Yield: 55 %

Procedure:
7.4 g of 2-trifluoromethylbenzaldehyde, 17.4 g of γ-ethoxyacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 80 ml of ethanol are heated under reflux overnight, the mixture is cooled and 2-ethoxymethyl-6-methyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of white-yellow crystals of melting point 112° C, in a yield of 55% of theory.
Reaction SMILES: [C:1]1([C:7]2[NH:12][CH2:11][CH:10]([CH2:13][Cl:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[ClH:14].[ClH:14].[C:1]1([C:7]2[NH:12][CH2:11][CH:10]([CH2:13][NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Reactant: ClCC1CNC(c2ccccc2)=NO1
Product: Cl
Product: c1ccc(C2=NOC(CNC3CCCCC3)CN2)cc1

Procedure:
To 5.0 g. of 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine (Chem. Ber. 108, 1911 (1975) 37 ml. of cyclohexyl amine are added. The reaction mixture is then refluxed for 10 hours. The excess of cyclohexyl amine is evaporated in vacuo and to the evaporation residue 100 ml. of ethyl acetate are added. The mixture is brought to the boil and the insoluble substances are filtered off while hot. The mother liquor is evaporated in vacuo, the residue is dissolved in isopropanol and the solution is acidified by introducing hydrogen chloride gas. 4.0 g. of 3-phenyl-6-cyclohexylaminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride are obtained, melting at 240° to 244° C. (after recrystallization from isopropanol).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](O)([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]3([CH3:25])[CH3:24])OCC[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:24][C:10]1([CH3:25])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2](=[O:3])[CH3:1])[CH:8]=2)[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH2:11]1
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C3(C)OCCO3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
A solution of (+/−) 6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene ((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 ml of benzene was refluxed for 12 h. During the reaction the water generated from the reaction was periodically removed by a Dean-Stark trap. The solvent was removed and the residue was purified by column chromatography (silica, ethyl acetate/hexane (1/3)) to give the title compound as an oil (215 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C:33]1[CH:34]=[CH:35][C:36]2[C:37]3[N:45]=[C:44]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)[CH:43]=[C:42]([C:54]([NH2:56])=[O:55])[C:38]=3[NH:39][C:40]=2[CH:41]=1.[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60]O>C1COCC1>[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60][O:32][C:33]1[CH:34]=[CH:35][C:36]2[C:37]3[N:45]=[C:44]([C:46]4[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=4)[CH:43]=[C:42]([C:54]([NH2:56])=[O:55])[C:38]=3[NH:39][C:40]=2[CH:41]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(O)ccc4c3n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OCCN(C)C)ccc4c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
Diethyl azodicarboxylate (0.057 mL, 0.360 mmol) was added to an ice-cooled solution of triphenylphosphine (94 mg, 0.360 mmol) in dry THF (1 mL). The bath was removed and a solution of 7-hydroxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (Example 207, 60 mg, 0.180 mmol) and 2-(dimethylamino)ethanol (24 mg, 0.270 mmol) in dry THF (1 mL) was added after 15 minutes. After stirring for 2 hr at room temperature, the reaction was quenched with brine and extracted with EtOAc. The extracts were dried with sodium sulfate and the solvent was removed. Radial silica gel chromatography of the residue (step gradient elution with methylene chloride containing 10 to 60% methanol) followed by SCX cartridge purification gave 7-(2-(dimethylamino)ethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (12 mg) as a yellow glass. MS (ESI) m/z 405.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.34 (1H, br. s.), 8.56 (1H, s), 8.28 (1H, s), 8.23 (2H, d, J=8.85 Hz), 8.10 (1H, d, J=8.55 Hz), 7.83 (1H, s), 7.28 (1H, d, J=2.14 Hz), 7.10 (2H, d, J=8.85 Hz), 6.89 (1H, dd, J=8.55, 2.44 Hz), 4.15 (2H, t, J=5.95 Hz), 3.85 (3H, s), 2.70 (2H, t, J=5.80 Hz), 2.27 (6H, s).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13].[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCCCOCCCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C

Procedure:
Air inside the reaction vessel as in Example 1 was replaced with a nitrogen gas in a satisfactory manner. Then, 180 ml of dibutyl ether solution containing 0.354 mol of ethyl magnesium bromide as hydrocarbon magnesium halide was charged to the reaction vessel. Further, 0.365 mol of bromopentafluorobenzene was charged to the dropping funnel as fluoroarylhalide. Next, after dropping the bromopentafluorobenzene in the dropping funnel over 120 minutes at 25° C., the content of the reaction vessel was stirred for thirty minutes at 25° C., thereby obtaining pentafluorophenyl magnesium bromide as the fluoroaryl magnesium halide, obtained as a colorless dibutyl ether solution.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10](F)[C:11]=1F)[N:8](C1C=CC([Cl:20])=CC=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=O.CN1CCNCC1>>[ClH:20].[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: CN1CCNCC1
Product: Cl
Product: O=C(O)c1cnc2ccccc2c1
Yield: 78 %

Procedure:
The synthesis is carried out analogously to Example 1. 6,7,8-Trifluoro-1,4-dihydro-4-oxo-1-(4-chlorophenyl)-quinoline-3-carboxylic acid and N-methylpiperazine are used as starting substances. The corresponding quinoline-3-carboxylic acid hydrochloride (I) (R=4--Cl--C6H4 --, X1 =X2 =F, A=4-ethyl-1-piperazinyl) of melting point >300° C. is obtained in 78% yield. Melting point of the betaine: 274°-278° C.