Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>CN(C)C=O>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][S:3][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])#[N:8]
Reactant: CN=C=O
Reactant: CC(C)(C)c1csc(N)c1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1scc(C(C)(C)C)c1C#N
Reaction time: 8 h

Procedure:
A solution of 4 g 2-amino-3-cyano-4-t-butylthiophene, 1.27 g methyl isocyanate and 3 ml triethylamine in 20 ml dimethylformamide was heated at 130°C. for 3 hours and then allowed to stand at about 25°C. overnight. The dimethylformamide was removed by distillation and the residue was crystallized from ether to give the product, as a tan solid, m.p. 212°-214°C. The infrared spectrum of the product showed cyano absorption at 4.6 microns. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C([Mg]Cl)(C)C.CON(C)[C:18](=[O:20])[CH3:19].[NH4+].[Cl-]>C1COCC1>[N:4]1([CH2:1][C:2]#[C:3][C:18](=[O:20])[CH3:19])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CON(C)C(C)=O
Reactant: C#CCN1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C#CCN1CCOCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
4-Prop-2-ynyl-morpholine (22 g, 176 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −40° C. Then a 2 M solution of isopropyl magnesium chloride in THF (97 mL, 193 mmol) was added while keeping the temperature below −20° C. Stirring at −40° C. to −30° C. was continued for 30 min. In a separate flask, N-methoxy-N-methylacetamide (20 g, 193 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −10° C. in ice/MeOH. The Grignard solution prepared above was transferred to the Weinreb amide solution at −10° C. via teflon tubing under slightly positive nitrogen pressure in vessel 1. There was no exotherm. Stirring at −10° C. to 0° C. was continued for 2 h. Ther resulting white suspension was poured on a 1:1-mixture of ice and saturated NH4Cl solution (400 mL). Extraction: 2×AcOEt, 1× saturated NaCl solution. One obtained a yellow oil (26.1 g, 89%). Chromatography on silica gel in heptane/ethyl acetate 1:2 gave 19.4 g (66%) of a brown oil which was distilled in the Kugelrohr at 130° C./0.2 mbar. One obtained 15.8 g (53%) of a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=[O:5])#[N:2].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:6]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[NH2:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCC(=O)NN
Product: N#CCC(=O)N(N)C(=O)c1ccccc1

Procedure:
in a second step treating the as-synthesized cyanoacetic hydrazide with benzoyl chloride in the presence of a buffer system to form an N-benzoylcyanoacetic hydrazide, and thereafter
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25][C@@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[CH3:27][C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:19]([CH3:21])([CH3:20])[CH3:18])[C:28]([NH:17][C:14]1[CH:13]=[N:12][C:11]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)=[N:16][CH:15]=1)=[O:29]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1cccc(Oc2ncc(N)cn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc(Oc2ncc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinamine (Intermediate 85, 229 mg) in acetonitrile (20 mL) were added N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (378 mg, 2 mmol), HBTU (474 mg, 1.25 mmol) and DIPEA (387 mg, 3 mmol) and the mixture was heated at reflux and stirred overnight. The resulting mixture was concentrated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=1/5−1/2) to afford the title compound (300 mg).
Reaction SMILES: C(OCC)C.[H-].[Na+].[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=1)=[O:12])[CH3:9].[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([N:14]1[C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=[C:13]1[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(C)=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A suspension of diethyl ether washed sodium hydride (0.28 g, 0.009 mole) in dry dimethylformamide (8 ml) at 0° C. was treated with a solution of 2-ethoxycarbonyl-6-acetyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (2 g, 0.0085 mole) in dry dimethylformamide (2 ml) and stirred for 20 minutes. The mixture was warmed to room temperature and stirred for 1 hour by which time solution was complete. The solution was cooled to 0° C., a solution of di-tert-butylcarbonate (1.85 g, 0.0085 mole) in dry dimethylformamide (2 ml) added dropwise over 10 minutes, and the solution stirred at room temperature for 4 hours. The mixture was quenched with water (200 ml), extracted with ethyl acetate (4×100 ml) the organic extracts washed with brine (3×100 ml), dried over sodium sulphate, and evaporated to give a yellow oil which was chromatographed on silica gel (20 g) eluting with dichloromethane:hexane (9:1) to give the title product as a pale yellow oil (1.4 g, 49%). Found: C, 60.12; H, 7.32; N, 8.15. C17H24N2O5 requires C, 60.70; H, 7.19; N, 8.33%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: Fc1ccccc1CCBr
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccccc3F)CC1)CC2
Yield: 52.5 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 2-fluorophenethyl bromide (220 mg) were treated as in Example 2 to give the title compound (190 mg) as a whitepowder (yield: 52%).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=O)[C:12]([CH3:20])([CH3:19])[NH:11]2.P(Cl)(OCC)(OCC)=O.[N+:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])#[C-:31]>C1COCC1>[CH3:19][C:12]1([CH3:20])[NH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:8][CH:9]=2)[N:14]2[CH:31]=[N:30][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:13]12
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)(C)Nc1ccccc1-2
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (1 M, 4.54 ml) is added to 1,2,3,4-tetrahydro-3,3-dimethylquinoxalin-2-one (IV, EXAMPLE 2, 0.762 g) in THF (4 ml) at ice/saline temperature. The reaction is stirred for 40 min, at which time diethyl chlorophosphate (0.656 ml) is added. After stirring at ice-saline temperature for 2 hr, ethyl isocyanoacetate (0.562 g) is added, followed by potassium t-butoxide (1 M, 4.97 ml). The reaction is stirred for 3.5 hr, allowing it to slowly warm to 20°-25°. The reaction is then quenched with several drops of acetic acid and then partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated and the organic phase is dried over magnesium sulfate, concentrated, and the resulting crude product chromatographed on silica gel (200 ml) eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, mp 145°-149°; NMR (CDCl3) 1.44, 1.74, 3.79, 4.40, 6.77, 6.82, 7.10, and 7.39 δ.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH3:35])=[O:27]>CC#N>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:15]2[CH2:16][CH:13]([CH2:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:14]2)=[C:29]([CH3:35])[CH:30]=1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: Cc1cc(F)ccc1C(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1C(=O)CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (75 mg, 0.28 mmol) in MeCN (5 mL) was treated with Et3N (97 μL, 0.7 mmol) and 2-bromo-1-(4-fluoro-2-methylphenyl)ethanone (72 mg, 0.31 mmol) and stirred for 30 min at room temperature. The reaction was evaporated and the residue dissolved in DCM and purified using 10 g silica bond-elute cartridge on the personal flash master. The column was eluted with 0.5% MeOH/DCM then 1% MeOH/DCM to give the title compound as a cream solid (60 mg, 56%). 1H NMR (500 MHz, CDCl3)δ2.49 (3H, s), 2.93–2.98 (1H, m), 3.08 (2H, t, J=7.4 Hz), 3.41 (2H, d, J=7.4 Hz), 3.62 (2H, t, J=7.4 Hz), 3.77 (2H, s), 6.89–6.95 (2H, m), 7.23–7.27 (2H, t, J=8.8 Hz), 7.61 (1H, dd, J=5.8 & 8.5 Hz), 7.90–7.92 (2H, dd, J=5.2 & 8.8 Hz). m/z (ES+) 380 (M+H)+.
Reaction SMILES: CO.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=O)[CH3:13])[N:7]=1)(=O)[CH3:4].[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[N:18]=[C:3]([C:6]1[N:7]=[C:8]([C:12](=[N:18][C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]=2[CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
100 ml of methanol, 1.63 g of 2,6-diacetylpyridine (molecular weight 163.18; 10 mmols), and 4.84 g of 2,4-dimethylaniline (molecular weight 121.18; 40 mmols) were put into a 300 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred for 12 hours to make the compounds reacted completely. The reaction mixture was left at −78° C. for 1 hour, and the resulting pale yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure. Its 1H-NMR spectrum was assigned as the intended product, 2,6-diacetylpyridine-bis(2,4-dimethylphenylimine) (molecular weight 369.52; 1.60 g, 4.33 mmols, yield 43%).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([CH:22]=1)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)(=O)C.[CH2:26]([O:28]CC)[CH3:27]>C(O)C.ClCCl.[Pd]>[C:26]([C:5]1[CH:4]=[CH:22][C:8]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[C:7]([CH:6]=1)[NH2:23])(=[O:28])[CH3:27]
Reactant: CCOCC
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Nc2cccc(-c3cccnc3)c2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Yield: 80 %

Procedure:
30a from Example 12 (2 g, 6 mmol) is suspended in a mixture of ethanol (50 ml) and dichloromethane (10 ml) and is hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent leaves an oil. Trituration with a mixture of diethyl ether and petroleum ether (1:1) affords 1.46 g pure 31a (80%). Mp 175-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[Br:14][C:15]1[CH:16]=[C:17]([F:34])[C:18]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[C:19]([CH:24]=1)[C:20]([NH:22][CH3:23])=[O:21]>>[Br:14][C:15]1[CH:16]=[C:17]([F:34])[C:18]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=4[CH:13]=3)[N:27]=2)=[C:19]([CH:24]=1)[C:20]([NH:22][CH3:23])=[O:21]
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
5-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a gray solid (61 mg, 38%). m.p.=274-278° C.; LCMS (m/e) 533 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.46 (bs, 1H), 9.43 (s, 1H), 9.38 (s, 1H), 8.66-8.57 (m, 1H), 8.21 (s, 1H), 7.79 (d, 1H, J=9.6 Hz), 7.68 (s, 1H), 7.19 (d, 1H, J=8.1 Hz), 7.08 (bs, 1H), 6.97 (d, 1H, J=8.2 Hz), 2.71 (d, 3H, J=4.3 Hz), 2.58 (t, 2H, J=6.4 Hz), 2.18-2.00 (m, 4H); 19F-NMR (d6-DMSO, 400 MHz) δ −111.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]c1=O
Temperature: 0 °C
Yield: 50.6 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (200 mg, 0.869 mmol) was dissolved in 8 mL of concentrated H2SO4 and the yellow-green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (87.8 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice H2O. The product was isolated by vacuum filtration as pale yellow crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 121.1 mg (50.6% yield). 1H NMR (d6 -DMSO) δ7.53 (s, 1H, ArH), 7.80 (s, 1H, ArH), 12.4 (s, 2H, NH). EIMS m/z 275 (81, M+), 217 (36), 201 (100, bp), EIHRMS calc. for C9H4N3O4F3 275.0153, found 275.0170.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12]C(C)(C)C)=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:17]([CH3:19])[CH3:18])[C:10]([OH:12])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Yield: 200.1 %

Procedure:
Following the procedure described in Example 3, except using the material from Example 19 (2.99 g, 10.51 mmol), CH2Cl2 (200 mL) and TFA (51 mL, 662 mmol), 4.8 g (quantitative yield) of the title compound is obtained as a tan syrup as a bis TFA salt. LC/MS (Condition A): ret. T=2.33 min, (M+H)+ 229.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:25]=3[F:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Product: COC(=O)c1ccc(-c2cc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cn2)c(F)c1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-methoxycarbonyl-phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.76 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=S)C.[S:15](=O)(=O)(O)O.O>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][SH:15])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(CS)cc1

Procedure:
The two step procedure for the preparation of 4-nitrobenzyl, (see, for example, Horn, W. J., J. Am. Chem. Soc., 43, 2603, 1921), and 2,4-dinitrobenzyl, (see, for example, Zhao Zhengyun, Ph.D. Thesis, London University, 181-182, 1993), mercaptans (17a and 17b, respectively) is indicated in outline in Scheme 3(a). Thus, when 4-nitrobenzyl chloride 15a was treated with an excess both of thioacetic acid and pyridine in THF solution at 50° C., 4-nitrobenzyl thioacetate 16a was obtained in 77% yield. When the latter compound 16a was heated, under reflux, in sulfuric acid--water (1:1 v/v), 4-nitrobenzyl mercaptan 17a was obtained in almost quantitative yield. 2,4-dinitrobenzyl mercaptan, (see, for example, Zhao, loc cit), 17b was similarly prepared from 2,4-dinitrobenzyl chloride, (see, for example, Cohn, P., and Friedlander, P., Ber., 35, 1265, 1902) 15b in 73% overall yield. N-(4-nitrobenzylmercapto)succinimide 18 was prepared [Scheme 3(b) and Experimental below] in 65 % yield by heating a suspension of the lead(II) salt, (see, for example, Pant, B.C., and Noltes, J. G., Inorg. Nucl. Chem. Lett., 7, 63, 1971), of the mercaptan 17a with N-bromosuccinimide (NBS) in benzene. Preliminary attempts to convert 2,4-dinitrobenzyl mercaptan 17b into the corresponding succinimide and phthalimide derivatives (13 and 14, R=2,4-(O2 N)2C6H3) were unsuccessful. However, di-(2,4-dinitrobenzyl) disulfide 19, (see, for example, Zhao, loc cit), which was easily prepared in good yield by the iodine-promoted oxidation [Scheme 3(c) and Experimental below] of the mercaptan 17b, proved (see below) to be an equally effective reagent for the required purpose. Finally, 2-cyanoethyl mercaptan 20, (see, for example, Bauer, L., and Welsh, T. L., J. Org. Chem., 26, 1443, 1961) was converted (see, for example, Behforouz, M., and Kerwood, J. E., J. Org. Chem., 34, 51, 1969), [Scheme 3(d) and Experimental below] via a putative intermediate sulfenyl chloride into N-(2-cyanoethylmercapto)phthalimide 21 which was isolated without chromatography as a crystalline solid in 58% yield. ##STR10## Scheme 4 Reagents and conditions: i, a, PCl3, 1,2,4-1H-triazole, Et3N, THF, -35° C., b, Et3N, H2O, RT; ii, for 24a: 18, Me3SiCl, Et3N, CH2Cl2, RT, for 24b: 19, Me3SiCl,4-methylmorpholine, CH2Cl2, RT, for 24c: 21, Me3SiCl, 4-methylmoxpholine, CH2Cl2, RT; iii, aq. Et NH+ HCO3 --.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=3[CH:21]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(S)cc1OC
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCBr)cc21
Product: COc1ccc(SCCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(6-bromohexyloxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxythiophenol.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH2:17])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2].[Br:39][CH:40]([CH2:44][CH2:45]Br)[C:41](Br)=[O:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:45][CH2:44][CH:40]([Br:39])[C:41]2=[O:42])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of N,N'-bis-[2,3-diacetyloxypropyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (8.73 g, 10 mmol) in N,N-dimethylacetamide (100 ml) was treated with 2,4-dibromobutyroyl bromide (4.02 g, 13.0 mmol) under an atmosphere of nitrogen and the reaction mixture was stirred for 50 hours at ambient temperature. The mixture was then treated with ground potassium carbonate (1.65 g, 12.0 mmol) and stirred for 30 minutes at ambient temperature. An additional portion (1.65 g, 12.0 mmol) of finely ground potassium carbonate was added and the mixture was stirred for 1.9 hours. The suspended salts were filtered and the solvent was evaporated to obtain a brown oil. This crude product was purified by silica gel flash chromatography to isolate N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide, as a white powder (7.28 g, 71% yield), m.p. 110°-112°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(SCC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Dissolve 4-methyl-benzenethiol (1.5 g, 12.08 mmol) in anhydrous DMF (6 mL). Cool the solution to 0° C., add sodium hydride (435 mg, 17.21 mmol, 95%) and stir the mixture under nitrogen atmosphere for 15 min. Add 1-iodo-2,2-dimethylpropane (1.93 mL, 14.5 mmol), stir the mixture for 1 h at 0° C., warm to room temperature and stir overnight. Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (1.476 g, 63% yield).