Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-:23].[Na+].OO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]([NH2:20])=[O:23])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: N#CCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)CCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reaction time: 23 h

Procedure:
A solution of 4-[N,N-Bis-(4-chlorobenzyl)amino]butyronitrile (2.0 g) prepared according to Example 1 in dichloromethane (10 ml) was cooled in ice, then treated with the phase-transfer catalyst nBu4.NHSO4 (0.5 g), 20% aq NaOH (3.2 ml) and 30% H2O2 (4.0 ml). The mixture was stirred vigorously at 0° for about half an hour, then at room temperature for 23 hours. After dilution with dichloromethane the layers were separated, and the organic phase washed with water and with dil. aq. NaHSO3, then dried (MgSO4). Filtration and evaporation gave a syrup (2.26 g) which was flash-chromatographed on neutral alumina eluted with neat toluene (to remove starting material (0.3 g) and then with 10% EtOH-toluene to recover the product (1.62 g). Repeat chromatography on silica eluted with 2-5% EtOH-toluene gave the title compound (1.55 g; 73.6%) as a syrup which set solid on standing. The resulting crystals had m.p. 66°-76°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH3:10])[N:3]=1.Br[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])=[C:4]([CH3:10])[N:3]=1
Reactant: FC(F)(F)c1ccccc1OCCCBr
Reactant: Cc1nc(N)nc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1OCCCOc1ccccc1C(F)(F)F
Yield: 23.4 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 12, using 2.4 grams (0.010 mole) of 2,4-diamino-5-hydroxy-6-methylpyrimidine hydrosulfate salt (prepared in Steps A-C of this Example), 3.0 grams (0.011 mole) of 2-trifluoromethylphenyl 3-bromopropyl ether, and 8.3 grams (0.060 mole) of finely ground potassium carbonate in 50 mL of N,N-dimethylformamide. The product was recrystallized from methanol and water, yielding 0.8 gram of 2,4-diamino-5-[3-(2-trifluoromethylphenoxy)propoxy]-6-methylpyrimidine, mp 132°-134° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.11 g, 7.63 mmol and 4,5-difluoro-1,2-diaminobenzene (110 mg, 0.763 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with hexanes and air dried. This ;gray brown solid was recrystallized from 20 ml of EtOH and the brown-white crystals collected by vacuum filtration and the crystals further dried under vacuum (0.5 torr, 25° C.) to yield 45.3 mg (30.0%) mp>360° C. (lit.>310° C.). 1H NMR (d6 -acetone) δ7.19 (t, 2H, ArH, JH-F =9.3), 10.9 (br s, 2H, NH).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].B(F)(F)F.[CH2:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]1[O:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:1][C:2]1([CH3:4])[O:12][CH:10]([CH2:9][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][O:3]1
Reactant: CCCCCOCC1CO1
Reactant: CC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCOCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a mixture of 406 g of acetone and 10 g of boron trifluoride, 163 g of n-pentyl glycidyl ether obtained in a similar manner to Example 3 was added dropwise over 2 hours while cooling to maintain the temperature at 20 to 30° C. After reaction for 1 hour, the reaction mixture was poured into a large amount of a diluted aqueous solution of sodium bicarbonate for neutralization. Diethyl ether was added and the resulting mixture was stirred. The reaction mixture was allowed to stand to cause separation. The diethyl ether layer thus separated was dehydrated by the addition of sodium sulfate. From the residue, the solid was removed by filtration and then, the solvent was distilled off from the filtrate at room temperature under reduced pressure (133 Pa). To 215 g of 2,2-dimethyl-4-pentyloxymethyl-1,3-dioxolane thus obtained, 1000 mL of ethanol and 1000 mL of 0.1 N sulfuric acid were added. While stirring, the resulting mixture was heated to 80° C. After reaction for 10 hours, the reaction mixture was cooled to room temperature. The solution thus obtained was treated twice with 1000 mL of diethyl ether to extract an oil layer. To the extracted oil layer was added an aqueous solution of sodium bicarbonate, and the remaining acid was thereby neutralized. After separation and removal of the resulting water layer, and diethyl ether was distilled off, 20 g of sodium acetate was added to the residue. The resulting mixture was heated to 180° C. and stirred for 5 hours. After neutralization with 16.8 g of sodium bicarbonate, purification was effected by distillation under reduced pressure (133 to 266 Pa, 114 to 115° C.), whereby 108.7 g of monopentyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting compound had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:15]([C:11]3[C:12]([CH3:14])=[N:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][CH:10]=3)=[O:17])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 66.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.34 mmol), DIPEA (158 mg, 4.02 mmol) and HATU (1.60 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-60% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (340 mg) as a solid. MS: 380 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 2.86 (s, 3H), 6.84 (d, H), 7.12-7.35 (m, 2H), 7.52 (q, H), 7.63 (t, H), 8.10-8.43 (m, 2H), 8.98 (br, N—H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>C(#N)C>[O:21]=[C:19]([CH3:20])[CH2:18][O:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1cccnc1C(N)=O

Procedure:
A mixture of 27.6 g of 3-hydroxy-2-pyridinecarboxylic acid amide and 31 g of potassium carbonate in 600 ml of acetonitrile is heated to the boil for 2 hours, while stirring well. 22.2 g of chloroacetone are added dropwise to the resulting thick paste in the course of 30 minutes. The reaction mixture is stirred for 20 hours whilst boiling under reflux. The undissolved material is filtered off after cooling and the filtrate is evaporated under reduced pressure. The residue is stirred with water, whereupon unconverted 3-hydroxy-2-pyridinecarboxylic acid amide remains as an undissolved residue. The aqueous solution is evaporated under reduced pressure and the residue is extracted with methylene chloride. The organic solution, after evaporation under reduced pressure, gives crude 3-(2-oxo-propoxy)-2-pyridinecarboxylic acid amide which melts at 135°-140° C. after crystallisation from ethanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][OH:19].[OH-].[Na+]>>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccnc2cc(C(F)(F)F)ccc12
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 4-chloro-7-(trifluoromethyl)quinoline (1.0 g, 4.7 mmol) and of 2-aminoethanol (0.86 g, 14.1 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 5 ml of a 10%, w/v, aqueous sodium hydroxide solution. The precipitate obtained is filtered off through sintered glass, washed with water and then brought to reflux in 10 ml of ethanol for 15 min. After returning to ambient temperature, water is added until a precipitate appears. The precipitate is filtered off through sintered glass, washed with 10 ml of water and then dried under vacuum. The product 10 is obtained in the form of a white powder: 0.82 g (yield=68%). Mp: 181-182° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[N:13]1[CH:12]=[CH:11][N:10]2[C:5]([S:4][CH2:3][CH2:2][N:16]3[C:17](=[O:19])[CH2:18][S:14][C:15]3=[O:20])=[CH:6][CH:7]=[CH:8][C:9]=12
Reactant: ClCCSc1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Product: O=C1CSC(=O)N1CCSc1cccc2nccn12

Procedure:
Using 2.29 g (10.8 mmol) of 5-(2-chloroethylthio)-imidazo[1,2-a]pyridine, 1.27 g (10.8 mmol) of thiazolidine-2,4-dione and 1.62 ml (10.8 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene, the same procedure as in Reference Example 2 was followed, to yield 1.49 g (38.7%, light orange crystal) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2
Reactant: CCCCCCBr
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OCCCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with 1-bromohexane and sodium hydride in abs. DMF.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Br:11]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)cc1CBr
Temperature: 85 °C
Yield: 102.7 %

Procedure:
To a stirred mixture of 4-Bromo-2-methyl-benzonitrile (5.00 g, 25.5 mmol) in CCl4 (40 mL) under argon was added N-bromosuccinamide (5.00 g, 28.1 mmol) and a catalytic amount of benzoyl peroxide. This mixture was heated at 85° C. for 2 days and cooled to room temperature. The precipitate was filtered off and the cake was rinsed with CCl4 (2×10 mL). The filtrate was concentrated in vacuo to give 7.2 g crude 4-Bromo-2-bromomethyl-benzonitrile (quantitative yield) which was used without further purification.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:8]([C:12]1[N:13]=[C:14](Cl)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:10])[CH3:9].C(O)=O>CN(C=O)C>[C:8]([C:12]1[N:13]=[C:14]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(C)(C)c1nc(OC2CCC2)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
A mixture of cyclobutanol (173 mg, 2.4 mmol) and NaH (4.8 mg, 0.12 mmol) in DMF (1 mL) was stirred for 30 min at room temperature. 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (26.9 mg, 0.08 mmol) was added and the mixture was stirred at room temperature overnight. Formic acid added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 4 mg (13%) of the title compound. MS(m/e): 372.3.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[N:21][CH:22]=2)=[N:14][CH:15]=1>N1C=CC=CC=1>[Br:9][C:10]1[C:11]([O:5][CH:3]([CH3:4])[CH:2]([OH:6])[CH3:1])=[N:12][C:13]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[N:21][CH:22]=2)=[N:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(O)C(C)Oc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
270 mg (1.5 mmol) of (2R, 3R)-(−)-2,3-butanediol is dissolved in 3 ml of pyridine and mixed with 30 mg (0.69 mmol) of sodium hydride. It is allowed to stir for 15 minutes at room temperature and then 110 mg (0.3 mmol) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide is added. After 1 hour at room temperature, it is stirred for 4 more hours at 50° C. Concentration by evaporation and flashing with dichloromethane/MeOH 4:1 yields 42 mg of 5-[5-bromo-4-(2-hydroxy-1-methyl-propoxy)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide: (34% of theory)°
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]1[N:11]=[C:9](/[CH:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=2)[O:10][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture was refluxed under heating for 8 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with water (20 ml) twice and concentrated under reduced pressure. To the residue was added methanol (4 ml) and the mixture was stirred at room temperature. The crystals were filtrated and dried under reduced pressure to give 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (733 mg, yield 55%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=5)[N:30]([CH3:40])[C:29]4=[O:41])[CH2:24][CH2:23]3)=[N:11][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:13]2)=[CH:8][C:7]=1[O:42][CH2:43][CH3:44])(O)=[O:2].[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH2:43]([O:42][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][C:1]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:2])[N:13]=[C:12]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:11]=[C:10]2[N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=3)[N:30]([CH3:40])[C:29]2=[O:41])[CH2:24][CH2:23]1)[CH3:44]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)O
Reactant: C1CCNC1
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)N1CCCC1
Yield: 15 %

Procedure:
The same procedure as in Example 57 was repeated, using 300 mg (0.50 mmol) of Compound 56 obtained in Example 56, except that pyrrolidine was used in place of isopropylamine, to give 48 mg (yield: 15%) of Compound 58 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:35]4[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:33][CH2:34]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(CCN2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CCc2ccccn2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-piperazinyl-2-(2-pyridinyl)ethane as in General Procedure 10 to give the title compound. LCMS: m/z=620.99 (M+H+); retention time=0.55 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C@H:12]([C:19](=[O:21])[NH2:20])[NH:13]OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C@H:12]([C:19](=[O:21])[NH2:20])[NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)ON[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
t-Butyloxy-D-isoglutamine benzyl ester (3.70 g, 11 mmol) was dissolved in trifluoroacetic acid (20 ml) and the solution was stirred at room temperature for 30 minutes. The solvent was then distilled off, ether was added and the solvent was distilled off again under reduced pressure. Petroleum ether was added to the residue to give crystals, which were dried in the presence of sodium hydroxide in a desiccator, giving D-isoglutamine benzyl ester trifluoroacetate. This product was dissolved in acetonitrile (10 ml) and, under ice-cooling, the solution was neutralized with triethylamine. Then, p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (4.74 g, 10 mmol) was added and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate (70 ml). The solution was washed with 5% aqueous solution of sodium bicarbonate (30 ml×3), 1N hydrochloric acid (30 ml×3) and saturated aqueous sodium chloride (30 ml×3) in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was precipitated as a gel from ethyl acetate-ethyl ether. The same procedure was repeated twice to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine benzyl ester (3.74 g), melting at 83°-85° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH2:12][NH2:13]>C(O)C>[CH3:18][O:17][C:15]1[CH:14]=[C:11]([CH2:12][NH:13][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])[CH:10]=[C:9]([O:8][CH3:7])[CH:16]=1
Reactant: C=CC(=O)NC
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CCO
Product: CNC(=O)CCNCc1cc(OC)cc(OC)c1
Temperature: 140 °C

Procedure:
N-methylacrylamide (ABCR; 500 mg, 5.87 mmol) and 3,5-dimethoxybenzylamine (Aldrich; 0.98 mL, 6.46 mmol) were dissolved in ethanol (4 mL) and heated in a microwave at 140° C. for 45 minutes. The mixture was poured onto a 20 g SCX-2 column, washed with methanol and eluted with 3.5N NH3 in methanol. The product fractions were evaporated to the title compound as a yellow oil (1.3 g, 88%).
Reaction SMILES: O[CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=[S:13])[S:12][C:4]=2[C:3]1=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>C(Cl)Cl>[OH:7][C:6]([C:5]1[S:10][C:11](=[S:13])[S:12][C:4]=1[C:3]1[CH:2]=[N:22][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:21]=1)([CH3:9])[CH3:8]
Reactant: Nc1ccccc1N
Reactant: CC1(C)OC(O)C(=O)c2sc(=S)sc21
Solvent: ClCCl
Product: CC(C)(O)c1sc(=S)sc1-c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 6-hydroxy-4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-7(6H)-one 6 (101.0 mg, 0.41 mmol) in CH2Cl2 (15 mL), 136.6 mg (1.26 mmol) of o-phenylenediamine was added, the resulting solution was refluxed for 1 hour. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by radial chromatography using CH2Cl2 as a mobile phase that yielded 4-(2-hydroxypropan-2-yl)-5-(quinoxalin-2-yl)-1,3-dithiole-2-thione 9 as a yellow-orange solid (119.6 mg, 0.37 mmol, 92.0%). 1H NMR in CDCl3 (δ, ppm): 9.01 (1H, s), 8.18 (1H, m, ArH), 8.07 (1H, m, ArH), 7.89 (2H, m, ArH), 1.59 (6H, s, CH3); 13C NMR in CDCl3 (δ, ppm): 207.8, 158.0, 145.1, 144.3, 141.9, 140.0, 133.81, 132.3, 131.9, 129.8, 128.7, 72.3, 31.0; IR (neat, cm−1): 3199, 3007, 2962, 2917, 1531, 1045, 759, 571, 457; HR APCIMS+ (m/z): 321.0179 (M+, C14H12N2OS3, 321.0185).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:3]=1[NH2:4].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[CH3:19][O:18][C:12]([C:13]1[C:2]2[C:3](=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([F:9])[CH:8]=2)[NH:4][C:14]=1[CH3:16])=[O:17]
Reactant: COC(=O)CC(C)=O
Reactant: COc1cc(F)cc(Br)c1N
Product: COC(=O)c1c(C)[nH]c2c(OC)cc(F)cc12

Procedure:
The above compound A was prepared from 2-bromo-4-fluoro-6-methoxy aniline and methyl acetoacetate according to the general procedure described above for Example 83, steps D and E. 238.0 (M+H), ret t: 3.64 min (A).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH3:18][N:19]=[C:20]=[O:21]>CO.O>[CH3:18][NH:19][C:20](=[O:21])[NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17]
Reactant: CN=C=O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Solvent: CO
Solvent: O
Product: CNC(=O)NC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 5'-amino-5'-deoxythymidine (2, 2.40 g, 9.95 mmol) in methanol-water (2.5:1, v/v) at 0° was added methyl isocyanate (0.63 g, 10.95 mmol). The reaction mixture was kept at 0° with stirring for 1 h, allowed to warm up to room temperature, and then clarified by filtration. The filtrate was evaporated to dryness under reduced pressure at a temperature not exceeding 35°, and the residue was then crystallized from methanol at 3° overnight to give 2.14 g (72%) of white fine needles: mp 238-239°. Anal. (C12H18N4O5) C, H, N.