Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:14])[C:11]([O-:13])=O)=[CH:2]1.[K+].[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:19]1[CH2:20][CH2:21][N:22]([C:11](=[O:13])[C:10]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[C@H:17]([CH3:16])[CH2:18]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2ncccc12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium 7-azaindole 3-glyoxylate 3a (25.4 g, 0.111 mol), (R)-3-methyl-N-benzoylpiperazine 4a (22.7 g, 0.111 mol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (33.3 g, 0.111 mol) and Hunig's Base (28.6 g, 0.222 mol) were combined in 500 ml of DMF. The mixture was stirred at room temperature for 8 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:26])=[O:25])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1nccnc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (commercially available) (2.0 g) and (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chloride (Example 1.2) (4.2 g) in dichloromethane (32 ml) was added dropwise pyridine (5.3 ml) over a period of 5 minutes at ambient temperature. The reaction mixture was stirred at ambient temperature for 23 hours. Dichloromethane (50 ml) was added to the reaction mixture and the mixture was washed with aqueous sulfuric acid (2M) (3×30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/dichloromethane from 0:10 to 1:9) to give 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as a white solid (4.728 g). 1H-NMR (400 MHz, CDCl3): 10.30 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.77 (bs, 1H), 7.54-7.60 (m, 2H), 5.15 (s, 2H), 4.04 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)=O>C(#N)C.CN(C)C=O>[O:14]=[C:7]1[NH:6][C:5]2[CH:15]=[CH:16][C:2]([O:1][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:3][C:4]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1[nH]c2ccc(O)cc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
The compound (60 mg, 0.28 mmol) prepared in step 2 and potassium carbonate (120 mg, 0.85 mmol) were dissolved in acetonitrile (6 ml)/N,N-dimethylformamide (3 ml), added with t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (240 mg, 0.85 mmol). The resulting mixture was stirred for 3 days at 100˜110° C. and cooled to room temperature. After extraction with chloroform, the reaction mixture was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (65 mg, yield: 58%, white solid).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N1CCCC1.C1C=CC=CC=1.C1(C[OH:47])C=CC=CC=1>C(O)(=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[C:15](=[O:47])[CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: OCc1ccccc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
4-Cholesten-3,6-dione was prepared using 4-cholesten-3-one (Aldrich Co.) as a starting material by reference to the method of Hevl and Herr (F. W. Hevl and M. E. Herr, J. Am. Chem. Soc., 75: 1918, 1953) and that of Malhotra et al. (S. K. Malhotra, J. J. Hostynek and A. F. Lundin, J. Am. Chem. Soc., 90: 6565, 1968). Stated specifically, pyrrolidine (2.85 g) was added to a benzene solution (50 ml) of 4-cholesten-3-one (3.84 g) and the mixture was refluxed under heating for 24 hours. After cooling, the solvent and the excess pyrrolidine were distilled off under vacuum. Upon recrystallization from methanol, a colorless crystal of dienamine (4.16 g) was obtained. Cupric acetate (100 mg) was added to a benzene-methanol (500:10) solution of the dienamine (4.16 g) and air was introduced into the mixture for 24 hours. Then, a 2% aqueous solution (20 ml) of acetic acid was added and the mixture was stirred for 30 minutes and washed successively with water, a 1% sodium carbonate solution and a saturated saline solution. The resulting residue was dried, filtered and subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to yield a colorless crystal of 4-cholestene-3,6-dione (3.23 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:19])[CH:7]=1>OS(O)(=O)=O>[F:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:19])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)c1ccc(F)cc1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)c1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
HNO3 (6.92 g, 71.4 mmol) was added dropwise to a suspension of ethyl 2-(4-fluoro-2-methylphenyl)-2-oxoacetate (15 g, 71.4 mmol) in conc. H2SO4 (50 mL) at ° C. After complete addition the resulting mixture was stirred at 0° C. for 30 min. The mixture was poured into ice water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)-2-oxoacetate (15 g, 83% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J=7.2 Hz, 1 H), 7.24 (d, J=7.2 Hz, 1 H), 4.47 (q, J=7.2 Hz, 2 H), 2.67 (s, 3 H), 1.43 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(S(C)(=O)=O)n1
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(Nc2ccccc2)n1

Procedure:
Compounds of Formula I are alternatively prepared by the treatment of 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine with aniline in the absence of solvent at a higher temperatures of 120° C. to afford 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-phenylaminopyrimidine, m.p. 85.7°-86.3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:9][C:25](=[O:26])[CH2:24][Cl:23])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCl)NC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 21.9 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanamine in 160 parts of 2-propanone were added 11.66 parts of sodium carbonate. Then there were added dropwise 12.43 parts of 2-chloroacetyl chloride at a temperature below 30° C. (cooling in an ice-bath was necessary). Upon completion, stirring was continued first for one hour at room temperature and further for 2 hours at reflux. After cooling to room temperature, the sodium carbonate was filtered off and washed with 2-propanone. The filtrate was evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 20.6 parts of N-[bis(4-fluorophenyl)-methyl]-2-chloroacetamide; mp. 127.6° C. (intermediate 4).
Reaction SMILES: [CH:1]1([C:6]2[CH:13]=CC=[CH:10][C:7]=2[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)=O.[CH3:17][CH:18](O)[CH3:19].S(=O)(=O)(O)O.O1COCOC1.[Cl:32]S(O)(=O)=O>>[Cl:32][CH2:17][C:18]1[CH:19]=[CH:13][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1ccccc1C1CCCC1
Reactant: CC(C)O
Agent: C1OCOCO1
Agent: O=C=O
Agent: O=S(=O)(O)O
Product: N#Cc1cc(CCl)ccc1C1CCCC1
Temperature: -7 °C

Procedure:
2-Cyclopentylbenzonitrile (1.3 g, 7.59 mmol) was transferred into a 2-necked RB flask, fitted with an addition funnel and dry nitrogen inlet. The starting material was stirred and cooled to −22° C. (dry ice/IPA bath). Sulfuric acid (3.25 mL, 61.0 mmol) was added in drops. 1,3,5-Trioxane (0.877 mL, 11.39 mmol) was added in 3 batches (The batches were added fairly quickly, one after another). Almost immediately, chlorosulfonic acid (0.915 mL, 13.67 mmol) was added in drops. Then the reaction mixture (dark brown in color) was allowed to warm up to −7° C. (over approx 15 min). It was stirred at between 6.9° C. and −5° C. for 1.5 h. The reaction was quenched by slowly pouring into ice water. MTBE was added and the mixture was stirred well and filtered through Celite®. The Celite® bed was washed with MTBE and the aqueous acid layer was separated. The acid layer was extracted with MTBE. The combined MTBE layer was washed with water followed by saturated NaHCO3 solution. The organic layer was washed with water until washings were neutral to pH paper. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.[O:17]=O.[C:19]([OH:22])(=[O:21])[CH3:20]>[Mn]>[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:20]=1[C:19]([OH:22])=[O:21])(=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:6]1[C:20]2[C:19](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:1](=[O:17])[C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1ccccc1Cc1ccccc1
Reactant: O=O
Agent: [Mn]
Agent: BrBr
Product: O=C(O)c1ccccc1C(=O)c1ccccc1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
It is further known from the Japanese patent publication 49-75563 (Ref: Chem. Abstr. 1975, 43096w) to oxidize o-benzyl-toluene in an aliphatic carboxylic acid, for example acetic acid, in the presence of cobalt salts and bromine compounds, to which manganese salts may also be added as additional catalytic agents. The reaction, carried out at the atmospheric pressure or slightly elevated pressure at temperatures from 70° to 200° C. with air or oxygen-containing gases, yields o-benzoyl-benzoic acid with an anthraquinone content of between 3 and 9% as product. The oxidation in the acetic acid solution is carried out in general with a weight ratio of o-benzyl-toluene to acetic acid of about 1:10. After a reaction time of 4-5.5 hours o-benzoyl-benzoic acid in a yield of about 90-92.5% of theory is recovered, along with about 3-4% of theory of anthraquinone. The purity of the o-benzoyl-benzoic acid is not further discussed. The product is then heated with a minimal amount of concentrated sulfuric acid to about 250°-350° C.; in order to purify the thus-obtained anthraquinone, it is distilled at normal pressure. The degree of purity of this product is also not given. It is further noted that it is advantageous to add to the reaction mixture a solvent which does not mix with water such as benzene, chlorobenzene or dichlorobenzene in order to eliminate the water produced by the reaction as an azeotrope. For example, half of the acetic acid can be replaced according to the publication by chlorobenzene; however, an azeotropic distillation during the oxidation is not achieved by following the example of the Japanese publication.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
Suspend 4-cyanobenzoyl chloride (2.0 g, 12 mmol) in anhydrous toluene (30 mL). Add aluminum trichloride (2.4 g, 18 mmol) in three portions and stir the reaction mixture at ambient temperature overnight. Cool to 0° C., add carefully water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give a solid. Suspend the solid in diethyl ether and filter to obtain the desired intermediate (1.30 g, 49%) that was used without any further purification. GC-MS m/z: 221 (Me).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)[CH:10]=1)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCC#N)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
A stirring mixture of ethyl 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylate (74) (100 mg, 0.411 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (75) was dried and used in the next step without further purification. MS m/z 416.07 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[S:6]([C:9]1[CH:10]=[C:11]([C:16](=[O:19])[CH2:17]Cl)[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[S:28])[CH3:25]>>[ClH:15].[CH2:30]([N:29]1[C:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([S:6](=[O:8])(=[O:7])[N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=2)([OH:19])[CH2:17][S:28][C:27]1=[N:26][CH2:24][CH3:25])[CH3:31]
Reactant: CCNC(=S)NCC
Reactant: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Product: CCCCN(CCCC)S(=O)(=O)c1cc(C2(O)CSC(=NCC)N2CC)ccc1Cl
Product: Cl

Procedure:
7.0 g of 3'-di-n-butylsulfamoyl-2,4'-dichloro-acetophenone were reacted according to Example 12 with 2.7 g of 1,3-diethylthiourea and worked up. Colorless solid body, decomposition beginning at 139° C., γ C=N 1615 cm-1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8]>CN(C=O)C>[NH:1]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C#CC(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn[nH]c1C(=O)OC

Procedure:
To a stirred suspension of sodium azide (5.03 g, 77.39 mmol) in DMF (120 mL) was added dropwise at 0° C. over 30 min, a solution of dimethyl acetylene-dicarboxylate (10.0 g, 70.36 mmol) in DMF (100 mL). After 30 min the solvent was removed in vacuo at 30° C. to leave a light purple-brown solid. The solid was washed twice with ether and taken up in water (100 mL). The aqueous solution was acidified with conc. HCl to pH 2. The aqueous layer was first extracted with ether (100 mL) and then with chloroform (100 mL). The combined organic layers were evaporated to give a light red colored solid: 128-130° C. The solid was washed with hot hexane and crystallized from benzene: Yield 11.0 g (85%); 1H NMR (CDCl3) δ4.00 (s, 6H), 11.87 (br s, 1H, NH).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 1.0 eq, 9.6 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.1 g, 1.1 eq, 10.5 mmol) was taken in annhydrous DMF (100 mL) and stirred at room temperature. Cs2CO3 (7.2 g, 2.3 eq, 22.1 mmol) was added to the above solution and the heterogeneous mixture was heated at 100° C. overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and partioned with H2O (50 mL). The layers were separated and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to leave a crude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:10 to 2:8) as eluent gave the product in 60% yield.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([CH3:19])=[CH:17][S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([CH3:19])=[CH:17][S:16][C:14]=2[N:15]=1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Reactant: NCc1ccccc1
Product: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>CN(C)C=O>[C:17]12([C:27]([O:9][C:8]3[N:7]=[CH:6][NH:5][C:4]=3[C:1](=[O:3])[NH2:2])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cnc1OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 23 h
Yield: 64.9 %

Procedure:
To a suspension of 4-carbamoylimidazolium-5-olate (1.016 g) in dimethylformamide (20 ml) was added triethylamine (1.942 g) at 0°-5° C. and then 1-adamantanecarbonylchloride (3.50 g) in dimethylformamide (20 ml) dropwisely over 24 minutes. The reaction mixture was stirred at 0°-5° C. for 23 hours. The solvent was removed under reduced pressure. To the residue was added ethyl acetate (20 ml) and water (20 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (1.5 g, α form, m.p. 206.5°-207.5° C. (dec.)), which was washed thoroughly with ethyl acetate to give pure product, α form, m.p. 211° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (50 mg, 0.13 mmol) was added selenium dioxide (146 mg, 1.30 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (52 mg, 99% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][N:29]1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:32]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:31][CH2:30]1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@@H:22]4[CH2:23][C:24](=[O:27])[NH:25][CH2:26]4)[CH3:21])=[CH:10][C:11]([C:13]4[CH:18]=[C:17]5[C:16]([N:29]([CH3:28])[CH2:30][CH2:31][N:32]5[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 45.6 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead tert-butyl 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (92.0 mg, 0.24 mmol) as a starting material to afford 40.0 mg (45.6%) of tert-butyl 7-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-4-methyl-3,4 dihydroquinoxaline-1(2H)-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H37N5O4:531.28; found 532.23.