Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([CH3:6])=O.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C([O-])(=O)C.[NH4+:26].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]1[N:2]([OH:1])[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:6])[N:26]=1
Reactant: CC(=O)C(=NO)c1cccnc1
Reactant: O=Cc1ccccc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2ccccc2F)n(O)c1-c1cccnc1
Yield: 28 %

Procedure:
To a solution 1-hydroxyimino-1-(3-pyridyl)acetone (0.5 g) in acetic acid (10 ml) was added 2-fluorobenzaldehyde (0.76 g) and ammonium acetate (2.35 g), and refluxed for 30 minutes. Then, the solution was poured into water (75 ml), neutrallized with aqueous potassium carbonate, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was triturated with diisopropyl ether to give 2-(2-fluorophenyl)-1-hydroxy-4-methyl-5-(3-pyridyl)imidazole (0.23 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]I>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The general procedure of Referential Example 106 was repeated through use of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.955 g) and methyl iodide (0.47 mL), to thereby give the title compound as an oily product (0.899 g, 89%).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([C:13]#[N:14])[CH:7]=1.[CH3:15][O:16]C(=O)OC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:11][CH:12]=1)[NH:10][C:15](=[O:16])[N:14]=[C:13]2[CH:1]1[CH2:3][CH2:2]1
Reactant: COC(=O)OC
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: BrC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: O=c1nc(C2CC2)c2cc(Cl)ccc2[nH]1
Temperature: 33 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
A 3-necked round bottom flask equipped with a thermometer, magnetic stirrer, addition funnel and septum inlet was oven dried and swept with Ar. The flask was charged with a suspension of 5.5 g (0.226 g-atom) of magnesium turnings (Aldrich) in 150 mL of dry THF. A 3.0 mL portion of cyclopropyl bromide (Aldrich, distilled) was added to the suspension in one portion, and the mixture heated to 33° C., at which time a gentle exotherm began. After this exotherm had stabilized at 48° C., the remaining 15.8 mL (0.235 mol total) of cyclopropyl bromide was added dropwise as a solution in 30 mL of dry THF to maintain an internal temperature of 48°-52° C. After the addition, the solution was kept at that temperature for 45 min using a heating mantle. (Note: 20 mL of this Grignard solution was removed via cannula for another reaction). A solution of 10.0 g (0.066 mol) of 4-chloro-2-cyanoaniline in 50 mL of dry THF was added dropwise at a rate which maintained an internal temperature of 47°-50° C. This temperature was maintained for 30 min after the addition was complete using a heating mantle. A 17.4 mL (0.206 mol) quantity of dimethylcarbonate (Aldrich) was added dropwise at a rate which maintained the temperature at 48°-55° C. After the addition, the reaction was kept at this temperature for 30 min using a heating mantle. The reaction solution was cooled to 25° C. and poured into a rapidly stirred mixture of ice and 500 mL of 1M citric acid. This mixture was extracted with two portions of CHCl3, the combined organic layers washed with 10% Na2CO3, dried over MgSO4, concentrated to a volume of approx. 450 mL and stored in the refrigerator under Ar overnight which caused the product to crystallize. The crystals were filtered and washed with cold CHCl3 to give 6.5 g (44%) of the title compound as a pale yellow solid. Chromatography of the mother liquors on 850 g of fine SiO2 using 35:1 CHCl3 --CH3OH provided an additional 5.2 g (35%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][C@@H:10]2[O:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])cc3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 5 L three necked flask equipped with a mechanical stirrer and thermocouple is changed with [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (210.4 g, 0.996 mol) and anhydrous pyridine (600 mL). The flask is immersed in an ice/brine bath to achieve an internal temperature of 0-1° C. To this is added a solution of p-toluenesulfonyl chloride (220.0 g, 1.15 mol) is dissolved in pyridine (200 mL) over 30 min. The bath is allowed to expire, and the mixture is stirred for 18 h at room temperature. Water (1600 mL) is added at a constant rate over 45 min. The resulting suspension is stirred for 1 h, and then the precipitate is collected by vacuum filtration onto a medium porosity fritted funnel. The filter cake is washed with water (1600 mL) and suction dried under nitrogen to give [(2R)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 98%) as a tan powder; m.p. 138° C. LCMS (Standard Method): 2.78 min, 388 (M+Na)+. 1H NMR (300 MHz, DMSO-d6) δ7.79-7.72 (m, 3H), 7.49-7.42 (m, 3H), 7.06 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.41 (dd, J=2.6, 11.6 Hz, 2H), 4.22 (dd, J=6.3, 11.5 Hz, 1H), 4.12 (dd, J=6.8, 11.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]1([CH:11]([OH:13])C)C=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(C)C>[C:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:11]([O:3][CH:2]([CH3:4])[CH3:1])(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(O)c1ccccc1
Reactant: CC(C)=O
Agent: CCCCCCOC(=O)CCCCC
Solvent: CC(C)O
Product: CCCCCC(=O)OC(C)C

Procedure:
Likewise, refluxing a toluene solution containing one equivalent of hexyl hexanoate, 2 equivalents of cyclohexanol and 1 mol % of the PNN complex 1 under argon atmosphere for 20 h resulted in 84% conversion of hexyl hexanoate as determined by GC analysis, with the exclusive formation of the ester cyclohexyl hexanoate in 83% yield (Table 30, entry 2). Notably, unlike the traditional transesterification methods, this reaction does not form an alcohol product; rather, an irreversible incorporation of both the acyl and alkoxo parts of the starting ester into the product ester takes place. While 2 equivalents of the alcohol with respect to the ester are sufficient, somewhat higher yields are obtained when 3 equivalents of alcohol were used. Thus, reaction of 3 equivalents of cyclohexanol with hexyl hexanoate resulted after 26 h in 96% conversion with 95% yield of cyclohexyl hexanoate, as observed by GC, and confirmed by GC-MS by comparison with an authentic sample (Table 30, entry 3). The pure product was isolated by evaporation of the solvent followed by passing through a basic alumina plug and analysis by NMR and GC-MS. Use of the PNP complexes 2 or 3 resulted after 20 h in 58% or 17% yield of cyclohexyl hexanoate, respectively. Studying the scope of this new reaction with regard to the secondary alcohol, reaction of hexyl hexanoate with cyclopentanol in the presence of 1 mol % 1 was carried out. After 26 h reflux in toluene, cyclopentyl hexanoate (70% yield) was formed, with 71% conversion of hexyl hexanoate (Table 30, entry 4). Similarly, upon reaction of hexyl hexanoate with excess of 1-phenylethanol, 50% conversion of hexyl hexanoate with the formation of 49% of the acylated product was observed (Table 30, entry 5). The lower conversion of the ester is a result of facile dehydrogenation of 1-phenylethanol to acetophenone (49%). Because of the expected easy dehydrogenation of the isopropyl alcohol to acetone, transesterification with this alcohol was performed in a closed vessel, to retard this dehydrogenation process. Thus, heating hexyl hexanoate with excess of isopropyl alcohol resulted after 19 h in 83% conversion of hexyl hexanoate with the formation of isopropyl hexanoate in 67% yield (entry 6). The reaction of hexyl hexanoate and 3-pentanol led to 91% conversion of the ester with formation of 3-pentyl hexanoate in 90% yield after 26 h reflux (entry 7).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[CH3:30][O:31][CH2:32][C:33]#[C:34][Sn](CCCC)(CCCC)CCCC>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:34]#[C:33][CH2:32][O:31][CH3:30])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Reactant: CCCC[Sn](C#CCOC)(CCCC)CCCC
Product: COCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Yield: 67.1 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(3-methoxy-1-propynyl)benzoate (4.23 g) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (7.73 g) and (3-methoxy-1-propynyl)tributylstannane (6.67 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-(1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (74.1 mg, 65%).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])C=[CH:2]1.S(Cl)([Cl:12])(=O)=O.C(OCC)C.C(OCC)C.[CH:24]([Cl:27])(Cl)Cl>[Ag-]=O>[Cl:12][C:2]1[C:1](=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[C:24]=1[Cl:27]
Reactant: O=C1C=CC(=O)C=C1
Reactant: ClC(Cl)Cl
Reactant: O=S(=O)(Cl)Cl
Agent: O=[Ag-]
Solvent: CCOCC
Product: O=C1C=CC(=O)C(Cl)=C1Cl
Reaction time: 1 h

Procedure:
To a solution of 1,4-benzoquinone Q-4 (2.0 g, 18.52 mmol) in diethyl ether-chloroform (4:1, 90 mL) at 0° C. and under N2 atmosphere was added sulfuryl chloride (3.0 mL, 37.0 mmol) dropwise over a period of 30 min. The reaction mixture was poured onto crushed ice, and extracted with diethyl ether (3×100 mL). Silver (I) oxide (10 g, 43.15 mmol) was added to the combined diethyl ether layers and the mixture was stirred for 1 h. After filtration, the filtrate was concentrated in vacuo to obtain crude Q-6, which was purified by column chromatography (silica gel, 10% ethyl acetate-pet. ether) to afford compound Q-6 (2.3 g, 71%) as a pale yellow solid. TLC Rf=0.6 (petroleum ether-EtOAc, 9:1); MS (ES) m/z 176 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([OH:33])([CH3:32])[CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[NH:12][C:13]([CH:16]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=3)[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:15]=2)=[CH:9][CH:10]=1)[OH:4].[OH2:34].C([O-])([O-])=O.C([O-])([O-])=O.[OH:43]O.OO.OO.[Na+].[Na+].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:32][C:2]([OH:33])([CH3:1])[CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[NH:12][C:13]([CH:16]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:31])(=[O:43])=[O:34])=[CH:26][N:25]=3)[CH2:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:14][CH:15]=2)=[CH:9][CH:10]=1)[OH:4]
Reactant: OO
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C(C)(C)O)cn3)[nH]2)nc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(O)C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cn3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a mixture of 2-methyl-1-[6-(5-{1-[5-(methylsulfanyl)pyridin-2-yl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]propane-1,2-diol (0.37 g), water (4 mL) and acetonitrile (6 mL) was added sodium percarbonate (0.25 g), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added sodium percarbonate (0.10 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.33 g, yield 84%) was obtained as a pale-yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (4:1, volume ratio). MS: 500 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=C2[Cl:15].NC1C=CC(C(CC)(CC)C#N)=CC=1.[BH:30]([OH:32])[OH:31]>>[ClH:15].[N:8]1[C:9]2[CH:10]=[CH:11][C:2]([B:30]([OH:32])[OH:31])=[CH:3][C:4]=2[N:12]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: OBO
Agent: CCC(C#N)(CC)c1ccc(N)cc1
Product: Cl
Product: OB(O)c1ccc2nccnc2c1

Procedure:
The following compounds (Table 2) are prepared in a similar manner as described in Example 1 by reacting 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) with 2-(4-amino-phenyl)-2-ethyl-butyronitrile (Example 12a), and with the appropriate boronic acid:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:28][CH:29]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a mixture of 4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid (100 mg) synthesized above, β-alanine ethyl ester hydrochloride (59.4 mg), 1-hydroxybenzotriazole monohydrate (59.3 mg), triethylamine (72 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (45% ethyl acetate/hexane) to give the title object compound (63.0 mg, 50%) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]([CH2:19][CH2:20][CH2:21][Cl:22])[N:5]=1)([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH:35][CH3:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>ClC1C=CC=CC=1>[ClH:22].[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]([CH2:19][CH2:20][CH2:21][N:35]([CH3:36])[CH2:34][CH2:33][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1cc2c(C(C)C)nn(CCCCl)c(=O)c2cc1OC
Solvent: Clc1ccccc1
Product: COc1ccc(CCN(C)CCCn2nc(C(C)C)c3cc(OC)c(OC)cc3c2=O)cc1OC
Product: Cl

Procedure:
1-[4-Isopropyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)amino]-propane hydrochloride was prepared analogous to Example 1(b) by reaction of 1-[4-isopropyl-6,7-dimethoxy-1 (2H)-phthalazinone-2-yl]-3-chloro-propane with 3,4-dimethoxyphenylethyl-N-methyl-amine in chlorobenzene. M.p.: 179 - 180° C.
Reaction SMILES: O.Br[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[C:14](=[O:17])([O-])[O-].[Na+].[Na+].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:9][N:8]1[C@H:7]2[C@@:20]([CH3:24])([C:20]3[CH:24]=[CH:4][C:3]([C:3]4[CH:4]=[C:5]5[C:9](=[CH:10][CH:11]=4)[NH:8][C:7](=[O:12])[C:6]5=[O:13])=[CH:11][C:21]=3[CH2:22][CH2:6]2)[CH2:21][CH2:22][C:14]1=[O:17]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)C(=O)C(=O)N5)cc3CC[C@@H]12
Yield: 15 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 5-bromoisatin hydrate (159 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 36 mg (15%) of the title compound as a white solid. mp >250° FDMS: m/e=374. α[D]589 =+75.33 (c=0.53, chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCCO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78947.4 %

Procedure:
28 ml (0.38 mmol) of 3-amino-1-propanol were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 47.15 g (0.30 mol, 83% yield) of a white solid.
Reaction SMILES: [Na+].[OH:2][CH:3]([CH2:7][CH3:8])[C:4]([O-:6])=[O:5].CN(C)C=O.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>C(Cl)(Cl)Cl.O>[F:24][C:23]([F:26])([F:25])[C:19]1[N:18]=[C:17]([O:2][CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH:22]=[CH:21][CH:20]=1
Reactant: CCC(O)C(=O)[O-]
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCC(Oc1cccc(C(F)(F)F)n1)C(=O)O
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
2-hydroxybutyric acid sodium salt (10 g) was added to dry dimethylformamide (100 ml) and oil free sodium hydride (2 g) added in a single portion with stirring under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes and then at about 80° C. for 10 minutes prior to addition of 2-chloro-6-trifluoromethylpyridine (10 g). The reaction mixture was then heated to 100-110° C. for 1 hour. The mixture was poured into an equal volume mixture of water and chloroform (1 liter) and the original layer made just acidic (pH4), followed by vigorous extraction into the organic phase which was separated, washed and dried. Chromatography gave a colorless solid which was recrystallized from hexane to give colorless crystals mp. 118° C. (11.9 g) of 2-(6-trifluoromethyl-2-pyridinyloxy)butyric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:27]#[N:28].[Cl:29][C:30]1[CH:31]=[C:32]([NH2:43])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.Cl.N1C=CC=CC=1>C(OCCO)C.CCOCC>[Cl:29][C:30]1[CH:31]=[C:32]([NH:43][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)[C:13]([O:25][CH3:26])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:27]#[N:28])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: CCOCC
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 59.1 %

Procedure:
A mixture of 1.98 g (4.98 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, 1.31 g (5.47 mmol) of 3-chloro-4(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.6 g (5.2 mmol) of pyridine hydrochloride in 2-ethoxyethanol is heated at 120° C. for 1.25 hours, then cooled. The crude mixture is poured into a solution of saturated sodium bicarbonate/ice and stirred for 45 minutes. The resulting solid is collected by filtration, then washed with water, ether and ethyl acetate successively. After drying in vacuo, the solid is purified by silica gel chromatography, using a 94:6 to 9:1 gradient of methylene chloride/methanol to provide a yellow solid. This solid is suspended in ether, filtered, and further washed with ether. After drying in vacuo, 1.77 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp.>300° C.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:32])[C:10]2[O:16][C:15]3[C:17]([Cl:28])=[CH:18][C:19]([N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl)=[CH:20][C:14]=3[CH2:13][S:12](=[O:30])(=[O:29])[C:11]=2[CH:31]=1)=[O:6]>CO>[Cl:28][C:17]1[C:15]2[O:16][C:10]3[C:9]([CH3:32])=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][C:11]=3[S:12](=[O:29])(=[O:30])[CH2:13][C:14]=2[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:2]([CH3:1])[CH2:26][CH2:25]2)[CH:18]=1
Reactant: CN
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCl)cc(Cl)c1O2
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(C)CC3)cc1CS2(=O)=O

Procedure:
Methanolic methylamine solution (20% v/v, 6 mL) was added to a solution of Example 102 (0.330 g, 0.69 mmol) in methanol (2 mL) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 100° C. for 6 h. It was brought to room temperature, flushed with N2 gas, treated with chilled water and dilute HCl to neutral pH. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, MeOH/CHCl3) to obtain the title compound as an off white solid. Yield: 0.260 g (86.37%). 1H NMR (DMSO-d6): δ 2.40 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.72-2.75 (m, 4H, 2CH2), 3.30-3.35 (m, 4H, 2CH2), 5.10 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.10 (s, 1H, Ar) and 8.25 (s, 1H, Ar); MS: m/e (ES+) 436 (M+1).