Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])/[CH2:3][OH:4].[C:18]([O:21][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:24][C@@H:23]1Br)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:24][C@H:23]1[O:4][CH2:3]/[C:2](/[CH3:1])=[CH:5]/[CH2:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])(=[O:20])[CH3:19]
Reactant: C/C(=C\CN1C(=O)c2ccccc2C1=O)CO
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](OC/C(C)=C/CN2C(=O)c3ccccc3C2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The general procedure of glucuronide formation of R. B. Conrow and S. Bernstein, 1971, supra, was followed. A mixture of 11 g (0.048 mol) of E-2-methyl-4-phthalimidobut-2-enol (mp 104°-105°, J. Corse and J. Kuhnle, Synthesis 618-619 (1972) and 17.2 g of CdCO3 (Johnson and Matthey, Seabrook, N. H.) in 1200 mL of toluene was dried by distilling about 200 mL of toluene from the flask (stirring). A solution of 39.7 g (0.1 mol) of 2,3,4,6-tetra-O-acetyl-α-glucopyranosyl bromide (acetobromoglucose) in 200 mL of dry toluene was added to the stirred, refluxing mixture over 1 h. The hot mixture was filtered through a Celite pad and the toluene was removed in vacuo from the filtrate. The resulting tan gum (46 g) contained the desired product, starting alcohol and its acetate. Purification was simplified by acetylating the entire mixture with 50 mL of acetic anhydride, 135 mL of pyridine and 1 g of 4-dimethylaminopyridine (steam bath, 1/2 h). The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and the solution washed with H2O, dilute HCl, KHCO3 solution and H2O. After drying and removal of the solvent, 29.8 g remained, which was divided into 4 portions and chromatographed on silica (J. T. Baker, flash chromatography grade, 40 μm, 50 cm×4 cm column, hexane:ethyl acetate (65:35); yield 14.36 g (53.3%); mp 118°-120°; 1H NMR identical to that reported by C. C. Duke et al., Australian Journal of Chemistry 31: 1291-1301 (1978).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>O1CCCC1.O>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1([CH3:27])[CH3:26])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(C)(C)C1
Temperature: 35 °C
Reaction time: 20 h

Procedure:
Benzyl chloroformate (50% in toluene, 450 ml, 1.57 mol) was added to a stirred suspension of 4-amino-1-t-butyloxycarbonyl-3,3-dimethylpiperidine (365 g) as prepared above and NaHCO3 (150 g, 1.78 mol) in dry tetrahydrofuran (1.5 L). The reaction mixture was stirred for 20 hr at 35° C. The reaction mixture was diluted with 3.5 L water and was extracted with 2.0 L×2 ethyl acetate. Combined organic extract was washed with water, dried over Na2SO4 and concentrated to dryness. The residue was subjected to chromatography on a silica gel column to give 4-benzyloxycarbonylamino-1-t-butyloxycarbonyl-3,3-dimethylpiperidine in 63% (350 g) yield. m/z 363 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].S([C:34]#[N:35])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:2]2[N:3]([C:34]#[N:35])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: C1CCOC1
Product: N#Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of compound 16 (0.52 g, 1.6 mmol, 1.0 eq) in 6 mL of dry THF stirred at −78° C. under N2 LiHMDS (1.7 mL, 1.05 eq) was added. The mixture was stirred for 15 min. at −78° C. and then TosCN (306 mg, 1.05 eq. in 1 mL of THF) was added dropwise. The reaction mixture was quickly allowed to warmed up to RT. The reaction mixture was quenched with 10 mL of NH4Cl (sat.), extracted into ethyl acetate, washed with brine and concentrated to give creamy solid. The crude was purified by column chromatography (ethyl acetate/hexanes) to give 79 (330 mg, 59%). MP=153.3-154.2° C. Anal/Calcd. for C19H16H4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found C, 65.59; H, 4.66; N, 16.06; S, 9.16.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(NC2=NCCN2)cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(NC2=NCCN2)cc2cc[nH]c12

Procedure:
A solution of 7-isopropenyl-5-(2-imidazolin-2-ylamino)indole (0.25 g, 1.0 mmol) and 10% Pd/C (100 mg) in 10 mL of MeOH was stirred for 12 h under H2 (18 psi). The reaction mixture was filtered and concentrated in vacuo, yielding an oil which, in NMR analysis, was highly pure and corresponds to the desired product. The product obtained was converted to the succinate salt and recrystallized from isopropanol-CHCl3 to afford 0.13 g of the product as a light brown solid: mp 254-255° C.; H NMR (CD3OD) δ 7.28 (d, J=1.8 Hz, 1H), 7.27 (d, J=3.2 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 3.67 (s, 4H) 3.30 (hep, 1H), 2.18 (s, 3H); Anal. Calc. for C14H18N4.1.0C4H6O4 requires C, 60.32; H, 6.19; N, 15.63. Found: C, 60.17; H, 6.25; N, 15.59.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[BH3-]C#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]([N:21]2[CH:30]3[CH:25]([CH2:26][CH2:27][CH2:28][CH:29]3[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:24][CH2:23][CH2:22]2)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:24]1[CH:25]2[CH:30]([CH:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:28][CH2:27][CH2:26]2)[N:21]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:22][CH2:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (93 mg, 1.3 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (82 mg, 1.3 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (101 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). A colorless resin was isolated.
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[K+].O>S1(CCCC1)(=O)=O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([O:5][CH:1]=[C:2]([CH3:3])[CH3:4])=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C=C(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)=COc1ccc(C(F)(F)F)cc1
Reaction time: 21 h

Procedure:
A mixture of 50.48 g of methallyl alcohol, 63.2 g of 4-chlorobenzotrifluoride and 69 g of 85% flake potassium hydroxide in 175 ml sulpholane was stirred under nitrogen at 120°-145° C. for 21 hours. The mixture was then cooled, added to 200 ml water and extracted twice with 60°/80° petroleum ether. The solvent was removed and the residue was purified by fractionation to give isobutenyl 4-trifluoromethylphenyl ether, b.p.: 77°-77.5° C. at 8 Torr.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: O=C(OCC=CCO)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl oleate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 30 gms (0.1 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][CH2:59][N:60]1[CH2:65][CH2:64][NH:63][C:62](=[O:66])[CH2:61]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][NH:63][C:62](=[O:66])[CH2:61]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCCN1CCNC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), HOBt (3 mg, 0.1 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 4-(2-amino-ethyl)-piperazin-2-one (30 mg, 1.1 eq.) in DMF (2 mL) at rt was added TEA (0.067 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM and then mixed with solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:5][CH:4]=1)=O.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][O:28][C:29]2=[O:34].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[O:34]=[C:29]1[C:30]2[C:26](=[C:25](/[N:24]=[CH:1]/[C:3]3[CH:4]=[CH:5][C:6]([CH:9]4[CH2:13][CH2:12][CH2:11][N:10]4[C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])=[CH:7][CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:27][O:28]1
Reactant: O=Cc1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(C4CCCN4C(=O)OCc4ccccc4)cc3)cccc21
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of benzyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate (0.62 g, 2 mmol), 4-aminoisobenzofuran-1(3H)-one (0.298 g, 2 mmol), MgSO4(2.4 g, 20 mmol) in CH3CN (20 mL) was refluxed at 120° C. for 4 days. After a hot filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography (EtOAc:DCM:hexane=1:1:6) to give the title compound (0.35 g, yield 30%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C:15]([C:35]#[N:36])([CH2:21][C:22]([O:24][CH:25]1[CH:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][CH:27]([CH3:34])[CH2:26]1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].OO>O.CC(C)=O>[C:7]([O:11][C:12]([NH:14][C:15]([C:35](=[O:2])[NH2:36])([CH2:21][C:22]([O:24][CH:25]1[CH:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][CH2:28][CH:27]([CH3:34])[CH2:26]1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])([CH3:8])([CH3:10])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C#N)(CC(=O)OC1CC(C)CCC1C(C)C)NC(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OC(C)(C)C)C(N)=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Potassium carbonate (586 mg, 4.24 mmol), water (2.5 ml), ethyl 2-(tert-butoxycarbonylamino)-2-cyano-3-[(−)-menthyloxycarbonyl]propionate (1.00 g, 2.46 mmol) and acetone (5 ml) were mixed and 30% aqueous hydrogen peroxide solution (0.8 ml) was added dropwise under cooling with water. Then the mixture was heated at 10-30° C. of inner temperature and stirred for about 4 hours. The precipitated crystals were filtered and washed with sprayed water. It was dried in airflow at 60° C. overnight to give ethyl 2-(tert-butoxycarbonylamino)-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (802 mg, yield 73.3%). Optical purity was 10.7% d.e.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)[C:7]1=[O:17].[O-][CH2:20][CH2:21][CH2:22]C.[Na+].Cl>C(O)CCC>[CH2:2]([O:3][C:4]([C:5]1[NH:6][C:14](=[O:15])[C:13]2[C:8]([C:7]=1[OH:17])=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[O-]
Reactant: COC(=O)CN1C(=O)c2ccc(I)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)c1[nH]c(=O)c2cc(I)ccc2c1O
Temperature: 80 °C

Procedure:
Freshly cut sodium metal, 0.40 g, was dissolved in 22 ml of n-butanol at 65° C. under a nitrogen atmosphere. A mixture of 3.0 g of (5-iodo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid methyl ester in 22 ml of n-butanol was added to the sodium butoxide solution and the reaction mixture was heated to 80° C. for 2 h. The cooled reaction mixture was acidified with 100 ml of 1 M hydrochloric acid to give a solid precipitate. The solid was collected by filtration and separated by silica gel chromatography (eluant; 19:1 dichloromethane:ethyl acetate) to give 0.219 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−)-ion, M−1=386.0 amu, and 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−) ion, M−1=386.0 amu.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl>[OH-].[Na+]>[CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH:5][C:9](=[O:11])[CH3:10]
Reactant: CSC[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSC[C@H](NC(C)=O)C(=O)O
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of 13.5 g (100 mmole) of S-methyl-L-cysteine dissolved in 210 ml of 1 N sodium hydroxide solution was ice cooled and 10.4 ml (110 mmole) of acetic anhydride was added thereto dropwise. After 2.0 hours at room temperature, the mixture was acidified to pH 1.0 with 6 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 15.9 g (89.6% yield) of S-methyl-N-acetyl-L-cysteine as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Clc1ccc2ccccc2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ccc4ccccc4n3)CC2)cc1
Yield: 18 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was reacted with 2-chloroquinoline (175 mg, 1.06 mmol), DIEA (0.37 ml, 2.12) and 1,4-dioxane (0.2 ml) at 185° C. to afford the title compound (39 mg), a white solid, in 18% yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15][CH3:16])=[CH:7][CH:6]=1.C(OO)(=[O:20])C>C(OCC)(=O)C.CCCCCCC>[CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15]([CH3:16])=[O:20])=[CH:7][CH:6]=1
Reactant: CNC(=O)Oc1ccc(SC)c2c1CCCC2
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNC(=O)Oc1ccc(S(C)=O)c2c1CCCC2
Yield: 90 %

Procedure:
This compound was prepared in 90% yield by allowing a solution of 4-methylmercapto-5,6,7,8-tetrahydro-1-naphthyl N-methylcarbamate in ethyl acetate to slowly react at 35°-40° with one equivalent of peracetic acid in ethyl acetate. An ice bath was required to maintain the reaction temperature in the proper range. At the conclusion of the reaction, the solution was diluted with heptane and the resulting precipitate collected by filtration and washed thoroughly with heptane. After drying, the product melted at 135°-138°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.BrC1C=CC(B2OC(C)(C)[C:31](C)(C)[O:30]2)=CC=1OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:6][C:7]=1[O:30][CH3:31]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Br
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Br

Procedure:
Prepared according to a procedure analogous to that described for 1-(4-bromophenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine except using 2-(4-bromo-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. MS (ES+): m/z 372.99, 374.96 [MH+].
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (46.9 mg, 0.0967 mmol, 1 eq), 1-piperidinepropanoic acid (40.5 mg, 0.255 mmol, 2.6 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (56.2 mg, 0.293 mmol, 3 eq), and 1-hydroxybenzotriazole (HOBt) (13.9 mg, 0.103 mmol, 1 eq) in anhydrous DMF (5 mL), DiPEA (85 μL, 0.48 mmol, 5 eq) was added under an atmosphere of N2 The reaction was stirred at rt for 18 h, after which all solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 5%→7N NH3/MeOH:DCM 2%→5%→8%→15%]. Fractions 25-39 were combined and concentrated in vacuo, yielding the desired amide, but which contained a considerable amount of 1-(3-dimethylaminopropyl)-3-ethylurea. The yellow solid was triturated in hot MeOH/sonication, giving the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=1.26 (s, br, 2H), 1.63 (m, 4H), 2.37-2.56 (m, 6H), 2.56-2.68 (m, 2H), 2.68-2.80 (m, 2H), 3.68 & 3.76 (t, J=5.6 Hz, rotamers, 2H), 4.22 & 4.25 (s, br, rotamers, 2H), 5.92 & 5.98 (s, rotamers, 1H), 6.18 & 6.22 (s, br, rotamers, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8, 1.6 Hz, 1H), 8.13 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 505.00/506.99 (27/10) [MH+]; m/z 407.96/409.98 (100/36) [MH+—C6H14N]. HPLC: tR=1.75 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)CCC>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH2:6][CH2:1][CH2:2][CH3:3])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 66.9 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of n-butanol are treated in the same manner as described in Example 13. 0.8 g of n-butyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 33.5%
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.[NH2:9][S:10]([C:13]1[CH:14]=[C:15]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:24]([F:35])=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[NH2:9][S:10]([C:13]1[CH:14]=[C:15]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]4[NH:4][C:5](=[O:8])[NH:6][N:7]=4)=[CH:30][CH:29]=3)[C:24]([F:35])=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19])(=[O:12])=[O:11]
Reactant: O=c1[nH]nc(CCl)[nH]1
Reactant: NS(=O)(=O)c1cc(Nc2ncc(F)c(Nc3ccc(O)cc3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1cc(Nc2ncc(F)c(Nc3ccc(OCc4n[nH]c(=O)[nH]4)cc3)n2)ccc1F
Yield: 20.4 %

Procedure:
To a solution of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one (35 mg, 0.26 mmol) in 2-butanone, were added N2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine (100 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol). The resulting mixture was microwaved at 140° C. for 5 hours, and then additional of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one was added as needed The reaction solvent was removed under a reduced pressure, and the residual was purified by column chromatography (silica gel, dichloromethane: methanol 8:2 v/v) to give 25 mg of N2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methoxyphenyl]-2,4-pyrimidinediamine (76) as a light yellow solid. 1H NMR (D2O): δ 7.90-7.89 (d, J=3 Hz, 1H), 7.60-7.58 (d, J=6 Hz, 1H), 7.34 (bs, 2H), 7.24-7.18 (m, 2H), 7.05-7.02 (d, J=9.0 Hz, 2H), 6.65-6.62 (d, J=9.0 Hz, 2H), 5.11 (br s, 2H); LCMS (m/z): 491.05 (MH+).