Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[CH3:13][O:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][C:16]=1[OH:30].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.FC1(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C1(F)F>[NH2:11][C:8]1[N:7]=[C:6]2[N:12]=[C:2]([C:19]3[CH:18]=[CH:17][C:16]([OH:30])=[C:15]([O:14][CH3:13])[CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Nc1cnc2ccc(Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Solvent: O
Product: COc1cc(-c2ccc3ncc(N)nc3n2)ccc1O
Temperature: 75 °C
Reaction time: 7.5 h
Yield: 94.1 %

Procedure:
To a suspension of 1.13 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (5.94 mmol; 1 eq) and 1.67 g 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (6.55 mmol; 1.1 eq.) in ethylene glycol dimethyl ether (45 mL) under Ar, a solution of 6.29 g sodium carbonate (59.3 mmol; 10 eq.) in water (20 mL) and a suspension of 378 mg FluoroFlash catalyst (0.24 mmol; 0.04 eq.) in undecafluoro(trifluoromethyl)cyclohexane (45 mL) were added. The mixture was heated to 75° C. for 5 hours. Additional 0.76 g (2.97 mmol; 0.5 eq) of 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol were added and the resulting mixture was stirred at 75° C. for 7.5 hours. After cooling to room temperature, the aqueous and organic phase were separated from the fluorous phase and concentrated in vacuo. The residue was dissolved in methanol and methylene dichloride and filtered. The black solution was again concentrated in vacuo. The residue was taken up in water and the resulting solution was neutralized with 1 N HCl whereas the product crystallizes. The brown solid was filtered of, washed with water and dried in vacuo to afford 1.5 g (80.2% yield) of 4-(3-Amino-pyrido[2,3-b]pyrazin-6-yl)-2-methoxy-phenol.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[C:16]2[S:15][CH:14]=[N:13][C:12]=2[O:11][CH2:10][CH2:9]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O.C(Cl)Cl>[S:15]1[C:16]2[CH:8]([OH:7])[CH2:9][CH2:10][O:11][C:12]=2[N:13]=[CH:14]1
Reactant: c1nc2c(s1)C(OC1CCCCO1)CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OC1CCOc2ncsc21

Procedure:
A soln. of 7-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-pyrano[2,3-d]thiazole (895 mg, 3.71 mmol) and PTSA (141 mg, 0.74 mmol) in THF/H2O (7.4 mL, 1:1) was stirred at RT overnight. The mixture was diluted with DCM, dried over Na2SO4, and conc. in vacuo. Purification by means of CC (40-100% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4]
Reactant: COC(=O)c1c(F)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(F)ccc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, 154 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (30.2 g, 50%) as a yellow oil: LC/MS m/e calcd for C19H19BrFNO2 (M+H)+: 393.27, observed: 392.0 & 394.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][C:7]1[NH:15][C:14]2[C:9](=[N:10][C:11]([Cl:16])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][C:7]1[N:15]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[C:14]2[C:9](=[N:10][C:11]([Cl:16])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(Cl)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1cc2nc(Cl)ccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(5-Chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acid ethyl ester (1.0 g, 3.56 mmol), 4-chlorobenzyl chloride (0.86 g, 5.34 mmol), Cs2CO3 (5.8 g, 17.80 mmol), and tetrabutylammonium iodide (1.3 g, 3.57 mmol) were suspended in DMF (˜5 mL) and stirred at 60° C. overnight under N2. DMF was removed in vacuo, the residue was dissolved in ether and water, and the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel (0-100% EtOAc in hexanes) to obtain the desired ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[O:14])[CH2:17][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 16 g of 5-fluoro-2-methylindole-3-carboxylic acid in 260 ml of tetrahydrofuran were added 16 g of 4-amino-1-benzylpiperidine and 19 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed under heating for 3 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the extract was concentrated. A mixture of the residue in 70 ml of tetrahydrofuran was stirred at room temperature and the insoluble dicyclohexylurea was filtered off. The filtrate was concentrated and the resulting residue was crystallized with hexane. The resultant crystals were filtered with suction and recrystallized from ethyl acetate to give 22.5 g of N-(1-benzyl-4-piperidyl)-5-fluoro-2-methylindole-3-carboxamide, melting at 166°-169° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)(=O)=O.[Na+].[I-]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH:5]=2
Reactant: CS(=O)(=O)OCCCN1CCN(S(C)(=O)=O)CC1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Temperature: 60 °C
Yield: 66 %

Procedure:
To a solution of 2-bromo-3-(2,4-difluorophenyl)-6-hydroxy-1H-inden-1-one (500 mg, 1.48 mmol) obtained in Step 5 of Example 82 in DMF was added K2CO3(3 eq), 3-[4-(methylsulfonyl)piperazin-1-yl]propyl methanesulfonate (669 mg, 2.23 mmol, 1.5 eq), and NaI (0.3 eq) sequentially. The mixture was heated to 60° C. for 16 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to obtain the title compound (66%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=O)[CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:1][CH:2]2[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH:36]=1
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC2CCC(CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a mixture of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) and 3-formyl-benzoic acid methyl ester (41 mg, 0.25 mmol) in DCM (1 mL) was added sodium triacetoxyborohydride (58 mg, 0.27 mmol). The mixture was stirred at room temperature for 18 h then quenched with excess water. The mixture was diluted with DCM and the organic layer separated and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by column chromatography using an ISCO combi-flash cartridge (silica gel, DCM/MeOH) to afford 3-[(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-methyl]-benzoic acid methyl ester (76 mg, 57%), m/z 589 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH:22]([CH3:24])[CH3:23])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:9]([CH2:30][O:31][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].CC(O)=O>CCOC(C)=O>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@H:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:9]([CH2:30][OH:31])[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OCc2ccccc2)cc1
Agent: *CC(*)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of methyl 2-azido-4-O-benzyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (32) (1.5 g, 2.2 mmol) and anhydrous AcOH (28.8 mL) in dry THF (169 mL) hydrogen fluoride-pyridine complex (20.3 mL) was added in a polypropylene container. The reaction mixture was kept at room temperature overnight, then diluted with EtOAc (1 L). The resulting solution was washed with saturated sodium hydrogen carbonate (4×1 L), saturated brine solution (1 L), dried over MgSO4 and evaporated to dryness. The residue was crystallized from MeOH. The mother liquor was evaporated, the residue was treated with hexane to get more solid. The solid products were combined affording methyl 2-azido-4-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (33) (735 mg, 75%).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@H:64]([C:69]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:26])[NH:27][CH3:28])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CNC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N-methylbenzamide (15, 150 mg, 0.38 mmol), DCC (94 mg, 0.45 mmol) and DMAP (5 mg, 0.038 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (133 mg, 0.38 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 100 mg (52%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[C:8]([NH2:11])[C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>CO>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:8]2[C:6](=[O:7])[N:5]([CH3:12])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[N:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CO
Product: Cn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.5 %

Procedure:
1,3-dimethyl-5,6-diaminouracil (0.01 mol) was suspended in 50 ml methanol. 2-amino-4-chlorobenzoic acid (0.01 mol) was added, followed by 0.01 mol of DICD. The reactants were stirred at room temperature for 15 min, then filtered and washed with methanol. The solid was boiled in 40 ml 1 2.5N NaOH for five min, filtered hot, and the eluate was left to cool for three hours. The material which precipitated on cooling was filtered without washing, redissolved in 40 ml water, and precipitated by neutralization with concentrated HCl. The solid was collected by filtration, washed with H2O, and dried. The product was purified by suspending in 100 ml water, adding NaOH until the compound was dissolved, filtering, precipitating the solid with HCl, filtering, washing with H2O, and drying. The product was identified by chemical ionization mass spectrometry and elemental analysis. Yield 12.5%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][NH:36][S:33]([C:29]1[CH:28]=[CH:27][CH:32]=[C:31]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:30]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Product: CNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-methyl-benzenesulfonamide (example B.32) (225 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 68%). MS (ISP) 525.2 [(M+H)+]; mp 213–214° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)=[O:13]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([CH:14]3[CH2:8][CH2:9][CH2:10][CH2:11][S:12]3=[O:13])[CH:16]=[CH:17][C:18]=12
Reactant: O=S(CCCCCl)Cc1ccc2nccn2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S1CCCCC1c1ccc2nccn2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
8.68 g of potassium t-butoxide was added to 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture, followed by the cooling with ice. A solution of 9.51 g of the 6-((4-chlorobutyl)sulfinylmethyl)imidazo[1,2-a]pyridine prepared in the Preparative Example 8 in 30 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture was dropped into the obtained mixture. The obtained mixture was stirred for one hour. Followed by the addition of ice-water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained oil was solidified by allowing to stand, followed by the addition of ether. The obtained mixture was filtered to give 5.84 g of the title compound as a dark-creamy powder (yield: 71%). The NMR spectroscopic analysis of this powder revealed that the powder was a mixture comprising two diastereomers at a ratio of about 2:1
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][C:5]([S:18][C:16]1[CH:15]=[C:14]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:13]([OH:23])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=1)([CH3:7])[CH2:4][C:2](=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
8.48 Grams of mesityl oxide (0.084 moles) is added dropwise to a solution of 21.0 grams of 2,6 di-tert-butyl-4-mercaptophenol (0.088 moles) and one gram of triethylamine in 30 ml of toluene. The mixture is heated at 50°-55° C. for six hours. The solvent is then stripped off under vacuum and the residue retained at 60°-65° C. and 0.20 mm. Hg. for two hours. The residue is dissolved in toluene and purified by flash chromatography using silica gel. The product is isolated from solution by distilling off the volatiles under vacuum to a final pressure of 0.10 mm. Hg for five hours.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].CN(C)C=O.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([CH:24]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Temperature: 55 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-aminobenzo[b]thiophene-3-carbonitrile (116 g), dimethylformamide (370 ml) and 2,4-difluoronitrobenzene (73 ml) was added pulverized potassium carbonate (276 g), and the mixture was stirred at 55° C. for 5.5 hours. The reaction mixture was stirred under ice-cooling for 30 minutes and water (1.9 L) was added. The mixture was further stirred for 30 minutes. The precipitated crystals were filtered by suction and washed with water (1.9 L) and dried in a drying box overnight to give crude crystals (198 g). The obtained crude crystals were suspended in ethyl acetate (700 ml) and the mixture was stirred under reflux with heating while removing water for 2 hours. The reaction mixture was cooled and stirred at 20° C. for 1 hour. The precipitated crystals were filtered by suction, washed with ethyl acetate (150 ml) and dried to give 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (123 g) as red crystalline powder.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]=3[N:22]=[C:23]([CH2:25][O:26][CH3:27])[N:24]=2)=[CH:14][CH:13]=1.Cl[C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[Cl:41][C:40]1[C:35]([N:29]2[CH2:30][CH2:31][C:20]3[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:32])[F:33])=[CH:13][CH:14]=4)=[N:24][C:23]([CH2:25][O:26][CH3:27])=[N:22][C:21]=3[CH2:28]2)=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Reactant: Clc1cccnc1Cl
Agent: CCN(CC)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 11.9 %

Procedure:
The solution of diisopropylethylamine (490 mg, 3.8 mmol), N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (˜1.9 mmol) and 2,3-dichloropyridine (562 mg, 3.8 mmol) in dioxane (5 mL) and N,N-diethylacetamide (1.0 mL) was irradiated in microwave at 180° C. for 10 h. Solvent was removed in vacuo and residue was purified by column chromatography, product was obtained as a beige solid (102 mg, 12%).
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCCN(C)C)ccc1N
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 85.4 %

Procedure:
To a mixture of 1.1371 g (4.0 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.6131 g (6.0 mmole) of 3-dimethylamino-propylamine followed by 1.0119 g (10 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8587 g 4-amino-N-(3-dimethylamino-propyl)-3-methoxy-benzamide, which was used without further purification.