Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]([OH:24])[CH2:22]O)[N:9]=2)=[CH:4][C:3]=1[CH3:25].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Br)(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(OC)(OC)OC.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]3[CH2:22][O:24]3)[N:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H](O)CO)C1
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H]2CO2)C1
Temperature: 0 °C
Reaction time: 17 h
Yield: 37.1 %

Procedure:
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (452 mg, 1.24 mmol) and pyridinium p-toluenesulfonate (85 mg) were combined in MeC(OMe)3 (50 mL) and briefly sonicated. The mixture was stirred for 17 h, concentrated, and the residue dissolved in CH2Cl2 (8 mL). The solution was cooled to 0° C. and treated with AcBr (0.15 mL, 2.0 mmol). After 5 h the mixture was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (75 mL). The EtOAc layer was washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The residue was combined with K2CO3 (243 mg, 1.84 mmol) in MeOH (50 mL) and stirred for 3 h then worked up as described above. Purification by column chromatography (silica, 10-40% acetone/CH2Cl2) gave 159 mg (37%) of the title compound. Chiral HPLC (Daicel OD, 0.5% Et2NH/MeOH) analysis indicated >95% optical purity. HPLC (reverse phase conditions), tR=4.97 min. MS (electrospray): exact mass calculated for C18H20ClN3O2 [M++Na], 368.11. m/z found 368.05. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.54 (br d, J=6.3 Hz, 2H), 7.41-7.35 (m, 3H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 4.81 and 4.74 (A and B of AB quartet, Jab=15.7 Hz, 2H), 4.60 (s, 2H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.42 (dd, J=15.4, 2.8 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H), 4.09 (dd, J=4.6 Hz, 1H), 3.93 (m, 2H), 3.74 (t, J=5.8 Hz, 1H), 3.73 (t, J=5.8 Hz, 1H), 3.34 (m, 2H), 2.85-2.75 (m, 6H), 2.53 (dd, J=4.6, 2.5 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C@H:13]1[CH2:18][C@@H:17]([C:19]2[O:23][NH:22][C:21](=[O:24])[CH:20]=2)[CH2:16][CH2:15][N:14]1C(OC)=O.Br>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[C@H:13]1[CH2:18][C@@H:17]([C:19]2[O:23][NH:22][C:21](=[O:24])[CH:20]=2)[CH2:16][CH2:15][NH:14]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(OC(F)(F)F)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(OC(F)(F)F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
(2R,4S)-Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (458 mg, 1.13 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 8.93 mL, 50.98 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (246 mg, 63%). 1H NMR (600 MHz, dmso) δ 1.37 (q, 1H), 1.47 (dq, 1H), 1.84-1.90 (m, 1H), 1.93-1.99 (m, 1H), 2.74 (dt, 1H), 2.87-2.94 (m, 1H), 3.07-3.13 (m, 1H), 3.94 (dd, 1H), 5.74 (s, 1H), 7.18-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.66 (t, 1H); HRMS Calculated for [C15H14F4N2O3+H]+: 347.1019. Found: 347.0995
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:12])[C:8]=1[C:9]([OH:11])=[O:10].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].[Cl-].[Na+]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:12])[C:8]=1[C:9]([O:11][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: ClCc1ccccc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Nc1cccc(Cl)c1C(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere a solution of 6.4 grams (0.031 mole) of 6-chloroanthranilic acid hydrochloride (prepared as in Example 3, Step B), 3.9 grams (0.031 mole) of benzyl chloride, and 6.2 grams (0.062 mole) of potassium bicarbonate in 100 mL of dimethylformamide was stirred at ambient temperature for about 48 hours. After this time the reaction mixture was poured into 250 mL of an aqueous solution saturated with sodium chloride. The mixture was extracted with three 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 20% ethyl acetate in heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 6.4 grams of phenylmethyl 6-chloroanthranilate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][C:13]([CH3:17])=[N:14]2)=[CH:9][CH:8]=1)C.[BH4-].[Na+].Cl>C(O)C>[CH3:17][C:13]1[CH:12]=[C:11]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:8][CH:9]=2)[N:14]=1
Reactant: CCOC(=O)COc1ccc2c(N3CCCC3)cc(C)nc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(N2CCCC2)c2ccc(OCCO)cc2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80 %

Procedure:
To a cooled (0° C.) solution of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-acetic acid ethyl ester (613 mg, 1.95 mmol) in ethyl alcohol (10 mL) was added sodium borohydride (506 mg, 12.84 mmol). The mixture was stirred 7 h at room temperature. Aqueous hydrochloride was added carefully (12M, 1 mL). The suspension was filtered and the solid was washed with MeOH. The solution was dried over sodium sulfate, filtered and the solvent was removed in a high vacuum to give 425 mg (80.0%) of 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol as a brown oil. ISP mass spectrum, m/e: 273.4 (M+1 calculated for C16H20N2O2: 273.4).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[CH2:10][CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5.09 g (0.015 mol) of 4-(4-aminobutyryl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in 50 ml of methylene chloride are added 5 ml (0.036 mol) of triethylamine and then at 0° 1.33 ml (0.019 mol) of acetyl chloride dissolved in 15 ml of methylene chloride, and the mixture is stirred at room temperature for 1 hour. Then, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Crystallization from methylene chloride/ether, chromatography on silica gel with ethyl acetate/methanol (9:1) and renewed crystallization from methylene chloride/ether gives N-[4-[8-chloro-2,3,5,6,-tetrahydrobenzo[f]quinolin-4(1H)-yl]-4-oxobutyl]acetamide as white crystals with melting point 142°-143°.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][C@H:36]([C:39]([OH:41])=[O:40])[CH2:37][OH:38]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:35][CH:36]([CH2:37][OH:38])[C:39]([OH:41])=[O:40])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Reactant: N[C@@H](CO)C(=O)O
Product: O=C(NC(CO)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Yield: 36 %

Procedure:
Compound 231 was synthesized from Compound 201 as described for Compound 235, except L-serine was used instead of L-5-hydroxytryptophane. Yield: 36%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc2cc(C3=CCN(Cc4ccccc4)CC3)ccc2c1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 92.2 %

Procedure:
A mixture of 2.92 gm 1-benzyl-4-(6-methoxynaphth-2-yl)-1,2,3,6-tetrahydropyridine and 0.3 gm platinum oxide in 50 mL tetrahydrofuran and 50 mL ethyl acetate was hydrogenated at room temperature for 16 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide 2.71 gm of the title compound as a white solid.
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH:16]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:20])[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Cc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
0.9 ml of piperidine is added to 24.8 g (0.2 mol) of 4-fluorobenzaldehyde and 32.4 g (0.2 mol) of benzyl isopropyl ketone in 150 ml of toluene and the mixture is heated to reflux overnight. After cooling to room temperature, the mixture is extracted several times using water and the organic phase is dried over magnesium sulphate and concentrated in vacuo. The residue is subjected to incipient distillation up to a bath temperature of 150° C. at 0.1 mbar in a high vacuum and 43.8 g of crude product are obtained in the distillation residue.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[CH2:13](OC(OCC)OCC)C.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:13][N:9]([CH:10]([CH3:12])[CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(C)Nc1cc(Br)ncc1N
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2cnc(Br)cc21
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-N4-isopropylpyridine-3,4-diamine (intermediate 257, 1.2 g, 5.22 mmol), triethylorthoformate (26.6 ml, 156 mmol) and TFA (0.24 ml, 3.12 mmol) was heated at 125° C. for 3.5 h and then concentrated. The residue was diluted with sat. aq. NaHCO3 and extracted with
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH:21]1[CH:25]=[N:24][C:23]([SH:26])=[N:22]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:26][C:23]3[N:24]=[CH:25][NH:21][N:22]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Sc1nc[nH]n1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2nc[nH]n2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-1,2,4-triazole-3-thiol. m/e+ 336 for C18H18N5S (M+H)+; 1H NMR (400 MHz, CDCl3) δ␣ 8.10 (s, 1H), 7.90 (s, 1H), 7.57 (m, 3H), 7.21 (d, J=7.7 Hz, 2H), 7.11 (dd, J=1.1, 9.1 Hz, 1H), 4.78 (s, 2H), 2.36 (s, 3H), 2.33 (s, 3H) 0.90 (bs, 1H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>[OH-].[Na+]>[C:15]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH:1][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:9][CH:8]=1)([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OC(=O)OCC=C)cc1)C(=O)O
Yield: 89 %

Procedure:
The first step (a) is the bis-protection of tyrosine amino acid using allyl chloroformate, as described in Stevens, C. M. and Watanabe, R., J. Am. Chem. Soc., 1950, 72, 725-727 (FIG. 11A). Tyrosine (n=0.03 mol, m=5.44 g) is dissolved in 15 ml of 4N sodium hydroxide and treated, when cold, with 7.02 ml (2.2 equiv.) of allyl chloroformate and additional 15 ml of 4N sodium hydroxide. After treatment and purification, O,N-dicarboallyloxy-L-tyrosine is obtained in 89% yield (Litt. 91%) as a crystalline derivative.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]1(/[CH:24]=[CH:25]/B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1(/[CH:24]=[CH:25]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)/C=C/c1ccccc1
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccccc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol) and (E)-phenylethenylboronic acid (56 mg, 0.38 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.03-2.18 (m, 4 H), 3.04-3.13 (m, 2 H), 3.13-3.18 (m, 1 H), 3.21-3.28 (m, 2 H), 4.24 (s, 2 H), 7.01 (t, J=7.6 Hz, 1 H), 7.19-7.28 (m, 3 H), 7.32-7.41 (m, 3 H), 7.60 (d, J=12.2 Hz, 1 H), 7.62-7.65 (m, 2 H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.Cl>CO.[Pd]>[ClH:1].[NH2:15][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:16]
Reactant: COC(=O)CCOc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCOc1cccc(CN)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
0.8 g (3.9 mmol) of the 3-(3-cyanophenoxy)propanoic acid methyl ester hydrochloride are dissolved in 20 ml of methanol. 0.4 ml of hydrochloric acid 10 N are added then, under an inert atmosphere, 100 mg of palladium on carbon. The mixture is agitated under a hydrogen atmosphere at ambient temperature and atmospheric pressure. The catalyst is eliminated by filtration, then the filtrate is concentrated under reduced pressure. The residue is recovered using toluene and evaporation is performed again. The product is recrystallised in a methanol/ethyl ether mixture (10/50; v/v), and dried under a vacuum. The expected product is obtained in the form of a white solid with a yield of 84%.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:7]([CH3:21])[C:8]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])C>C(O)(=O)C.[Pd]>[CH3:21][N:7]1[C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[NH:18][C:4](=[O:3])[C:5]1=[O:6]
Reactant: CCOC(=O)C(=O)N(C)c1c([N+](=O)[O-])ccc2c1CCCN2
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3
Reaction time: 15.5 h
Yield: 66.4 %

Procedure:
A solution of the product from Example 94 (1.1 g) in 100 mL of acetic acid was treated with 20% Pd/C (0.3 g) and shaken on a Parr apparatus under a hydrogen atmosphere (50 psi) for 15.5 hours. After removing the catalyst by filtration through a celite pad, the filtrate was evaporated and the yellow solide was washed with diethyl ether and dried to give the title compound (0.55 g, 69% yield) mp>285° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22].[SH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: O=C(Nc1cccc2c(Cl)c(Br)cnc12)c1c(Cl)cccc1Cl
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1cccc2c(Sc3ncc[nH]3)c(Br)cnc12)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromo-4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (120 mg) in N-methylpyrrolidone were added 2-mercaptoimidazole (33.5 mg) and potassium carbonate (50.1 mg), and the mixture was stirred for 40 minutes at ambient temperature, for 1 hour at 40° C., for 1 hour at 80° C. and for 1 hour at 90° C. To the mixture was added water, and the resulting precipitate was collected by filtration and washed with water and ethanol to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(imidazol-2-ylthio)quinoline (88.0 mg).
Reaction SMILES: [F:1][Sb-:2]([F:7])([F:6])([F:5])([F:4])[F:3].C(OC1C=CC([S+](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)CCCCCCC.F[Sb-](F)(F)(F)(F)F.[CH2:43]([O:53][C:54]1[CH:59]=[CH:58][C:57]([I+:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:56][CH:55]=1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CC.F[Sb-](F)(F)(F)(F)F.C(OC1C=CC([I+]C2C=CC=CC=2)=CC=1)CCCCCCCCCCCCCCCCC>>[F:1][Sb-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH2:43]([O:53][C:54]1[CH:55]=[CH:56][C:57]([I+:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:58][CH:59]=1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Agent: CCCCCCCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: F[Sb-](F)(F)(F)(F)F
Product: CCCCCCCCOc1ccc([I+]c2ccccc2)cc1

Procedure:
(4-octyloxyphenyl) diphenyl sulfonium hexafluoroantimonate; (4-decyloxyphenyl) phenyl iodonium hexafluoro antimonate; and (4-octadecyloxyphenyl) phenyl iodonium hexafluoro antimonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].B.Cl>C1COCC1>[CH3:14][O:13][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][NH2:10])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1C
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of methyl 2-methyl-4-[(E)-2-nitroethenyl]phenyl ether (7.89 g; 40.88 mmol) in dry THF (50 ml) was added to borane (245 ml of 1M solution in THF; 245 mmol), under nitrogen, dropwise over 20 minutes. The reaction mixture was then heated to 90C. After 14 hr it was cooled to rt and ice-cold water (100 ml) was added dropwise over 30 minutes. The pH was adjusted to ˜2 with 1N HCl and heated to reflux for 5 hr. Upon cooling, the reaction mixture was extracted with ethyl ether (2×300 ml) and the ether phases were discarded. The pH of the aqueous phase was adjusted to 10 with 1N NaOH and extracted with ethyl ether (2×200 ml). The combined organic phases were dried over MgSO4, filtered and concentrated to provide 2-(4-methoxy-3-methylphenyl)ethanamine (5.46 g; 81% yield), which was used without any further purification.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:3]([C:4]([O:6][CH3:7])=[O:5])([C:2](=[O:1])[CH2:8][CH3:9])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: C=CC(=O)OC
Solvent: C1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
39.9 g (0.31 mol) of methyl 3-oxo-pentanoate and 1.9 g (0.012 mol) of DBU were mixed at room temperature in a three necked round bottom flask, equipped with a dropping funnel and a reflux condenser. 66.4 g (0.77 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior has leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. Cyclohexane was added and the mixture was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 21.4 g (0.20 mol) of 4-(methoxycarbonyl)-4-(1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 64%; boiling temperature: 130° C. at 0.02 mbar; colorless).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[C:14]1([CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1C(c1ccccc1)c1ccccc1
Reaction time: 0.3 h
Yield: 43 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 50.8 g (0.25 mole) of benzhydryl chloride. The reaction mixture was heated with rapid stirring to 100° over 0.3 hr, held at 100° for 1.5 hours and poured into 1.5 l of H2O. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness under reduced pressure leaving 27 g (43%) of a semi-solid. The crude product was washed with 100 ml of ether, air dried and dried at 60° for 2 hours to give 19 g (30%) of a white solid, m.p. 200°-202°. Recrystallization from acetonitrile provided an analytical sample, m.p. 201°-203°.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].Cl[C:14]1[N:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCO>[Cl:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[N:22]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(=O)Cc2nc(Cl)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Elemental sodium (173 mg, 7.5 mmol) was added to 40 mL of absolute EtOH stirring under nitrogen. After all of the sodium reacted, 4-methoxyacetophenone (1.44 g, 7.5 mmol) was added, and the reaction stirred an additional 15 minutes. 2,6-Dichloronicotinic acid (1 g, 5.2 mmol) and copper acetate (80 mg, 0.65 mmol) was added and the reaction was stirred at reflux for 16 hours. The reaction was cooled to room temperature and quenched with 1 mL concentrated acetic acid. The mixture was concentrated to a solid, and redissolved in EtOAc. A small portion of fine inorganic precipitate was filtered off. The organic layer was extracted with 3×100 mL 1N NaOH. This was acidified with 1 N HCl to a pH of ˜4. A precipitate formed and was collected by vacuum filtration, yielding 6-chloro-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (1 g, 63%) as a tan solid.