Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:31][O:32][NH:33][CH3:34].O>C(Cl)Cl>[CH3:31][O:32][N:33]([CH3:34])[C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a suspension of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (3 g, 12.33 mmol) in DCM (35 mL) was added CDI (4.00 g, 24.66 mmol) portion-wise. The resulting mixture was stirred for 1 hour, and then O,N-dimethylhydroxylamine hydrochloride (1.804 g, 18.50 mmol) was added, and the mixture was stirred at RT for 16 hours. Water (30 mL) was added, and the mixture was stirred for 1 hour and then extracted with DCM (50 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to afford tert-butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (3.3 g, 93% yield).
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@H:13]([N:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[C:35]2=[O:43])[O:12]1)(=O)C1C=CC=CC=1.N>CO>[OH:25][C@@H:14]1[C@H:15]([OH:16])[C@@H:11]([CH2:10][OH:9])[O:12][C@H:13]1[N:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[C:35]1=[O:43]
Reactant: NC(=O)c1nccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c1=O
Agent: N
Solvent: CO
Product: NC(=O)c1nccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
In 4 mL of methanol was dissolved 0.37 g of [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate. While cooling the solution with ice, gaseous ammonia was introduced until saturation. The reaction mixture was stirred at room temperature for 15 hours, and the solvent was removed under reduced pressure. Methanol was added to the residue, and the precipitate was collected by filtration to obtain 0.12 g of 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a light brown-colored solid product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]3[CH2:13][C:12]2=[O:23])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]3[CH2:13][C:12]2=[O:23])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)Cc2cc(Cl)ccc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)Cc2cc(Cl)ccc2C1=O

Procedure:
The mixture of 1.7 g of N-(4-nitro-o-tolyl)-5-chlorohomophthalimide, 0.8 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at 2.4 atm. and room temperature until the hydrogen uptake has ceased. It is filtered, the filtrate evaporated and the residue recrystallized from acetonitrile to yield the N-(4-amino-o-tolyl)-5-chlorohomophthalimide of the formula ##STR7## melting at 250°-252° with decomposition.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.CN(C)CCN(C)C.C([Li])CCC.[I:26]CI>O.C(OCC)C>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[C:7]([I:26])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2ccccc21
Reactant: ICI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCOc2c(I)cccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.00 g (12.3 mmol) of 4,4-dimethylchroman and 30 ml of ethyl ether are introduced into a three-necked flask under argon. 2.4 ml (15.9 mmol) of tetramethylethylenediamine (TMEDA) are added dropwise, the mixture is cooled to −78° C. and 5.9 ml (14.8 mmol) of n-butyllithium (2.5M in hexane) are added dropwise. The temperature is allowed to return to −20° C. over two hours and then to room temperature and the mixture is stirred for 12 hours. 1.3 ml (16.0 mmol) of diiodomethane and 15 ml of ethyl ether are introduced into another three-necked flask under argon. Cooling is carried out to 0° C. and the preceding solution, cooled beforehand to −78° C., is introduced, then the reaction mixture is allowed to return to room temperature and stirred for 12 hours. The reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, 1.30 g (37%) of the expected compound are collected in the form of a pale-yellow oil.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Oc1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To an argon-flushed flask containing a suspension 0.486 g (1.68 mmol) of 4'-hydroxy-4-biphenylyl benzoate in 10 ml of acetic acid at 10°-15° C., 0.345 ml of HNO3 (d: 1.41) was added dropwise (about a drop per min). Then the reaction mixture was vigorously stirred at the same temperature for 30 min. Water (40 ml ) was added and the mixture was again stirred for 30 min. The yellow precipitate was filtered, washed several times with water, dried and purified by flash chromatography on silica gel using dichloromethane/hexanes [65/35] as eluent to give 4'-hydroxy-3'-nitro-4-biphenylyl benzoate (compound 15, Scheme II) as a yellow solid (0:539 g, 96%). This material was recrystallized from ethanol to give product of mp. 163° C.; Rf [hexanes/dichloromethane 40/60]: 0.42; 1H NMR (300 MHz, CDCl3): δ7.25(d, 1H, J=8.7 Hz), 7.33(d, 2H, J=8.7 Hz), 7.50-7.70(m, 5H), 7.84(dd, 1H, J=2.7 Hz, J=8.7 Hz), 8.23 (d, 2H, J=7.2 Hz), 8.32(d, 1H, J=2.7 Hz), 10.60(s, 1H); 13C NMR (300 MHz, CDCl3): δ120.54, 122.45, 122.81, 127.85, 128.65, 129.33, 130.23, 133.04, 133.78 136.04, 136.22, 150.91, 154.44, 165.15; IR (CHCL3): 3250(broad), 3020, 1740, 1620, 1540, 1510, 1490, 1325, 1270, 1225, 1220, 1170, 1080, 1065, 1025, 1000, 850 cm-1 ; Mass spectrum, m/z(rel.intensity): 335(M+ 7), 105(100), 77(16).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]([N:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:28]([C@@H:30]1[C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][N:32]([C@H:41]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:42]([O:44]CC2C=CC(OC)=CC=2)=[O:43])[CH2:31]1)=O>>[CH2:8]([NH:15][C:16]([N:18]([CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C@@H:30]2[C@@H:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:33][N:32]([C@H:41]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[C:42]([OH:44])=[O:43])[CH2:31]2)[CH2:26][CH2:27]1)[CH2:19][CH2:20][CH3:21])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCN(C(=O)NCc1ccccc1)C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccccc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 39.8 %

Procedure:
The title compound was prepared from 4-(N-(N-benzylcarbamoyl)-N(prop-1-yl)amino)-piperidine trifluoroacetate (19 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 6.4 mg (40%) of the title compound. ESI-MS: 575.4 (M+H); HPLC A: 2.32 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1.C([Li])(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([F:35])[C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: N#CC(F)c1ccc(-c2nc3ccccc3o2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (98 mg, 0.36 mmol) and dry THF (5 mL) was cooled to −78° C. A solution of tert-butyllithium (500 μL, 0.80 mmol, 1.7M solution in pentane) was added dropwise via syringe at −78° C. After 1 h, a solution of N-fluorobenzenesulfonimide (113 mg, 0.36 mmol) and dry THF (1.5 mL) was added dropwise via syringe at −78° C. The cooling bath was removed, and the reaction mixture was gradually allowed to warm to rt, and was maintained at rt for 8 h. The reaction was quenched with silica gel (300 mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc:hexanes, 1:3) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl](fluoro)acetonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.32 (s, 1H), 8.24 (2, 1H), 7.74–7.84 (m, 2H), 7.56–7.60 (m 1H), 7.35–7.43 (m, 2H), 6.45 (d, 1H). MS (ESI) 287 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32][CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:35].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:33])=[O:35])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.84 mmol) in methanol (12 mL) was added a sodium metaperiodate (540 mg, 2.53 mmol) solution in water (4 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H25N3O3S2 [M+H]+ 492.64, observed 492.2.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:23](B(O)O)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:18][N:19]1[C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1
Reactant: O=C(O)c1ccc(Oc2ccc(I)cc2)cc1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(4-iodophenoxy)benzoic acid (Preparation 143, 470 mg, 1.38 mmol), 1-methyl-3-trifluoromethylpyrazole-5-boronic acid (322 mg, 1.66 mmol), palladium tetrakis triphenyl phosphine (239 mg, 0.207 mmol) and cesium carbonate (1.35 g, 4.15 mmol) in dioxane/water (10 mL/5 mL) was heated to 80° C. for 6 hours then left to stir at room temperature overnight. The reaction was quenched by the addition of 1N HCl and extracted into ethyl acetate. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo to furnish the crude title compound that was taken on directly to the next step.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
In a round-bottomed flask ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (10.97 g, 43.0 mmol) was dissolved in ethanol (150 mL) followed by the addition of aqueous sodium hydroxide solution (1M, 129 ml, 129 mmol). The resulting mixture was stirred overnight at room temperature and then the solvent was evaporated under reduced pressure. Aqueous citric acid solution (2M, 129 ml, 258 mmol) was slowly added and the resulting mixture was stirred for 0.5 h at room temperature. The suspension was filtered and the solids were washed twice with water (2×50 mL) and then dried in the vacuum oven at 45° C. overnight to afford 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (8.38 g, 36.9 mmol, 86% yield); MS (ESI) m/z 228.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 3-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated in vacuo to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.66 g (99.5%) of the 3-methylisatoic anhydride as an off white solid. MS (Cl mode) m/z 160 (M-18, 100%), 178 (M+H, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:6]=2[N:7]=1.[OH:18]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:18])=[O:12])[N:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CCC(CC)n1c(C=O)cc2cnc(Cl)nc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
To a mixture of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (283 mg, 1.11 mmol) in DMF (3 mL) is added oxone (820 mg, 1.33 mmol) at room temperature. The mixture is stirred at room temperature for 5 h and is quenched with 20% Na2S2O3 aqueous solution. After stirring for 10 min, the reaction mixture is acidified with 1N HCl aqueous solution (pH=5). The mixture is extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo. The solid is filtered, washed with acetonitrile, and dried under vacuum to give 130 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[C:3]1=[O:29].[C:30](OC(=O)C)(=[O:32])[CH3:31].CO>CN(C)C1C=CN=CC=1.ClCCl>[C:30]([N:11]1[C:8]2=[N:9][C:10]3[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH3:20])[C:5](=[O:14])[C:6]=3[N:7]2[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a stirring mixture of (R)-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (280 mg, 0.65 mmol) and p-dimethylaminopyridine (160 mg, 1.30 mmol) in dichloromethane (10 ml) was added acetic anhydride (100 mg, 0.98 mmol). After stirring at room temperature for 2 hours, the reaction mixture was treated with methanol. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate to provide (R)-8-acetyl-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 67% yield) as a white powder.
Reaction SMILES: N[C:2](N)=[O:3].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].N>>[NH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][NH:11][C:2]1=[O:3]
Reactant: NCCNCCN
Reactant: NC(N)=O
Agent: N
Product: NCCN1CCNC1=O
Temperature: 140 °C

Procedure:
In a suitable reactor equipped with agitation and a reflux condenser, 465 parts by weight of urea and 798 parts by weight of diethylenetriamine were charged. The reaction mix was slowly heated to 140° C. Ammonia started to evolve at about 130° C. The temperature was slowly raised to 150° C. As the evolution of ammonia subsided, vacuum was applied and the remaining ammonia was removed. Product yield was approximately 1000 parts by weight. The product had a viscosity of 6000 cps at 25° C. and an MEQ/g of 6.5. (MEQ=milliequivalent weight). Gel phase analysis of the product showed approximately 95% purity. The product can be used as is or further purified by vacuum distillation. The major impurity is unreacted diethylenetriamine.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[C:3]3[N:4]([CH:13]=[CH:14][N:15]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Fc1ccc2nc(Cl)c3nccn3c2c1
Reactant: NC1CCCCC1
Product: Fc1ccc2nc(NC3CCCCC3)c3nccn3c2c1

Procedure:
By reacting 4-chloro-8-fluoroimidazo[1,2-a] quinoxaline (example 25) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylamino-8-fluoroimidazo[1,2-a]quinoxalin. m.p. (DSC)=157.6° C.(onset); IR (KBr): 3415, 2927, 1556 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,dd, J=2 Hz), 7.7÷7.35 (1H,dd, JHF =16 Hz), 7.55 (1H,d, J=2 Hz), 7.55÷7.25 (1H,dd, JHF =16 Hz), 7.05 (1H,dd), 6.0 (1H,d), 4.25 (1H,m), 2.35÷1.2 (10H,m); UV (EtOH): λmax =226, 239, 285, 297, 323, 337 nm. Elementary analysis for C16H17FN4 (m.w. 284.33): calcd. C 67.59, H 6.03, N 19.71%; found C 67.31, H 6.04, N 19.70%.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([O:15]C)(=[O:14])[CH:12]=[CH2:13].[Li+].[OH-].Cl>C(O)(=O)C.CO>[N:1]1([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (3.0 g, 22.5 mmol) and methyl acrylate (3.9 g, 45.0 mmol) in acetic acid (15 mL) was refluxed for 16 hours. Upon cooling, volatiles were removed in the rotary evaporator and the residue obtained was co-evaporated with methanol (3×20 mL) and then dissolved in methanol (15 mL). To this mixture an aqueous solution of LiOH (1.9 g, 45 mmol) was added and it was stirred at room temperature for 2 hours. Reaction mixture was acidified with conc. HCl to pH ˜3 and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over MgSO4 and evaporated to dryness to yield 2.91 g of Compound 7 as a dark brown viscous liquid. This product was used without any further purification. The structure of Compound 7 is given below:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][C:13]1[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=1[CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1>>[CH3:11][O:12][C:13]1[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=1[CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: COc1ccccc1Cc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with sulfuryl chloride (8.4 mmoles, 0.7 ml), DMF (9.8 mmoles, 0.8 ml) and 2-(2-methoxybenzyl)-benzo[b]thiophene (4.9 mmoles, 1.25 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.94 g (54%) of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].CN>>[C:12]([C:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)=[CH:22][N:21]([CH3:23])[CH:20]=1)(=[O:14])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Product: CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Ten g. of 1-(3-trifluoromethylphenyl)-2,4-pentanedione was reacted with 40 ml. of N,N-dimethylformamide dimethyl acetal, and then with 10 ml. of 40% aqueous methylamine, as described in the examples above. The reaction mixture was evaporated under vacuum, and the residue was taken up in 1.5 liters of dichloromethane. The solution was washed with 1 liter of water, and the organic layer was dried with magnesium sulfate, treated with activated charcoal, filtered and evaporated under vacuum. The residue was triturated under diisopropyl ether, and a yellow powdery solid crystallized. The solid was found to be 4.56 g. of the desired product, m.p. 130°-131°, showing the following peaks in nmr analysis: δ8.10 (d, J=3 Hz, H2 of pyridine); 8.0-7.3 (m, 4H, aromatic); 7.43 (d, J=3 Hz, H6 of pyridine); 3.77 (s, 3H, N--CH3); 2.73 (s, 3H, COCH3).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:15]([NH2:18])[CH:16]=C.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:16]=[CH:15][NH:18]1
Reactant: Oc1ccccc1
Reactant: C=CCN
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C1=Cc2ccccc2ON1
Yield: 75.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:0.8:1.5. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 75.5%.