Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([CH3:23])=[C:8]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:23][C:7]1[C:6](=[O:24])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[C:18]1[O:19][CH:20]=[CH:21][N:22]=1
Reactant: Cc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(CBr)c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 48.8 %

Procedure:
In a 250 mL round bottom flask, 7-chloro-3-methyl-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (0.50 g, 1.48 mmol), N-bromosuccinimide (291 mg, 1.63 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 36.6 mg, 0.223 mmol) were combined with carbon tetrachloride (20 mL). The mixture was heated to reflux for 2 hr. The reaction was cooled to room temperature and solids were filtered off. The mother liquor was concentrated and purified by flash chromatography using 3:2 hexane-ethyl acetate to afford 3-bromomethyl-7-chloro-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (300 mg, 49% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:48])([F:47])[C:21]1[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=1)[CH2:24][NH:25][C:26](=[O:43])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37](F)[CH:36]=[CH:35][C:34]=2[N+:40]([O-:42])=[O:41])[CH:28]=1>CN(C)C=O.O>[F:47][C:20]([F:19])([F:48])[C:21]1[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=1)[CH2:24][NH:25][C:26](=[O:43])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])[CH:36]=[CH:35][C:34]=2[N+:40]([O-:42])=[O:41])[CH:28]=1
Reactant: COCCNCCOC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Into a 10-mL vial, was placed a solution of bis(2-methoxyethyl)amine (285.6 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (277 mg, 2.14 mmol, 2.99 equiv). This was followed by the addition of a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide (300 mg, 0.72 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL). The resulting solution was stirred for 48 h at 80° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×70 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜1). The product was obtained as 270 mg (71%) of a yellow to green oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 98% purity HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH:9][C:11](=[O:13])[CH3:12])[CH:7]=1
Reactant: NCc1cc(Br)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NCc1cc(Br)ccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-chlorobenzenemethanamine (i.e. the product of Step A) (600 mg, 2.72 mmol) in toluene (10 mL) at 0° C. was added acetic anhydride (0.55 mL, 5.45 mmol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then extracted with ethyl acetate (3×), and the organic layers were combined, washed with water and brine and dried (Na2SO4). The solvent was evaporated to provide the title product (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=CC=1>CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][CH:27]=[N:26][CH:25]=2)=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Clc1ccc(-c2cnco2)cn1

Procedure:
To a stirred suspension of 6-chloronicotinaldehyde (1.5 g, 10.59 mmol, Organic Letters 2005, 7(14) 2965-2967) and potassium carbonate (1.46 g, 10.5 mmol) in MeOH (50 mL) was added toluenesulphonylmethyl isocyanide (2.06 g, 10.59 mmol, Aldrich). The reaction mixture was heated to reflux for about 4 h. The reaction mixture diluted with water (50 mL) and the product was extracted with EtOAc (2×150 mL). The combined organic layers were washed successively with water (2×50 mL) and brine (1×50 mL), dried over sodium sulphate and evaporated to dryness. The crude material was purified by silica gel column chromatography eluted with 15% EtOAC in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 5-(6-chloropyridin-3-yl)oxazole as an off white solid 1.2 g (42.8. %), 1H NMR (400 MHz, CDCl3): δ 8.7 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), MS m/z: 181 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH:13](O)[C:14](=[CH2:19])[C:15](OC)=[O:16])([O-])=O>C(O)C.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH:13]=[C:14]([CH3:19])[C:15](=[O:16])[NH:1]2)=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2ccc(N)cc2[nH]c1=O

Procedure:
Methyl 2-[(2,4-dinitrophenyl) (hydroxy)methyl]acrylate was reacted in ethanol in the presence of palladium/carbon under a hydrogen atmosphere to obtain 7-amino-3-methyl-quinolin-2(1H)-one.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[NH4+:4].N1CCCC(C(OCC2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)C=CC=CC2)=O)C1>[Pd].CO>[CH3:27][O:26][C:24]([C:20]1[CH:19]=[C:18]([N:4]2[CH2:22][CH2:23][CH2:18][CH:19]([C:1]([OH:3])=[O:2])[CH2:20]2)[CH:23]=[CH:22][CH:21]=1)=[O:25]
Reactant: O=C[O-]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(C2(COC(=O)C3CCCNC3)C=CC=CC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N2CCCC(C(=O)O)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 180.7 %

Procedure:
In an argon atmosphere, 10% palladium on activated carbon (234 mg) and ammonium formate (1.66 g, 26.4 mmol) were added to 1-[3-(methoxycarbonyl)phenyl]benzyl nipecotate (2.34 g, 6.60 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 4 hours. Subsequently, the mixture was filtered through Celite and the filtrate was concentrated. 5% aqueous citric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was then washed with brine and was dried over sodium sulfate. The solvent was evaporated to give 1.57 g (90%) of the desired compound as a pale reddish brown powder.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:4][CH2:3][C:14]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[NH:11][C:12]([NH2:16])=[N:13][C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1)=[O:15]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21

Procedure:
Acyclovir (ACV, 0.5 g, 2.22 mmol, used as a dry white powder) was suspended in anhydrous pyridine (10 ml) and to the mixture stirred under dry nitrogen was added GLA acid chloride (0.788 g, 2.664 mmol). The reaction mixture was stirred overnight at room temperature after which period TLC indicated conversion to the required product. The pyridine was removed in vacuo and the residual syrup was dissolved in chloroform. This was introduced into a column of silica gel (30 g) pre-equilibrated in chloroform:ethanol (30:1, v:v). Elution with chloroform followed by chloroform:ethanol (30:1), (20:1) and finally (15:1), gave the required product, AK-5, as a TLC homogeneous semisolid. Yield, 48% (0.517 g, 1.065 mmol).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:26]=[C:25]([C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=3)[N:24]=2)(=[O:21])=[O:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:11][C:12]1[CH:13]=[C:14]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:26]=[C:25]([C:36]3[CH:42]=[CH:41][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:38][CH:37]=3)[N:24]=2)(=[O:20])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.208 mL, 1.66 mmol) was added to 4-[4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (693 mg, 1.50 mmol) and sodium hydrogen carbonate (190 mg, 2.26 mmol) in dioxane (10 mL). The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-80% ethyl acetate in isohexane, to give the desired product as a yellow dry film (827 mg).
Reaction SMILES: C(O)CCCCCO.[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCCO.[C:23]([C:27]1[CH:28]=[C:29]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:30]2[O:34][C:33](=[O:35])[CH:32]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=3)[C:31]=2[CH:46]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:30]2[O:34][C:33](=[O:35])[CH:32]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH2:45][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:43])=[CH:38][CH:37]=3)[C:31]=2[CH:46]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reactant: OCCCCCCCCCCCCO
Agent: OCCCCCCO
Product: CCCCCCCCOC(=O)c1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1

Procedure:
Compounds (111), (112), (113), (114), (115), (116) and (117) (Table 1) are obtained in analogy to Example 5 using 1-dodecanol, 1-octadecanol, 1-nonadecanol, 1-docosanol, 2-ethylhexanol, 1,6-hexanediol and 1,12-dodecanediol instead of 1-octanol. For the preparation of compounds (116) and (117) only half of an equivalent of 1,6-hexanediol and 1,12-dodecanediol in respect to the compound (109) was used.
Reaction SMILES: [CH2:1]([N:8]([C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30]C)=[O:28])[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=[CH:11][C:10]=1[C:20]([O:22]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>>[CH2:1]([N:8]1[C:25](=[O:32])[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:20]([OH:22])[C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)N(Cc1ccccc1)c1c(C(=O)OCC)cnn1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1c(O)c2cnn(-c3ccccc3)c2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared from the product of Example 138B and sodium methoxide according to the procedure of Rowley, and co-workers as described in J. Med. Chem., 1993, 36, 3386-3396. MS (ESI−) m/z 374 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)=[CH:15][CH2:14]2)[C:3]1=[O:29].C(O)(=O)C.[H][H].[ClH:37]>C(O)C.[Pt]=O.C>[ClH:37].[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:17][CH2:18]2)[C:3]1=[O:29]
Reactant: [H][H]
Reactant: CC1(C)C(=O)N(CCN2CC=C(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)C(=O)N(CCN2CCC(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21

Procedure:
3,3-Dimethyl-1-{2-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-1,3-dihydro-2H-indol-2-one (0.6 g, 1.36 mmol) dissolved in ethanol (40 mls) and acetic acid (4 mls) was added to 10% platinum oxide/charcoal. Hydrogen was admitted for 12 h at 60 psi the catalyst was then removed by filtration, the catalyst washed with ethanol (3×75 mls), concentrated in vacuo and the resulting oil purified by column chromatography on silica with ethyl acetate/Hexane. The fractions containing product were collected and the solvent evaporated in vacuo to give a solid which was converted to the hydrochloride, which was subsequently dried in vacuo to give a solid, mp 172-174° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[C:5]([O:22][CH3:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([NH:29][CH3:30])=[CH:27][CH:26]=1>CN(C)C=O>[ClH:1].[CH3:23][O:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:29]([C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1)[CH3:30])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: CNc1ccc(F)cc1
Reactant: COc1cccc2c(N3CCc4ccccc4C3)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3)nc(N(C)c3ccc(F)cc3)nc12
Product: Cl
Yield: 37.9 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.0 g of the compound (6.14 mM) prepared in Example 4 and 15 ml of dimethyl-formamide, 1.5 g of 4-fluoro-N-methylaniline(12.2 mM) was added, 1.05 g of the title compound was prepared.
Reaction SMILES: Cl.[F:2][C:3]1([F:20])[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:20][C:3]1([F:2])[CH2:4][CH2:5][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])[CH2:7][CH2:8]1
Reactant: COC(=O)C1CCNC(CC2CCC(F)(F)CC2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
Methyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-4-carboxylate hydrochloride (5.1 g, 16.36 mmol) was dissolved in DCM (150 mL), then DIPEA (7.14 mL, 40.89 mmol) was added. Methyl carbonochloridate (1.803 mL, 22.90 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 2 h. The mixture was washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase separator and evaporated yielding crude dimethyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-1,4-dicarboxylate (5.7 g, 105%)
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.[OH-].[NH4+].C(O)(=O)C>O>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: OCC(O)CO
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])ccc2cccnc12
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methyl-3-nitroaniline (10 g), glycerin (20.57 g) and As2O5.xH2O (Baker, 88% As2O5, 8.5 g) is heated slowly to 150° C. in an open round-bottom flask, then stirred for 6 hrs at 150° C. The resulting mixture is cooled to room temperature and diluted with water (200 mL), then basified with ammonium hydroxide (28-30%, 100 mL). After about 10 minutes, the solution is acidified to pH=5 with glacial acetic acid and extracted with CH2Cl2 (3×200 mL). The combined extracts are washed with H2O (200 mL), sat. NaHCO3 (200 mL), then dried over MgSO4 and rotary evaporated. The crude quinoline is filtered through a short pad of silica gel, using CH2Cl2 as solvent. The filtrate is rotary evaporated and the residue recrystallized from hexane/CH2Cl2 to afford 8-methyl-7-nitroquinoline as a tan solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[N:12]=[CH:13][NH:14][C:15](=[O:17])[CH:16]=1>C(#N)C>[I:1][C:16]1[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=1[C:10]([F:9])([F:18])[F:19]
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: O=c1[nH]cnc(C(F)(F)F)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
N-Iodosuccinimide (2.75 g) was added to a stirred suspension of 4-trifluoromethylpyrimidin-6-one (1 g) in dry acetonitril (13 ml). The reaction mixture was stirred at the ambient temperature for 2 hours, and then heated under reflux for 10 hours. After cooling, removal of the solvent under reduced pressure gave a brown solid which was recrystallised from water to give 5-iodo-4-trifluoromethylpyrimidin-6-one as a pale orange solid (150 mg);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:36]1[C:44]2[C:39](=[C:40]([CH2:46][S:47][CH3:48])[CH:41]=[C:42](F)[CH:43]=2)[NH:38][CH:37]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:36]2[C:44]3[C:39](=[C:40]([CH2:46][S:47][CH3:48])[CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
503 mg (1.86 mmol) of the compound from Example 80A and 75 mg (0.34 mmol) of indium(III) chloride were added to 300 mg (1.69 mmol) of the compound from Example 8 in 15 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h, a further 187 mg (0.85 mmol) of indium(III) chloride were added, and the mixture was again stirred for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 107 mg (15% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:16][C:17]([OH:19])=O)[CH2:12][C:13]([OH:15])=[O:14]>C(Cl)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][C:17](=[O:19])[O:15][C:13](=[O:14])[CH2:12]1
Reactant: O=C(O)CC(CC(=O)O)c1ccc2ccccc2c1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of commercial 2-naphthaldehyde (7.81 g) and ethyl acetoacetate (13 g) in ethanol (15 ml) piperidine (1 ml) was added with stirring at rt. The yellowish solution was kept at rt for 20 h. The precipitate was isolated by suction filtration, washed with ethanol, and dried in vacuo to give 14.7 g light yellow crystals (the bis-adduct of acetoacetate to the aldehyde). The crystals were added in portions to 40% NaOH (400 g) with stirring and the resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (360 ml). A resinous precipitate is formed. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the combined organic layers dried (sodium sulfate). After filtration and evaporation of the solvent the crude (8.5 g) was triturated with ethyl acetate to leave 3-(2-naphthyl)glutaric acid (3.6 g) as colourless solid. The suspension of 3-(2-naphthyl)glutaric acid in acetyl chloride (10 ml) was heated to reflux with stirring for 1 h. After cooling to rt the precipitate is isolated by suction filtration, washed with acetyl chloride (4×3 ml) and petrol ether, and dried in vacuo to provide 3-(2-naphthyl)glutaric anhydride (2.88 g) as colourless powdery solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[C:7](OC)[C:6]=1[O:27]C)[CH3:2].O1CCCC1.C(O)C.Cl>O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[OH:27])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)c(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
To a solution of 4-[3-cyano-4-(2-hydroxyphenyl)pyrrole-1-yl]-2-methoxy-methoxy benzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (3 mL) and ethanol (5 mL) was added 2 mol/L hydrochloric acid (2 mL), and this mixture was stirred at 70° C. for 18 hours. To this reaction mixture was added water, the precipitated solid was collected by filtration, and this solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.054 g).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>CC(O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc2c(c1)OCO2)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,4-methylenedioxybenzaldehyde (15.013 g, 0.1 mol), benzyl acetoacetate (20.18 g, 0.105 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (500 mL) was stirred at room temperature for 48 hours. The white solid, benzyl 2-{(3,4-methylenedioxyphenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2×50 mL) and dried (29.84 g, 92%); m.p. a , 137-138° C.