Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH3:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10].[CH:13](=O)[CH2:14][CH3:15].OP(O)(O)=O>O.C(OCC)(=O)C>[CH3:4][CH:5]([CH3:12])[CH2:6][CH2:7]/[C:8](=[CH:13]\[CH2:14][CH3:15])/[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)CCCC(C)C
Reactant: CCC=O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC/C=C(\CCC(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.2 %

Procedure:
Anhydrous MgCl2 (27.0 g, 284 mmol) was charged into a 1 liter, 4-necked round bottom flask, and ethyl acetate (150 ml) was added. The suspension was stirred at room temperature, and a solution of TiCl3(OiPr) (34% in ethyl acetate; 21.50 g, 34.3 mmol) was added dropwise over 1.5 hour. The reaction mixture was stirred overnight at room temperature, and after that heated to 70° C. 6-Methyl 2-heptanone (110.0 g, 858 mmol) was added over 2.5 hours, followed by a slow addition of propanal (105.0 g, 1716 mmol) over 6 hours. Stirring at 70° C. was continued for 22 hours. After cooling at room temperature, the black reaction mixture was poured onto a mixture of ice (100 g), water (300 ml) and 25% aqueous H3PO4 (100 ml). The aqueous phase was discarded and the organic phase washed with 25% aq. potassium citrate, then twice with 10% aqueous K2CO3 and twice with brine. Drying over Na2SO4 and evaporation of the solvent afforded the crude product. Fractional distillation though a Vigreux column followed by a second distillation through a Fischer column afforded the desired ketone (32.0 g, 22.2% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[BH4-].[Na+]>CO>[OH:9][CH:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)C(=O)CCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)CCCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2,2-dimethylcyclohexane-1,3-dione (2.00 g, 14.3 mmol) in MeOH (20 mL) was added sodium borohydride (135 mg, 3.58 mmol) portion-wise at 0° C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.6 g, crude). MS (ESI) m/z 143.2 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:19]5[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]5)=[N:15][C:16]=4[O:17][CH3:18])[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[CH:49]=[N:48]1
Reactant: COc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 85.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (Intermediate 66L) (75 mg, 0.108 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (65 mg, 0.217 mmol) using sodium carbonate (35 mg, 0.326 mmol) and Pd(dppf)Cl2 (4 mg, 0.005 mmol) in toluene/ethanol/water (20/10/5 mL). This afforded 68 mg (85% yield) of the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:10][CH2:9][CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCc2cccnc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 3-pyridinepropanol (0.960 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.242 g, 58%). Mass (m/z): 417.2 (M++1), 415.2 (M+−1).
Reaction SMILES: S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[CH2:42]([O:49][C:50](=[O:66])[CH2:51][N:52]=[C:53]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Br[CH2:68][C:69]1[CH:81]=[CH:80][C:72]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])=[CH:71][CH:70]=1>ClCCl.CCOCC>[CH2:42]([O:49][C:50](=[O:66])[CH:51]([N:52]=[C:53]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:68][C:69]1[CH:70]=[CH:71][C:72]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])=[CH:80][CH:81]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
Tetrabutyl ammonium sulfate (3.0 g. 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL). 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g. 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g. 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pretreated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2-((diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy) carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g. 3 mmol) in 36% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)#[N:9]
Reactant: N#Cc1cnccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccncc2C#N)cc1

Procedure:
Synthetic Scheme XXVII shows the 5-step preparation of the alkylating reagent 4-(4-bromomethylphenyl)-3-cyanopyridine (73) from 4-bromopyridine (74) (Aldrich). In step 1, the ortho-bromo carbanion was generated with LDA in THF at -78° C. and reacted with anhydrous DMF to give 4-bromo-3-carboxaldehyde 75. In step 2, the aldehyde 75 was reacted with hydroxylamine to give the oxime 76. In step 3, the oxime 76 was dehydrated with 1,1'-carbonyldiimidazole in methylene chloride at reflux to give 4-bromo-3-cyanopyridine (77). In step 4, the nitrile 77 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-4-(4-methylphenyl)pridine (78). In step 5, 78 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 73. ##STR91##
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([O:8][C:9]1([CH3:13])[CH2:12][CH2:11][CH2:10]1)=[O:7].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:13][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:7])[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(OC(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:40][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][C:27]([CH2:28][CH3:29])([OH:30])[CH2:31][CH3:32])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1
Reactant: CCC(O)(CC)CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 99.9 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(3-ethyl-3-hydroxypentyloxy)-20-methylpregna-5,7,16-triene (85 mg, 0.12 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (1.2 ml) and tetrahydrofuran (4.6 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by preparative thin layer chromatography (3 sheets (each 0.5 mm thickness), ethyl acetate:dichloromethane=4:1) to give the titled compound (55 mg, 100%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:30][O:31][CH2:32][CH2:33][OH:34]>>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCO
Product: COCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 2, 461 mg of the title compound was prepared from 436 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step a) in Example 2 and 7 ml of 2-methoxyethanol.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[OH:13]>CC(C)=O>[O:13]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[O:15][CH2:5][CH:2]1[C:3]#[N:4]
Reactant: Oc1ccccc1O
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1COc2ccccc2O1

Procedure:
1.45 g (15.5 mmol) of 2-chloroacrylonitrile and 6 g (43.5 mmol) of dry potassium carbonate are added in succession to 6.6 g (60 mmol) of catechol dissolved in 80 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the mixture is then heated to boiling. After 18 hours at reflux under argon, the reaction mixture is cooled and then filtered over Celite. After evaporation of the solvent, the residue is taken up in a water/ethyl acetate mixture (50:50) and then the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is evaporated under reduced pressure. The title nitrile is obtained pure in the form of a white solid after purification on a silica column (eluant:AcOEt/PE 30/70).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>O1CCCC1>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=4[CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)n1c(=O)oc2cc(N3C[C@H](CN)OC3=O)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture is stirred at room temperature overnight and then concentrated. The product is isolated by column chromatography (silica gel, methylene chloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:21])=[CH:10][C:11]3[CH2:12]O[CH2:14][C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)[N:5]=[C:4]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[O:27])[N:3]=1.B(Br)(Br)Br.O.O.O.O.O.O.O.O.O.[S-2:42].[Na+].[Na+].C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:19]3[C:20]4[C:11]([CH2:12][S:42][CH2:14][C:15]=4[CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=2[Cl:21])[N:5]=[C:4]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[O:27])[N:3]=1
Reactant: NC(=O)CCCSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Reactant: [S-2]
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)CCCSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)CSC3)n1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
4-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-butyramide (100 mg, 0.24 mmol) obtained in Example 339 was dissolved in dichloromethane (4 ml) at room temperature. To the solution was added boron tribromide (1.0M in dichloromethane, 0.96 ml) and the resulted suspension was stirred overnight. The mixture was concentrated followed by dilution with N,N-dimethylformamide (6 ml). To the mixture were added sodium sulfide nonahydrate (220 mg, 2.46 mmol) and N-ethyldiisopropylamine (0.2 ml) successively at room temperature for 6 hours. The mixture was diluted with ethyl acetate (100 ml), and washed with water (50 ml, 3 times), brine successively, and then dried over anhydrous sodium sulfate. After removal of inorganic salts by filtration, the filtrate was concentrated. The resulting residue was purified by silica gel thin layer chromatography (developing solvent; dichloromethane/methanol=9:1) to give 4-[4-amino-6-(5-chloro-1H,3H-2-thia-phenalen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-butyramide (52 mg, 49%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.ClC1N=C([NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)C=C(Cl)N=1.C1(N)CCCC1>>[CH:18]1([NH:17][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Clc1cc(NC2CCCC2)nc(Cl)n1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: NC1CCCC1
Product: Clc1cc(Cl)nc(NC2CCCC2)n1
Yield: 35.2 %

Procedure:
Preparation of 2-cyclopentylamino-4,6-dichloroplrrimidine and 2,6-dichloro-4-cyclopentylaminopyrimidine 2,4,6-Trichloropyrimidine is reacted with cyclopentylamine as described in Example 2 to obtain the less polar 2-cyclopentylamino-4,6-dichloropyrimidine in a yield of 35.2%, m.p.: 48°-52° C.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+:13]([C:16]1[C:25](Cl)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)([O-:15])=[O:14]>>[N+:13]([C:16]1[C:25]([C:5]23[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]2[C:3]([NH:2][C:6]3=[O:7])=[O:12])=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)([O-:15])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Product: O=C1NC(=O)C2(c3ccc4ncccc4c3[N+](=O)[O-])C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 5-nitro-6-chloro-quinoline were reacted to form 0-(5-nitro-6-quinolyl)-phthalimide melting at 185° C. which was reacted to obtain 0-(5-nitro-6-quinolyl)hydroxylamine melting at 165° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CCOCC>[F:1][C:2]([F:12])([F:13])[CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:31]([C:27]1[O:26][CH:30]=[CH:29][CH:28]=1)=[O:32])[OH:11]
Reactant: Nc1ccccc1C(O)C(F)(F)F
Reactant: O=C(Cl)c1ccco1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1C(O)C(F)(F)F)c1ccco1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a solution of 1,1,1-trifluoro-2-hydroxy-2-(2-aminophenyl)ethane from Step 2 (600 mg, 3.14 mmol), methylene chloride (10 mL) was added N,N,-diisopropylethylamine (893 mg, 6.91 mmol) followed by 2-furoyl chloride (902 mg, 6.91 mmol) dropwise over 5 min under an argon atmosphere at 23° C. After 18 h, the reaction was diluted with ether (100 mL), washed with KHSO4 (1N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was taken on to the next step. The residue was dissolved in ethyl acetate (300 mL), washed with KHSO4 (2×50 mL) and with brine (1×50 mL), dried (Na2SO4), and concentrated in vacuo. To a solution of the residue and methanol (3 mL) was added NaOH (1.5 N, 3 mL) at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL) and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]furan-2-carboxamide (717 mg, 80%) as an oil: 1H NMR (CDCl3) δ5.14 (q, J=6 Hz), 6.55 (m), 7.16-7.58 (m), 8.25 (m); 13C NMR (CDCl3) 72.7 (q, J=33 Hz), 112.2, 115.0, 122.7,123.1, 126.5 (q, J=280 Hz), 129.7, 136.8, 144.7, 149.5, 169.6. MS (EI) 285 (M+), 245, 216. IR (neat) 3500-3000, 1650 cm−1. Anal. Calc'd. for C13H10NO3F3: C, 54.74; H, 3.53; N, 4.91. Found: C, 54.63; H, 3.50; N, 4.90.
Reaction SMILES: [O:1]=[C:2]1[C@H:11]2[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@@H:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[C:4]=2[NH:3]1.Cl>CCOCC>[O:1]=[C:2]1[C@@H:11]2[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][C@H:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:22]([F:25])([F:23])[F:24])[C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C(=O)Nc3c(cccc3C(F)(F)F)[C@H]2C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@H]2C(=O)Nc3c(cccc3C(F)(F)F)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
To a solution of the first eluting compound from Part B above, tentatively assigned as (3aR,9bS)-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (50 mg, 0.14 mmol) in 4 mL of ether was added 1 mL of 12 N HCl. The resulting mixture was stirred at ambient temperature for 15 min and then was concentrated and dried in vacuo to a solid. This solid was triturated twice with ether and dried in vacuo to afford 30 mg (75%) of the title compound of Example 7 as a white solid. 1H NMR (DMSO-D6): δ 9.73 (s, 1H), 9.65 (broad s, 1H), 9.53 (broad s, 1H), 7.62 (d, 1H), 7.50 (d, 1H), 7.25 (t, 1H), 3.95-3.88 (m, 1H), 3.55-3.42 (overlapping m, 2H), 3.32-3.22 (overlapping m, 2H), 3.10-3.00 (m, 1H). LRMS (ESI): 257.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 2.5 g of 3-aminoanisole and 1.5 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 3 hours, the mixture is poured onto water and extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated and the residue is crystallised from ether/hexane. Methyl N-(3-methoxyphenyl)-oxamate is obtained.