Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34](CCl)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:33][CH:32]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 69 %

Procedure:
(S)-1-(4-Methoxybenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11b) was prepared according to the same procedure for compound 11a, except using 4-methoxybenzyl chloride, and purified with hexanesether (1:3) to afford 175 mg (69%) of 11b as a yellow solid, mp 126.7-128.8° C. 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.95 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.28-7.21 (m, 4H), 6.96-6.80 (m, 6H), 4.86 (s, 2H), 4.18-4.11 (m, 1H), 3.97-3.88 (m, 2H), 3.80 (s, 3H), 3.50 (m, 1H), 3.23 (m, 1H), 2.02 (m, 2H), 1.78 (m, 2H). Anal. Calcd for C27H2(N2O6S: C, 64.02, H, 5.17; N, 5.53. Found: C, 64.76, H, 5.24; N, 5.06.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.[OH:18]CCOC1C=CC(S(C2C=CC(OCCO)=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:18])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=S(=O)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, then 6.97 g of bis[4-(2-hydroxyethoxy) phenyl]sulfone (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from tetrahydrofuran with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a fifth dimeric fluorenone derivative, which was a yellow solid (9.3 g, 60% yield). A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 4.35–4.43 (t, 4H); 4.72–4.81 (t, 4H); 6.95–7.05 (m, 4H); 7.27–7.38 (m, 4H); 7.40–7.52 (dd, 2H); 7.66–7.74 (dd, 2H); 7.79–7.94 (m, 8H); 8.25–8.33 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13]([N:19]([CH3:20])[CH3:18])(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Reactant: CNC
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (7.3 g) and dimethylamine (33% w/w solution in industrial methylated spirit; 150 ml) was stirred at room temperature for 72 hours. The precipitate and residue from evaporation of the filtrate were combined and crystallised from industrial methylated spirit. The product was ground under water, collected and dried to give the novel compound 7-chloro-1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 207°-209°.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>O>[CH2:1]([O:8][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCCCCCCCOCc1ccccc1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a mixture of 2.16 g of benzyl alcohol and 30 ml of dimethylformamide was added 1.2 g of oily sodium hydride (60%). After stirring the mixture for 30 minutes at 20° to 25° C., 10 g of 1,12-dibromododecane was added to the mixture in one portion followed by stirring for 2 hours at 25° to 30° C. After the reaction was over, 300 ml of water was added to the reaction mixture and the product was extracted with n-hexane. The extract was washed with water, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The oily residue was applied to silica gel column chromatography and eluted with a mixture of n-hexane and ether (9:1) to provide 3.8 g of 12-benzyloxy-1-bromododecane as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([C:14]2[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[NH2:23]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[NH2:23][N:15]1[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:14]1[C:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=1)=[O:13]
Reactant: CCc1ccc(C(=O)c2ccc(C(=O)OC)c(Br)c2)[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2ccc(C(=O)OC)c(Br)c2)n1N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate (330 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride in oil (58.4 mg) in an ice-bath over 5 minutes. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over 40 minutes. The resulting mixture was stirred for 1 hour in the bath. The reaction was quenched by adding water (10 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times) and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetatec-hexane (1-5), and to the solution was added silica gel. The mixture was filtered, and the filtrate was evaporated to give methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate as an orange solid (310 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:14][CH2:15][CH:16]([CH2:21]Br)[C:17]([CH3:20])([CH3:19])[CH3:18])(=O)C.O>CN(C)C=O>[CH2:3]([S:10][CH2:21][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)OCC(CBr)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(CO)CSCc1ccccc1
Yield: 33.7 %

Procedure:
Sodium hydride (2 g; 80%) was added to a stirred solution of benzyl mercaptan (9.4 g) in dry dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 1 hour when a solution of 2-bromomethyl -3,3-dimethylbutyl acetate (13.3 g) in DMF (10 ml) was added. After a further hour at reflux, the mixture was allowed to cool and then poured into water (300 ml). The aqueous mixture was extracted with ether and then the combined ethereal extracts were washed with water before drying over anhydrous magnesium sulphate and evaporation in vacuo. The resulting residue was taken up in a mixture of 10% aqueous potassium hydroxide and ethanol (1:1, 50 ml) and heated to reflux for 1 hour. After cooling, the aqueous solution was exhaustively extracted with ether. The combined ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica. Gradient elution with hexane/diethylether mixtures gave 2-benzylthiomethyl-3,3-dimethylbutanol as an oil (4.5 g).
Reaction SMILES: C[N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@H:4]2[CH2:3]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH2:3]1[C@@H:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[CH2:19][CH2:20][N:2]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Yield: 97.6 %

Procedure:
A solution of 5.52 g of (S)-1,2,3.4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in preparation 6) in 30 ml of toluene was added dropwise to a solution of 6.8 g of ethyl chloroformate in 50 ml of toluene at 80° C. over a period of 10 minutes, and the mixture was heated under reflux for 3 hours. At the end of this time, the crystals which precipitated were removed by filtration, and solvent was removed from the filtrate by evaporation under reduced pressure, to give 6.57 g (yield 98%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methylpyrazole (1.98 g, 24.11 mmol) in DMF (8 mL) was added to sodium hydride (60% in oil, 0.97 g, 24.25 mmol) in DMF (6 mL) and the resulting mixture was stirred 2 h at RT. 4-Fluorobenzaldehyde (1.26 g, 7.45 mmol) was added dropwise and the resulting mixture heated to 80° C. for 3 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) followed by recrystallization from hexane yielded the title compound. MS 187 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.Br[C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:29][C:27]1[CH:28]=[CH:21][C:22]([CH:23]=[O:24])=[C:25]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:7][CH:8]=2)[CH:26]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C#Cc2cc(F)ccc2C=O)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 79.2 %

Procedure:
A degassed mixture of 1-ethynyl-4-methanesulfonyl-benzene (2.5 g, 13.87 mmol), bis(triphenylphosphine)palladium(II) chloride (0.49 g, 0.69 mmol), copper(I) iodide (0.13 g, 0.69 mmol), triethylamine (28 mL), and 2-bromo-4-fluorobenzaldehyde (3.38 g, 16 mmol) in dichloromethane (10 mL) was stirred at 80° C. for 3.5 hours, then at room temperature overnight. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 15-35% ethyl acetate in hexane) gave 4-fluoro-2-(4-methanesulfonyl-phenylethynyl)-benzaldehyde (3.32 g, 79%). MS (ESI+) cald. for C16H11FO3S [(M+H)+] 302, obsd. 302.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[CH:30]1(/[CH:33]=[CH:34]/[C:35]#[N:36])[CH2:32][CH2:31]1>>[C:35]([CH2:34][CH:33]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[CH:30]1[CH2:32][CH2:31]1)#[N:36]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Reactant: N#C/C=C/C1CC1
Product: N#CCC(C1CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and (2E)-3-cyclopropylacrylonitrile. LCMS (M+H)+: m/z=495.2.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:27])([CH3:26])[CH2:20][O:21][CH2:22][C:23]([OH:25])=[O:24])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29]C1C=CC(CN2C3C(=CC=CC=3)C(COC(C)(C)CO)=N2)=CC=1>>[CH3:28][O:29][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][O:18][C:19]([CH3:27])([CH3:26])[CH2:20][O:21][CH2:22][C:23]([OH:25])=[O:24])=[N:9]2)=[CH:3][CH:4]=1
Reactant: CC(C)(COCC(=O)O)OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: COc1ccc(Cn2nc(COC(C)(C)CO)c3ccccc32)cc1
Product: COc1ccc(Cn2nc(COC(C)(C)COCC(=O)O)c3ccccc32)cc1

Procedure:
The product was obtained with the method described for the preparation of compound 39b, using 2-{[1-(4-methoxybenzyl)-1H-indazol-3-yl]methoxy}-2-methylpropan-1-ol as starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[C:14]([N:16]([CH3:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:15])=[S:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([SH:10])=[N:11][N:12]=[C:13]2[C:14]([N:16]([CH3:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: CN(Cc1ccncc1)C(=O)C(=O)NNC(=S)Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccncc1)C(=O)c1nnc(S)n1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 26 h
Yield: 15.4 %

Procedure:
A mixture of 2-(2-((4-fluorophenyl)carbamothioyl)hydrazinyl)-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (79) (0.75 g, 2.075 mmol) and sodium bicarbonate (0.35 g, 4.17 mmol) in methanol/water (1:1) (20 mL) was stirred at 80° C. for 26 h. After evaporation of solvent, the residue was extracted with dichloromethane/methanol (10:1) (3×60 mL). The combined organic phase was evaporated and the crude product was purified by flash column chromatography on silica gel (0%-20% MeOH in dichloromethane) to provide 4-(4-fluorophenyl)-5-mercapto-N-methyl-N-(pyridin-4-ylmethyl)-4H-1,2,4-triazole-3-carboxamide (80) as a white solid (0.11 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])[CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])[CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:11][CH:10]=1)=[O:6]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NC(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 10 mL round-bottomed flask 5-[3-(4-amino-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 353, step 1, 100 mg) was dissolved in dichloromethane (1.3 mL) and pyridine (41 mg). Then the reaction mixture was cooled in an icebath and 4-chlorobutyryl chloride (41.6 mg) was added slowly. The icebath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed 1× with 1 M HCl and 2× with water. The aqueous layers were extracted 2× with ethyl acetate, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% methanol in dichloromethane) to give the title compound as a light yellow foam, MS (ESI+): m/z=485.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH3:13].O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:13])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: Clc1ccnc2cc(Br)cnc12
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccnc2cc(Br)cnc12
Temperature: 160 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
In a sealed reactor, 500 mg (2.04 mmol, 1 eq) of 7-bromo-4-chloro-1,5-naphthyridine (G. B. Barlin et al. Aust. J. Chem. 1985, 38, 459-465) and 12 mL (71.3 mmol, 35 eq) of 20% aqueous ammonia solution were introduced in 12 mL of dioxane. The mixture was stirred at 160° C. for 24 h. The mixture was allowed to reach rt and water was added. Aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 350 mg of white powder with 76% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(N)c(C#N)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Using a literature procedure described in the following literature reference which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein, a dry round bottom flask was charged with 2-amino-5-bromo benzonitrile (1 equivalent) and zinc cyanide (2 equivalents), and DMF was added: J. Med. Chem. 2000, 43, 4063. Nitrogen was bubbled through the solution for 5 minutes, and Pd[P(Ph)3]4 was added in one portion. The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, saturated NaHCO3 was added, and the mixture was extracted with EtOAc. The organic extracts were collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification by column chromatography on silicagel (2% methanol in methylene chloride) afforded the desired 4-aminobenzene-1,3-dicarbonitrile as a white solid. GC/MS m/z: 143 (M+, 100%), Rt 14.7 minutes.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.CN(C)C=O.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>C(O)(=O)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CSc1n[nH]c(N)n1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To the solution of 6.5 g (0.05 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 60 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 6.5 g (51.1%) of 2-methylthio-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([N:7]([CH2:32][CH:33]2[CH2:34][CH2:35]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([OH:26])=[O:25])=[CH:30][CH:31]=3)=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-({4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}amino)butanoate (Example 74, 50 mg; 0.10 mmol) in a mixture of MeOH (2 ml) and THF (2 ml) was treated with an aqueous solution (5 N) of sodium hydroxide (300 μl; 1.5 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was acidified with HCl 1N until pH 4. The precipitate was filtered and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([N:15]3[CH2:21][CH:20]4[O:22][CH:17]([CH2:18][CH2:19]4)[CH2:16]3)[N:12]=[C:11](O)[N:10]=1)[CH2:2]2.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[N:10]=[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)[CH:14]=[C:13]([N:15]2[CH2:21][CH:20]3[O:22][CH:17]([CH2:18][CH2:19]3)[CH2:16]2)[N:12]=1
Reactant: Oc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
In a 25 mL round-bottomed flask was placed 4,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-ol (27), 12 mg, 0.038 mmol) in POCl3 (3 ml) to give a yellow solution. The mixture was stirred at 100° C. for 4 h. The mixture was cool to room temperature, poured on ice, and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound as a white crystalline solid (12 mg, 93%).