Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][N:29]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:4])[CH3:3].FC(F)(F)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])(O)=O.[Na+]>CCO>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][N:29]=4)[CH2:22][N:21]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:4])[CH3:3]
Reactant: Cc1cnc(C2CNCC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)o1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)o1
Temperature: 80 °C
Yield: 8.6 %

Procedure:
A mixture of (4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt (32 mg, 0.07 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (17 μL, 0.11 mmol) and NaHCO3 (24 mg, 0.28 mmol) in anhydrous EtOH (800 μL) was heated at 80° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to room temperature, microfiltered and purified by Waters mass directed LC/MS: (10-99% ACN/H2O (5 mM HCl)) and concentrated in vacuo to yield (4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (3 mg, 9%) as a white solid. ESI-MS m/z calc. 495.5. Found 496.7 (M+1)+; Retention time: 1.99 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.27-7.13 (m, 2H), 6.96 (d, J=9.0 Hz, 1H), 6.82 (d, J=1.2 Hz, 1H), 4.86 (dd, J=12.0, 4.7 Hz, 1H), 4.71-4.54 (m, 1H), 3.32-3.14 (m, 5H), 3.07 (dd, J=11.5, 2.6 Hz, 1H), 2.90-2.83 (m, 1H), 2.70 (dd, J=18.3, 7.2 Hz, 1H), 2.41-2.23 (m, 6H), 2.13 (s, 3H), 1.64-1.39 (m, 3H), 1.29 (d, J=6.0 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:18][CH:19]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 62.4 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.07 mL, 0.92 mmol), triethylamine (0.08 mL, 0.92 mmol), and 1-(4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B-1, 0.127 g, 0.31 mmol) provided 0.087 g of the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]([C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:32][N:33]=1)[CH:3]([NH:6][C:7](=[O:28])[CH:8]([CH2:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[CH2:9][C:10](=[O:16])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[O:16]=[C:10]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:9][CH:8]([CH2:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[C:7]([NH:6][CH:3]([C:2]([C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:32][N:33]=1)=[O:1])[CH2:4][CH3:5])=[O:28]
Reactant: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccncc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 102 mg of 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide; H1NMR (DMSO-d): 9.0–8.85(3H, m), 8.1–8(2H, m), 7.44–7.3(5H, m), 5.05–4.9(1H, m), 4.55–4.35(2H, m), 3.4–3.(8H, m), 2.6–2.4(1H, m), 2.05–1.9(1H, m), 1.9–1.6(5H, m), 0.96(3H, t); MS: 552.6(M−1), 554.6(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]([S:16]([CH2:19][Cl:20])(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14]>C(O)C.[Ir]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]([S:16]([CH2:19][Cl:20])(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: CC(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)S(=O)(=O)CCl
Agent: [Ir]
Solvent: CCO
Product: CC(=O)N(c1cc(N)c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 80 °C
Yield: 70 %

Procedure:
65.7 g (0.19 mol) of N-(2-chloro-4-fluoro-5-nitrophenyl)-N-[(chloromethyl)sulfonyl]acetamide were dissolved in 1200 mL of ethanol and transferred into an autoclave. 2.5 g of an iridium catalyst (5% on carbon) were added and the apparatus was purged with nitrogen and hydrogen, respectively. A hydrogen pressure of 2,000 kPa (20 atmospheres) was applied and the mixture was heated to 80° C. After 4 hours the hot reaction mixture was filtered and cooled to room temperature whereas some of the product precipitated. The crystals were filtered off and the mother liquor was concentrated and cooled. The precipitates were combined and dried to yield 41.9 g (70.2%) of the title compound as a solid melting at 176-180° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=1>O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=3)[C:14]2=[O:21])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CSc1nccc(CCl)n1
Reactant: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)n1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a suspension of 1.74 g of sodium hydride (60%) in 70 mL of tetrahydrofuran are successively added, dropwise under an inert atmosphere of argon, a solution of 4.52 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-imidazolidine-2,4-dione obtained in stage c) in 25 mL of tetrahydrofuran, followed by a solution of 5.14 g of 4-(chloromethyl)-2-(methylthio)pyrimidine in 50 mL of tetrahydrofuran. After addition, the reaction mixture is refluxed for 48 hours, cooled to room temperature and poured into distilled water, and the aqueous phase is washed with ethyl acetate. The organic phase is then washed successively with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with dichloromethane, to give 5.92 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([C:9]1[C:10]([OH:22])=[C:11]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[C:12](O)=[O:13])([CH3:8])[CH3:7].[C@H]1(N)CCCC[C@@H]1[NH2:29].C(N(CC)CC)C>CN(C)C=O.C1(C)C=CC=CC=1.O1CCCC1>[CH3:5][C:6]([C:9]1[C:10]([OH:22])=[C:11]([C:12]([NH2:29])=[O:13])[CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)([CH3:8])[CH3:7]
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)c(O)c(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5.95 g, 50 mmol) was added to a mixture of 3,5-bis(1,1-dimethylethyl)-2-hydroxybenzoic acid (alternatively named 3,5-di-tert-butylsalicylic acid) (2.50 g, 10 mmol) and N,N-dimethylformamide (10 drops) in dry toluene (50 mL) at 60° C. After 1 hour at 60° C., the light yellow solution was evaporated in vacuo to leave a thick oil and then diluted with dry tetrahydrofuran (THF) (40 mL). After heating to 50° C., a solution of (1S,2S)-(+)-1,2-cyclohexanediamine (0.560, 4.90 mmol) in 10 mL of dry THF was added followed by triethylamine (1.01 g, 10 mmol). After 1 h at 50° C., the reaction mixture was quenched with water (25 mL) and then poured into ethyl acetate/water. The organic phase was separated, and the aqueous phase extracted with additional ethyl acetate (35 mL). The combined organic phase was washed once more with water and then evaporated onto silica gel. Purification by flash chromatography (hexanes-ethyl acetate, 0 to 20% ethyl acetate over 1 hour) and evaporation of the chromatography solvent in vacuo afforded the product as a foamy off-white solid (1.18 g). The product was further purified by stirring the white solid in methanol (5 mL) and then decanting the mother liquor from a small amount of insoluble, gummy solids. Evaporation of the methanol mother liquor afforded the title product as an off-white solid (1.15 g). 1H NMR (CDCl3) δ 1.29 (s, 18H), 1.38 (s, 18H), 1.82 (s, 2H), 2.22 (br s, 2H), 3.96 (br s, 2H), 6.95 (br s, 2H), 7.16 (d, J=2 Hz, 2H), 7.41 (d, J=2 Hz, 2H), 12.70 (s, 2H). MS ESI Positive: 579 (M+1), ESI Negative: 577 (M−1).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[CH:1]1[C:11]2[C:10](=[N:18][OH:19])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2CSc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2CSc2ccccc21

Procedure:
19.7 G. of dibenzo[b,e]thiepin-11(6H)-one and 14.6 g. of hydroxylamine hydrochloride in 350 ml. of pyridine are stirred under reflux conditions for 16 hours. After the addition of a further 7.3 g. of hydroxylamine hydrochloride, the mixture is stirred for a further 5 hours under reflux conditions. The mixture is evaporated and purified by chromatography over aluminum oxide using chloroform and chloroform/methanol (93:3) for the elution. The purified product is recrystallized from acetone. There is obtained dibenzo[b,e]thiepin-11(6H)-one-oxime of melting point 241°-243° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=2)[C:23]#[N:24])[N:10]=1
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Temperature: 150 °C

Procedure:
A mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (0.1 g, 0.27 mmol), zinc cyanide (0.032 g, 0.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.01 mmol) in N,N-dimethylformamide (4 ml) was heated to 150° C. Fog 600 s in a Smith Synthesiser microwave reactor (Personal Chemistry, Uppsala, Sweden). The reaction was partitioned between ethyl acetate (80 ml) and water (40 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was chromatographed on silica gel, eluent 50% ethyl acetate in isohexane, to give 5-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]-2-fluorobenzonitrile as a yellow solid (0.054 g): δH (400 MHz, CDCl3) 7.02-7.14 (2H, m), 7.48 (1H, t, J 8.6 Hz), 8.33-8.39 (1H, m), 8.49-8.53 (1H, m), 8.62 (1H, dd, J 2.2, 6.1 Hz), 9.65 (1H, s); m/z(ES+) 313.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:9]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[CH:10][N:11]=2)[CH:21]=[N:22][CH:23]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: COC(=O)c1cc(Cl)ncc1-c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cncc(C)c2)ncc1-c1nccs1
Temperature: 65 °C

Procedure:
Methyl 2-chloro-5-(1,3-thiazol-2-yl)isonicotinate (7-2, 6.5 g, 26 mmol, 1 equiv), (5-methylpyridin-3-yl)boronic acid (3.8 g, 28 mmol, 1.1 equiv), cesium carbonate (29 g, 89 mmol, 3.5 equiv) and PdCl2(dppf)-CH2Cl2 adduct (4.2 g 5.1 mmol, 0.2 equiv) were suspended in DMF (102 mL) and water (4.6 mL, 255 mmol, 10 equiv). The reaction mixture was heated for 45 minutes at 65° C., diluted with EtOAc (200 mL) and filtered through celite. The organic layer was washed with water (2×200 mL), dried over MgSO4 and concentrated. The residue was purified by normal phase column chromatography (40-80% EtOAc in hexanes) to afford the title compound (7-3) as a tan solid. ESI+MS[M+H]+C16H14N3O2S=312.1
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:23](O)=[O:24])[N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:23]([C:12]1[N:13]([CH3:22])[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)[N:11]=1)=[O:24]
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: CN
Product: CNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using methylamine (0.20 mL of 2N methylamine in THF), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: O=C1CCC(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CCC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To 2,4-dimethoxybenzyl-alcohol (4.3 g, 25.6 mmol) and pyrrolidine-2,5-dione (succinimide, 1.2 g, 12.2 mmol) dissolved in tetrahydrofuran (25 ml) and dichloromethane (25 ml) was added triphenyphosphine (6.4 g, 24.4 mmol). After cooling to 0° C., diethylazidodicarboxylate (DEAD, 4.25 g, 24.4 mmol) was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm to room temperature and kept at room temperature with stirring overnight. Following concentration in vacuo, 100 ml of a (1:1)hexane/ether solution was added and this mixture was stored at 0° C. overnight. The resulting solid precipitate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (3/1—ethyl acetate/hexane) to afford 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol, 46%). 1H NMR (CDCl3) δ 7.07 (d, 1H), 6.38 (m, 2H), 4.60 (s, 2H), 3.76 (s, 3H), 2.62 (s, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]([C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2cncnc2)cc1
Product: CS(=O)(=O)c1ccc(N(Cc2ccc(Br)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-methylsulfonylphenyl)amino]pyrimidine and 4-bromobenzyl bromide
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[Cl:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:13][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.9 %

Procedure:
7-Nitro-1H-indole (1.076 g, 6.64 mmol) was dissolved in 30 ml of acetonitrile, followed by the addition of 920 mg (6.89 mmol) of N-chlorosuccinimide. The obtained mixture was stirred at room temperature for 36 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture to form a precipitate. The precipitate was recovered by filtration and washed with water to give 1.2 g of powdery 3-chloro-7-nitro-1H-indole. This powder (863 mg, 4.39 mmol) was suspended in 10 ml of ethanol, followed by the addition of 4.95 g (21.9 mmol) of stannous chloride dehydrate and 100 μl concentrated hydrochloric acid. The obtained mixture was heated under reflux for 30 minutes, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was filtered to remove insolubles. Ethyl acetate was added to the filtrate to conduct extraction. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 490 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[O:11][C:10](=[O:12])[CH2:9]1>O1CCCC1>[N:1]1([C:10](=[O:12])[CH2:9][C:8](=[O:11])[CH3:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
To a solution of piperidine (4.94 ml, 50 mmol) in dry tetrahydrofuran (100 ml) at room temperature was added 4-methyleneoxetan-2-one (3.8 ml, 50 mmol) dropwise. The reaction mixture was stirred for 24 hours at room temperature, then the solvent removed under reduced pressure and the residue dissolved in ethyl acetate. The organic phase was poured into a separatory funnel and washed with 1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The organic phase was separated and the solvent removed under reduced pressure to provide 1-(piperidin-1-yl)butane-1,3-dione (8.5 g, 100%) as a viscous oil. 1H NMR (CDCl3, 400 MHz) δ 3.56 (2H, app t); 3.54 (s, 2H); 3.24 (2H, app t); 2.28 (s, 3H); 1.70-1.5 (m, 6H). The compound was utilized in the next reaction without purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28]O)[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[C:50]([O-:53])(=[S:52])[CH3:51].[K+]>O1CCCC1.CS(C)=O.CCCCCC>[C:50]([S:52][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][C@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])(=[O:53])[CH3:51]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.3 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (4.00 g, 7.34 mmol) in tetrahydrofuran (70 ml), triethylamine (4.10 ml, 29.4 mmol) was added and methanesulfonyl chloride (1.70 ml, 22.0 mmol) was further added dropwise at −10° C., followed by stirring for 20 minutes. After warming to room temperature, a solution of potassium thioacetate (3.73 g, 29.4 mmol) in dimethyl sulfoxide (70 ml) was added to the reaction mixture. The reaction mixture was stirred for 30 minutes, diluted with hexane, washed with water and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give the titled compound (3.91 g, 88%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[CH3:15]>O1CCCC1.C(=O)([O-])O.[Na+]>[N:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[CH3:15])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(C(N)=O)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1N=C=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
Thiophosgene (2.57 mL, 34.6 mmol) was added dropwise to a stirred mixture of 4-amino-3-methylbenzamide (2.60 g, 17.3 mmol) in tetrahydrofuran (43 mL) and saturated aqueous sodium hydrogen carbonate (43 mL) at 0° C. The mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropylether to give the title compound as a brown solid (3.02 g, 15.7 mmol, 91%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[C:17]([F:18])=[C:16]([N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH3:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Na+].Cl>C1COCC1>[F:18][C:17]1[C:5]([C:4]([OH:25])=[O:3])=[CH:6][C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])=[CH:15][C:16]=1[N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH3:20]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)c(F)c(N(C)S(C)(=O)=O)c1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Dissolve the 6-fluoro-5-(methanesulfonyl-methyl-amino)-N-methyl-N-propyl-isophthalamic acid ethyl ester (110 mg, 0.30 mmol) in THF (7.5 mL). Add 1 N sodium hydroxide solution (1.48 mL, 1.48 mmol) and stir the resulting biphasic mixture vigorously for 4 h. Acidify with 1 N HCl (1.55 mL, 1.55 mmol) and concentrate the solution to a volume of about 3 mL. Extract the solution with diethyl ether (2×20 mL). Combine the organic layers, dry (magnesium sulfate) and concentrate to give the title compound as a solid (95.2 mg, 93%).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]2[S:11][CH:12]=[CH:13][C:7]=2[NH:6][C:5]1=[S:14])[CH2:2][CH3:3].I[CH3:16]>[OH-].[Na+]>[CH3:16][S:14][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[O:10])[C:8]2[S:11][CH:12]=[CH:13][C:7]=2[N:6]=1
Reactant: CI
Reactant: CCCn1c(=S)[nH]c2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCCn1c(SC)nc2ccsc2c1=O
Temperature: 0 °C

Procedure:
To a mixture containing 3.6 g of the title compound of Step A suspended in 70 mL of 10% propanolic sodium hydroxide was added 1.46 mL of iodomethane with stirring. The mixture was stirred at room temperature for 1 h, then cooled to 0° C. and filtered to obtain an off-white solid. The off-white solid was purified by partially dissolving it in methylene chloride, filtering and evaporating the filtrate to obtain 3.13 g of the title compound of Step B as a white solid melting at 136-138° C.