Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C)C=O>[O:28]1[CH2:27][CH:26]1[CH2:25][O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13]
Reactant: O=C1OCCC1Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCC[C@@H]1Cc1ccccc1OCC1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.2 %

Procedure:
Dimethylformamide (100 ml) and potassium carbonate (10 g) were added to α-(2′-hydroxybenzyl)-γ-butyrolactone (5.0 g), and (S)-glycidyl nosylate (6 g) was added. The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (6.1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N+](C1C=CC=CC=1)([O-])=O.[C:18]([C:20]1[CH:45]=[CH:44][CH:43]=[CH:42][C:21]=1[O:22][C:23]1[CH:24]=[C:25]([NH2:41])[C:26]([NH2:40])=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1)#[N:19]>CO>[C:18]([C:20]1[CH:45]=[CH:44][CH:43]=[CH:42][C:21]=1[O:22][C:23]1[C:28]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=2)=[CH:27][C:26]2[NH:40][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:41][C:25]=2[CH:24]=1)#[N:19]
Reactant: O=Cc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)cn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
0.007 ml of pyridine-2-carboxaldehyde and 0.5 ml of nitrobenzene were added to a methanol (1 ml) solution of 37 mg of 4-(2-cyano-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in (step 5), and the reaction liquid was stirred overnight at 120° C. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=20/1) and through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[CH2:10][C@@H:11]3[C@@H:16]([CH2:17][C:8]=2[CH:7]=[CH:6][C:5]=1[O:18]C)[NH:15][CH2:14][CH2:13][CH2:12]3.[BrH:20]>>[BrH:20].[NH:15]1[C@H:16]2[C@@H:11]([CH2:10][C:9]3[C:4]([OH:3])=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=3[CH2:17]2)[CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1OC)C[C@H]1CCCN[C@@H]1C2
Agent: Br
Agent: Cl
Product: Oc1ccc2c(c1O)C[C@H]1CCCN[C@@H]1C2
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Intermediate II (19 mg) was placed in a microwave reactor vial and 48% HBr was added. The vial was sealed with a septum, and mixture was stirred at 160° C. for 0.5 h under microwave irradiation. The crude mixture was concentrated in vacuo, and the residue was purified by preparative LC/MS. Yield of example 2a1: 12.6 mg as a white solid. LC/MS (method 17): RT 1.48 min, ELSD 95.9%, UV 87.1%. MH+: 220.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+]>CN(C)C=O.CO.O>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1/[CH:8]=[CH:24]/[C:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1)=[O:25]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(CO)CO)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) (8.0 g, 24.8 mmol) and 4-acetylbenzenesulfonamide (4.9 g, 24.8 mmol) were dissolved in a dimethylformamide-methanol solution (170 mL, 7:3). After complete dissolution, lithium methoxide (3.8 g, 99.2 mmol) was added and the resulting red-orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (6×200 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (150 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 7.0 g (60%) of the title compound as a light orange solid, mp 123–124° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.25–8.29 (m, 3H), 7.90–8.11 (m, 4H), 7.66 (d, 1H, J=3.0 Hz), 7.56 (brs, 1H), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz), 6.88 (s, 1H), 4.67 (t, 2H, J=10.8 Hz), 4.24 (d, 2H, J=6.0 Hz), 4.00 (s, 3H), 3.54–3.65 (m, 4H), 2.09–2.13 (m, 1H). MS (ESI) m/z=504 ([M+H]+, 100%). Anal. Calcd. C24H25NO7S2H2O: C, 57.24; H, 5.00; N, 2.78; S, 12.73. Found: C, 56.72; H, 5.27; N, 2.71; S, 12.11.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][C:34](B(O)O)=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[O:15])[C:5]4[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=4[N:7]=3)=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: OB(O)c1ccc2[nH]nnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]nnc4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 1H-1,2,3-benzotriazol-5-ylboronic acid (39.7 mg, 0.243 mmol), DMSO(2 mL), sodium carbonate (0.281 mL, 0.562 mmol) and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 22 mg (26%). LCMS E-S (M+H)=457.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, 6 J=6.4 Hz, H), 2.14 (s, 3 H), 2.24 (s, 3 H), 4.43 (d, J=4.3 Hz, 2 H), 5.31-5.46 (m, 1 H), 5.91 (s, 1 H), 8.07 (br. s., 1 H), 8.34 (s, 1 H), 8.41 (m, 2 H), 8.85 (br. s., 1 H), 9.02 (br. s., 1 H), 11.59 (br. s., 1 H).
Reaction SMILES: [OH:1][C@H:2]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[C:17]([S:25][CH:26]([CH3:28])[CH3:27])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:4].[OH-].[Na+].[ClH:38]>CO>[ClH:38].[OH:1][C@H:2]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([S:25][CH:26]([CH3:28])[CH3:27])[CH:16]=2)=[CH:13][CH:14]=1)[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1SC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Sc1cc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethoxy]-3-(isopropylthio)-4-biphenylcarboxylate (110 mg) in methanol (1.65 ml) was added sodium hydroxide aqueous solution (1N 1.11 ml) and stirred at room temperature overnight. To the mixture was added hydrochloric acid aqueous solution (1N, 1.22 ml) and concentrated in vacuo. The residue was solved with methanol, added hydrogen chloride 1,4-dioxane solution (4M), concentrated in vacuo and dried to give 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-amino]ethoxy]-3-(isopropylthio)-4-biphenylcarboxylic acid hydrochloride (97 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1>[Pd].C(Cl)Cl.CO.[H][H]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cc3cc([N+](=O)[O-])ccc3n2C)ccc1C#N
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2cc3cc(N)ccc3n2C)ccc1C#N

Procedure:
Prepared analogously to Example 1c from 4-(1-methyl-5-nitro-1H-indol-2-yl)-methyl-benzonitrile, palladium on activated charcoal in methylene chloride/methanol and hydrogen.
Reaction SMILES: [F:1][C@@:2]12[C@:15]3([CH3:16])[C:10](=[CH:11][C:12](=[O:17])[CH:13]=[CH:14]3)[C@@H:9]([F:18])[CH2:8][C@H:7]1[C@@H:6]1[CH2:19][C@@H:20]3[C@:24]([C:25](=[O:31])[CH2:26][O:27]C(=O)C)([C@@:5]1([CH3:42])[CH2:4][C@@H:3]2[OH:43])[CH2:23][N:22]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH2:21]3>CO>[F:1][C@@:2]12[C@:15]3([CH3:16])[C:10](=[CH:11][C:12](=[O:17])[CH:13]=[CH:14]3)[C@@H:9]([F:18])[CH2:8][C@H:7]1[C@@H:6]1[CH2:19][C@@H:20]3[C@:24]([C:25](=[O:31])[CH2:26][OH:27])([C@@:5]1([CH3:42])[CH2:4][C@@H:3]2[OH:43])[CH2:23][N:22]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH2:21]3
Reactant: CC(=O)OCC(=O)[C@@]12CN(c3ccc4ccccc4n3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(c5ccc6ccccc6n5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A solution of compound 16 (171 mg, 0.290 mmol) in MeOH (4 ml) was degassed bubbling nitrogen at RT for 20 minutes. After cooling to 0° C. K2CO3 (12 mg, 0.0.87 mmol) was added, and the mixture was stirred for 1 hour. The mixture was partitioned between AcOEt and brine. The organic phase was separated, dried over Na2SO4 and concentrated. The crude was purified by preparative HPLC(CH3CN/H2O without CF3COOH) to give the title compound (45 mg, 28% yield).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][CH:42]=1)[CH2:26][N:27]([CH3:39])[C:28](=[O:38])[CH2:29][NH:30]C(=O)OC(C)(C)C.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C(Cl)(Cl)Cl.O>[CH3:39][N:27]([CH2:26][C:25]1[CH:40]=[CH:41][CH:42]=[C:23]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH:24]=1)[C:28](=[O:38])[CH2:29][NH2:30]
Reactant: CC1(C)OB(c2cnc(N3CCCCC3)nc2)OC1(C)C
Reactant: CN(Cc1cccc(Br)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(Cc1cccc(-c2cnc(N3CCCCC3)nc2)c1)C(=O)CN
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a mixture of 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (14 mg), tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (9 mg), and DMF (0.2 ml) were added tetrakis(triphenylphosphine)palladium (3 mg), sodium carbonate (5 mg), and water (0.1 ml), followed by stirring at 60° C. overnight. After cooling to room temperature, to the reaction mixture was added CHCl3 (2 ml), and the reaction mixture was filtered in a column preconditioned by the addition of 0.8 ml of water to a diatomaceous earth column (manufactured by Varian Inc., ChemElute 1 ml). The obtained filtrate was concentrated, and then to the residue were added MeOH (0.5 ml) and a 4 M hydrogen chloride/EtOAc solution (0.5 ml), followed by leaving to stand for 30 minutes. Thereafter, the reaction mixture was concentrated and the compound was purified by preparative liquid chromatography (MeOH/0.1% aqueous formic acid solution) to obtain N-methyl-N-{3-[2-(piperidin-1-yl)pyrimidin-5-yl]benzyl}glycinamide (3.8 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[N:16][N:15]3[CH:23]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Br-].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Zn+]>C1COCC1.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]>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:23]=[C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[CH:3]=3)[N:13]=2)[N:16]=1)[CH3:22]
Reactant: [Zn+]c1ccccn1
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(Br)c3)cn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(-c4ccccn4)c3)cn2n1
Temperature: 60 °C
Yield: 8.8 %

Procedure:
To a solution of 2-(3-bromo-4-(trifluoromethyl)phenyl)-6-ethoxyimidazo[1,2-b]pyridazine (0.025 g, 0.0647 mmol) in THF (0.647 mL) containing pyridin-2-ylzinc(II) bromide (0.323 mmol) is added Pd(dppf)Cl2 (0.0194 mmol). The mixture is heated at 60° C. for 12 hours, then cooled, quenched with sat. aqueous NaHCO3 (1 mL) and extracted with CH2Cl2 (3×3 mL). Organic layer is collected and concentrated to dryness. The crude product is purified via preparative TLC using CH2Cl2:EtOAc:methanol (1:1:0.1) to afford 0.0022 g (9%) of the title compound as a white solid: Rf 0.35 (1:1 EtOAc:hexanes); LCMS (m/z)=385.4 [M+H]+, tR=2.69 min. (compound same as Example 218)
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.N1C=CC=CC=1.[CH2:16]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:36]=1)[CH2:32]O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:16]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:36]=1)[CH2:32][Cl:8])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCC)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCC)c1
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
A 1 L RBF was prepared containing 5 mL dry dichloromethane, a stir bar, a septum, an out-vent line, and a nitrogen gas line. DMF (3.3 ml, 40.3 mmol) was added and the reaction mixture was cooled in an ice bath. Thionyl chloride (2.7 ml, 40.3 mmol) was added and the reaction mixture was allowed to stir for 10 minutes. The ice bath was then removed and the reaction was allowed to stir for an additional 10 minutes. The RBF was placed in the ice bath and a mixture of pyridine (2.72 ml, 33.6 mmol) and 3,5-didodecoxybenzyl alcohol (13.2 g, 33.6 mmol) were added and dissolved in approximately 50 mL dichloromethane, drop-wise through the septum. After 15 minutes, the RBF was removed from the ice bath and the reaction mixture was stirred for 2 hours. The reaction mixture was then placed in a refrigerator overnight. The solvent was removed by rotary evaporation. To the remaining organic matter, 100 mL of 50% ether/hexanes was added to dissolve the desired derivative. A solid orange precipitate formed, the remaining liquid was decanted off, and the precipitate was washed with an additional 100 mL 50% ether/hexanes. The combined organic liquid was vacuum filtered through silica gel into a RBF and the solvent was removed under reduced pressure. Trace solvent was removed by high vacuum overnight. There was a 10.2 g yield or a 88.5% yield. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 6H, CH2CH3), 1.15-1.6 (m, 36H, CH2(CH2)9), 1.76 (p, J=8.0, 4H, OCH2CH2), 3.9 (t, J=6.6, 4H, OCH2CH2), 4.5 (s, 2H, ArCH2), 6.36 (t, J=2.2, 1H, ArH), 6.50 (d, J=2.2, 2H, ArH).
Reaction SMILES: [NH:1]([CH2:3][C:4](O)=O)[CH3:2].[CH3:7][O:8][C:9](=[O:12])[CH:10]=[CH2:11].C=O>C1(C)C=CC=CC=1>[CH3:2][N:1]1[CH2:3][CH2:4][CH:10]([C:9]([O:8][CH3:7])=[O:12])[CH2:11]1
Reactant: CNCC(=O)O
Reactant: C=CC(=O)OC
Agent: C=O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A solution of sarcosine (30 g, 0.34 mol), methylacrylate (29 g, 0.34 mol) and paraformaldehyde (20.2 g, 0.67 mol) in toluene (3 l) was refluxed in a Dean-Stark trap apparatus for 0.5 h. The reaction mixture was cooled to room temperature and stirred for 16 h. Filtration through cotton wool and concentration under vacuum gave the title ester as a pale yellow liquid (21 g) m/e 143 (M+); δ(250 MHz, CDCl3) 2.05-2.16 (2H, m, CH2); 2.36 (3H, s, N--Me); 2.48-2.84 (4H, m, 2 of CH2 --N); 2.98-3.10 (1H, m, CH--CO2Me); 3.70 (3H, s, CO2Me).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([C:17]1[C:22]([Br:23])=[CH:21][CH:20]=[C:19]([Si:24]([CH3:27])([CH3:26])[CH3:25])[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[I:28]I.S([O-])([O-])=O.[Na+].[Na+]>CCCCCC.C1COCC1.COC(C)(C)C.O>[C:13]([C:17]1[C:22]([Br:23])=[C:21]([I:28])[CH:20]=[C:19]([Si:24]([CH3:27])([CH3:26])[CH3:25])[N:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc([Si](C)(C)C)ccc1Br
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)c1nc([Si](C)(C)C)cc(I)c1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Procedure analogous to P. N. W. Baxter, Chem. Eur. J. 2003, 9, 2531: 65.6 ml (105 mmol) of n-BuLi, 1.6 M in hexane, are added dropwise over the course of 15 min. to a vigorously stirred mixture, cooled to −78° C., of 14.0 ml (100 mmol) of diisopropylamine and 500 ml of THF. The reaction mixture is stirred at −78° C. for 45 min. and then cooled to −90° C. A solution, pre-cooled to −90° C., of 30.1 g (105 mmol) of 2-tert-butyl-3-bromo-6-trimethylsilylpyridine in 100 ml of THF is added dropwise at such a rate that the temperature does not exceed −80° C. After stirring at −90° C. for a further 1 h, the reaction mixture is warmed to −75° C., stirred at −75° C. for a further 15 min. and then re-cooled to −90° C. A solution of 30.5 g (120 mmol) of iodine in 80 ml of THF is then added dropwise at such a rate that the temperature does not exceed −75° C., the reaction mixture is stirred at −75° C. for a further 4 h and allowed to warm to room temperature. After addition of 10 ml of water and removal of the THF in vacuo, 1000 ml of tert-butyl methyl ether are added, and 100 ml of saturated sodium sulfite solution are added dropwise to the mixture in order to reduce excess iodine. The org. phase is separated off, washed three times with 300 ml of water each time, dried over sodium sulfate, the solvent is removed in vacuo, and the residue is recrystallised once from cyclohexane. Yield: 14.8 g (36 mmol), 34%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CO>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cccc(NC(=O)c4cccc(Cl)c4)c3C2=O)CCC(=O)NC1=O
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added 3-chlorobenzoyl chloride (0.12 g, 0.70 mmol) The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (73%) of product as an off-white solid: mp 283–285° C.; 1H NMR (DMSO-d6) 11.06 (s, 1H), 10.43 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.98–7.61 (m, 6H), 2.80–2.51 (m, 3H), 2.11–2.01(m, 1H), 1.92 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 171.72, 171.64, 168.53, 167.11, 163.55, 135.81, 135.75, 135.35, 133.59, 132.07, 131.03, 130.73, 127.03, 126.37, 125.58, 118.43, 118.06, 58.80, 28.90, 28.37, 20.84; Anal. Calcd. For C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87 Found: C, 59.00; H, 3.80; N, 9.70.
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:22][C:21](=O)[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:9]2)=[CH:5][CH:4]=1.Cl.[CH3:33][O:34][NH2:35].N1C=CC=CC=1>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:22][C:21](=[N:35][O:34][CH3:33])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:9]2)=[CH:30][CH:31]=1
Reactant: CON
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2)NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CC2(CCCN(Cc3ccc(F)cc3)C2)Oc2ccc(/C=C/C(=O)NO)cc21
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of (E)-3-(1′-(4-fluorobenzyl)-4-oxospiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide hydrochloride (80 mg, 0.179 mmol) and O-methylhydroxylamine hydrochloride (32.6 mg, 0.390 mmol) in ethanol (2 ml) and pyridine (0.031 ml, 0.390 mmol) was heated at 80° C. for 2 h. The solvent was removed in vacuo and the crude product was purified by preparative LC-MS to give the title compound (33.04 mg) as its trifluoroacetate salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([N:23]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH3:24])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][C@@H:43]([N:50]=[C:51]=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:51]([NH:50][C@@H:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:42])=[O:52])[C@@H:17]2[C:21]([N:23]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH3:24])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)[C@H]1NC(=O)[C@@H]1Cc1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)S(=O)(=O)c1ccc(F)cc1
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)[C@H]1C(=O)N(C)S(=O)(=O)c1ccc(F)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 99 in DMF (0.75 mL) was added (R)-α-methylbenzylisocyanate (6 uL, 2.0 eq.) and TEA (8.5 uL, 3.0 eq.). The reaction was stirred under an atmosphere of argon for 20 hours. The reaction was then concentrated in vacuo and taken on to the next step without further purification.