Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.[CH:31]1([CH2:34][NH:35][CH:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH2:38])[CH2:33][CH2:32]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:31]1([CH2:34][N:35]([CH:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:37]=[CH2:38])[C:13](=[O:15])[CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:16][CH:17]=[CH2:18])[CH2:33][CH2:32]1
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: C=CC(NCC1CC1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCC(C(=O)N(CC1CC1)C(C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (4b) (166 mg) in DCM (1 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (156 mg) and DMAP (3 mg) in DCM (1 mL) portionwise. This mixture stirred for ten min. before N-(cyclopropylmethyl)-1-phenylprop-2-en-1-amine (4a) (127 mg) in DCM (0.5 mL) was added dropwise. The reaction mixture was stirred for 1 h at −20° C. and 3 h at RT, then diluted with DCM (50 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (5% then 10% EtOAc/hexanes) to give the desired product (214 mg, 76%). 1H NMR (300 MHz) The NMR of this compound in both CDCl3 and DMSO-d6 (with elavated temperatures) was complex, thus limiting interpretation. MS APCI, m/z=415 (M+1). LC/MS 2.86 min., Method A.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5].[C:24](O)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:24]([O:1][CH2:2][CH2:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5])(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCO
Product: CCCCCCCCCCCCCCCCCCN(C)CCOC(=O)CCCCCCCCCCCCCCCCC
Temperature: 180 °C
Yield: 96.5 %

Procedure:
A four-neck flask provided with a stirrer, a thermometer and a dehydrating tube was charged with 200 g of the N-(2-hydroxyethyl)-N-methyloctadecylamine and 174 g of octadecanoic acid. The mixture was heated to 180° C. and maintained at this temperature for 12 hours while distilling off the water thus formed. Thus 350 g of N-(2-octadecanoyloxyethyl)-N-methyloctadecylamine was obtained. Based on the NMR and IR spectra, it was confirmed that this product had the following structure. This compound will be referred to as the enhancer 25 hereinafter. ##STR30##
Reaction SMILES: [CH:1]([CH:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:5]([C@@H:6]([OH:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1)=O.[OH-].[Na+].Cl.Cl.[NH2:28][CH2:29][CH2:30][O:31][NH2:32]>O1CCOCC1.O.O>[NH2:28][CH2:29][CH2:30][O:31]/[N:32]=[CH:1]\[C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:5]([C@@H:6]([OH:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1
Reactant: C[C@]12CCC(C=O)C[C@@H]1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](/C=N\OCCN)C[C@@H]1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
A solution of 3-formyl-5α-androstan-6α,17β-diol (II-c, Prep. 3, 240 mg) in dioxane/water (2/1, 30 mL) was treated with sodium hydroxide (0.1 N) to pH=13-14 and stirred for 15 minutes, then a solution O-(2-aminoethyl)-hydroxylamine dihydrochloride (170 mg) in water (3 mL) was poured in. After 1 hr. the organic solvent was distilled off and the acqueous solution was extracted with chloroform (5×20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO2, chloroform/methanol/ammonia 90/10/1) to give (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol, which was dissolved in ethyl acetate/methanol 70/30 and treated with oxalic acid to give 85 mg of (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate (I-d) as a white solid mp 190-192° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].Cl.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[CH3:30].C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[CH3:30]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cn1ccc2c(N)cccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)c2cc1OC
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.028 g, 0.10 mmol), 4-amino-1-methylindol hydrochloride (0.026 g, 0.14 mmol) and sodium acetate (0.013 g, 0.16 mmol) in DMF (0.6 ml) was heated at 100° C. for 8 h. After cooling, the mixture was diluted with water and made alkaline with saturated NaHCO3. The gummy precipitate was collected and crystallized from methanol-water to give the title compound (24 mg, 60%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH3:29]>CN1C(=O)CCC1>[C:27]([C:25]1[N:26]=[C:21]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:22]([CH3:29])=[CH:23][CH:24]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1ccc(C#N)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)nc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (491 mg, 2.62 mmol) in NMP (4 mL) was added Cs2CO3 (1025 mg, 3.15 mmol). The mixture was stirred at 0° C. for 1 hour at which time 6-chloro-5-methylpicolinonitrile (400 mg, 2.62 mmol) was added. The reaction mixture was heated at 140° C. for 1 hour in a microwave reactor to give the title compound in a crude reaction mixture that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:13])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1c[nH]c2ccc(F)cc12
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccc(F)cc12
Yield: 83 %

Procedure:
To a solution of 5.1 g of 5-fluoroindole-3-carboxylic acid in 150 ml of tetrahydrofuran were added 5.5 g of 4-amino-1-benzylpiperidine and 5.8 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed under heating on a water bath for 3 hours. After completion of the reaction, the precipitated dicyclohexylurea and a part of the objective product were filtered and suspended in 200 ml of hot tetrahydrofuran. The suspension was stirred and the insoluble dicyclohexylurea was filtered off with suction. The combined filtrates were concentrated and the residue was crystallized with ethyl acetate. The resulting crystals were filtered to give 8.3 g of N-(1-benzyl-4-piperidyl)-5-fluoroindole-3-carboxamide. The product, when recrystallized from a mixture of ethyl acetate and ethanol, melts at 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34].Cl>>[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH:34][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=[C:2]([Cl:1])[N:3]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1cccc(I)c1
Agent: Cl
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (63, 375 mg, 0.87 mmol) and 3-iodobenzylamine.HCl (1.31 mmol, 352 mg). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 366 mg (0.67 mmol, 77%), mp 80–82° C.; Rf 0.53 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.97 (bs, 1H, NH), 8.40 (s, 1H, H-8), 7.74 (s, 1H, CCHCI), 7.60 (d, 1H, J=6.87 Hz, CCHCHCH), 7.35 (d, 1H, J=8.24 Hz, CCHCH), 7.12 (t, 1H, J=7.21 Hz, CCHCH), 5.84 (d, 1H, =4.46 Hz, H-1′), 5.56 (d, 1H, J=5.49 Hz, OH-2′), 5.30 (d, 1H, J=5.15 Hz, OH-3′), 4.60 (d, 2H, J=4.46 Hz, NHCH2), 4.51 (d, 1H, J=5.15 Hz, H-2′), 4.14–4.11 (m, 1H, H-3′), 4.02 (q, 1H, J=3.43 Hz, H-4′), 3.63–3.58 (m, 2H, H-5′), 3.49 (q, 2H, J=6.52 Hz, CH2CH3), 1.13 (t, 3H, J=6.52 Hz, CH3); MS m/z 546 (+H)+; Anal. (C19H21ClIN5O4.0.8 HCON(CH3)2) C, H, N.
Reaction SMILES: COC1N=C(C)C=CC=1C([O-])=O.CN(C=O)C.[C:18]([O:22][C:23]([N:25]([CH3:48])[C:26]([C:28]1[C:29]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[N:30][N:31]2[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([F:40])[C:32]=12)=[O:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].Br[C:50]1[C:51]([CH3:62])=[N:52][C:53]([O:60][CH3:61])=[C:54]([CH:59]=1)[C:55]([O:57][CH3:58])=[O:56]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(N(CC)CC)C>[C:18]([O:22][C:23]([N:25]([CH3:48])[C:26]([C:28]1[C:29]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[N:30][N:31]2[CH:36]=[CH:35][C:34]([C:50]3[C:51]([CH3:62])=[N:52][C:53]([O:60][CH3:61])=[C:54]([CH:59]=3)[C:55]([O:57][CH3:58])=[O:56])=[C:33]([F:40])[C:32]=12)=[O:27])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(B(O)O)c(F)c12
Reactant: COC(=O)c1cc(Br)c(C)nc1OC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccn3nc(-c4ccc(F)cc4)c(C(=O)N(C)C(=O)OC(C)(C)C)c3c2F)c(C)nc1OC
Temperature: 50 °C

Procedure:
Methyl 5-(3-(tert-butoxycarbonyl)methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate. To a degassed solution containing palladium (II) acetate (0.014 g, 0.063 mmol) and DMF (0.70 mL) was added 1,1′-Bis(diphenylphosphino)ferrocene. The solution was heated to 50° C. and maintained for 15 minutes. The solution was cooled to room temperature and 3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-ylboronic acid (0.10 g, 0.21 mmol) and methyl 5-bromo-2-methoxy-6-methylnicotinate (0.054 g, 0.21 mmol) were added. Triethylamine was then added and the solution was heated at 90° C. for 3 h. The mixture was cooled to room temperature, filtered to remove solids and concentrated. Purification on silica gel (0-75% ethyl acetate/hexanes, 60 min gradient, 25 g column) afforded methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate as a white residue. 1H NMR (400 MHz, MeOD) δ ppm 8.60 (1H, d, J=7.03 Hz), 8.13 (1H, s), 7.77 (2H, d, J=3.26 Hz), 7.75 (1H, s), 7.24 (2H, s), 6.99 (1H, s), 4.07 (3H, s), 3.89 (3H, s), 3.29 (3H, s), 2.45 (3H, s), 1.01-1.13 (9H, m). LCMS retention time: 3.803 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 3 micron, C18, 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 567 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:4][CH2:3]1.O.NN.Cl.C([O-])([O-])=O.[K+].[K+]>C(O)C.CO.C(Cl)Cl>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Agent: NN
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN1CCN(CCCN)CC1
Temperature: 25 °C
Yield: 39 %

Procedure:
A solution of N-(3-(4-methylpiperazin-1-yl)propyl)phthalimide (6.2 g, 21.6 mM) and hydrazine monohydrate (1.13 g, 26 mM) in ethanol (60 mL) and methanol (60 mL) was refluxed for 4 hours. After cooling to room temperature, concentrated HCl (2.4 mL) was added and the mixture heated under reflux for another hour. After removing the solvent, water (100 mL) was added, the mixture stirred and insoluble material removed by filtration. Solid K2CO3 (1.2 eq) and CH2Cl2 (100 mL) was added to the aqueous layer; the mixture stirred, and was then filtered. The organic layer was washed with water (3×20 mL). The combined aqueous layers were washed with Et2O. Water was removed from the organic layers, which were then dried and evaporated to give 1-(3-aminopropyl)-4-methylpiperazine as an oil in 39% yield. 1H NMR (CDCl3): δ=1.55 (m, 2H, CH2), 2.20 (s, 3H, CH3), 2.34 (t, 2H, CH2), 2.67 (t, 2H, CH2). MS (ES+): 157.9.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][N:25]=1)(=O)=O>C(O)C>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[N:25][CH:26]=1)[CH3:31]
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: CCc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1

Procedure:
0.5 g of 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione is dissolved in ethanol (7 ml) with KOH (0.25 g) and mixed at room temperature for 2 hours. To the obtained salt 2-(5-ethyl-2-pyridyl)ethyl tosylate is added and the reaction mixture is refluxed for 5 hours. After cooling the precipitated salt is filtered off, pH is adjusted and the solvent is evaporated. The semi-solid residue is mixed in water and the solid portion of 5-[[4-[2-(5-ethyl-2-pyridyl) ethoxy]phenyl]methyl]-2.4-thiazolidinedione (0.18 g) is filtered off and recrystallized from the mixture DMF-water.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[ClH:20].[N:23]1([CH2:22][CH2:21][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1OCCN1CCOCC1

Procedure:
B-16a is prepared analogously to B-15a starting from N-hydroxyphthalimide (5.0 g, 30.7 mmol), potassium carbonate (4.24 g, 30.7 mmol) and N-(2-chloroethyl)morpholine hydrochloride (6.27 g, 33.7 mmol). The product is isolated as the hydrochloride. Yield: 4.22 g.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl.Br[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:14]([NH:13][C:9]1[CH:8]=[C:7]([C:4]2[CH2:5][CH2:6][N:1]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH:3]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cccc(C2=CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1

Procedure:
A solution of N1-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide.HCl (8.24 mmol), tert-butyl N-(3-bromopropyl)carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight. The solids were removed by filtration, the solution was concentrated in vacuo and the product was chromatograghed, giving the desired product (110 mg). 1H NMR (CDCl3) δ 7.65 (s, 1H), 6.98 (s, 1H), 7.45 (d, 1H, J=7.8 Hz), 7.16 (apparent t, 1H, J=7.8 Hz), 7.10 (d, 1H, J=7.8 Hz), 6.02 (s, 1H), 5.23 (b, 1H), 3.40 (b, 2H), 3.30–1.80 (m, 10H), 2.18 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:1]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 72 h
Yield: 56.9 %

Procedure:
The sultam 3 (R2, R3=H; R10=t-Bu; n=2) (198 mg) was dissolved in methylene chloride along with copper (II) acetate (153 mg), triethylamine (426 mg), 4 Å molecular sieves (180 mg), and 4-benzyloxybenzeneboronic acid (384 mg). The reaction was stirred open to air for 3 days. The mixture was filtered and concentrated. Purification of the crude material by silica gel chromatography (10-45% ethyl acetate/hexanes) provided the sulfonamide 4 (R2, R3=H; R=4-benzyloxyphenyl; R10=t-Bu; n=2) (190 mg, 54%). MS found: (M+Na+MeCN)+=481. (39b) The sulfonamide 4 (R2, R3=H; R=4-benzyloxyphenyl; R10=t-Bu; n=2) (190 mg) was dissolved in methanol prior to the addition of 20% Pd(OH)2/C (20 mg). A hydrogen balloon was added, and the solution was stirred overnight. The hydrogen balloon was removed, and the solution was filtered and concentrated. This gave the phenol 4 (R2, R3=H; R=4-hydroxyphenyl; R10=t-Bu; n=2) (quant.) ready for subsequent reactions. MS found: (M+Na+MeCN)+=391. (39c) A solution of phenol 4 (R2, R3=H; R=4-hydroxyphenyl; R10=t-Bu; n=2) (149 mg), potassium carbonate (314 mg), and 2-methyl-4-chloromethylquinoline (87 mg) in acetonitrile was heated at reflux for 2 hr. The solution was cooled to rt, filtered, and concentrated. The crude material was purified by silica gel chromatography (20-65% acetonitrile/water) to provide ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=t-Bu; n=2) (140 mg) MS found: (M+H)+=483. (39d) To a solution of ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=t-Bu; n=2) (140 mg) in methanol was added thionyl chloride (3.0 g). The mixture was allowed to stir for 1 h and concentrated to give methyl ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=Me; n=2) (quant.). MS found: (M+H)+=441. (39e) The ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=Me; n=2) (128 mg) was treated as in (35b) to yield the title hydroxamate 5 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; n=2) (15 mg). MS found: (M+H)+=442.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH2:9]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Brc1ccc2c(c1)NCC21CCSCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2(CCSCC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred ice-cooled solution of 6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] (0.7 g, 2.46 mmol), 4-dimethylaminopyridine (0.03 g, 0.25 mmol) and Et3N (0.37 g, 3.69 mmol) in DCM (25 mL) was added acetyl chloride (0.21 mL, 2.96 mmol) via syringe. The resulting mixture was stirred at 0° C. for 5 min and at rt for 1.5 h. After this time the mixture was poured into ice and 2N aqueous HCl and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. Purification by column chromatography (EtOAc:hexanes) gave 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] as an off-white solid. Mass Spectrum (ESI) m/e=326.0 [(M+1) (79Br)] and 328.0 [(M+1) (81Br)].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:14])=[N:9]2)([O-:3])=[O:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:33][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2nc(CBr)ccc12

Procedure:
A solution that consists of 800 mg (4.25 mmol) of 5-nitro-2-methylquinoline in 20 ml of tetrachloromethane is mixed with 11 mg (0.04 mmol) of benzoyl peroxide and 794 mg (4.46 mmol) of N-bromosuccinimide. The reaction mixture is allowed to reflux for 8 hours in the presence of UV light. Insoluble components are filtered off, and the filtrate is concentrated by evaporation. After purification on silica gel with hexane-ethyl acetate (0-100%), 320 mg (28% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:16][C:17]1[CH:18]=[C:19]([C:24](Cl)=[O:25])[C:20]([Cl:23])=[N:21][CH:22]=1.BrC1C=C(C(O)=O)C(O)=NC=1.O=S(Cl)Cl>CC#N>[Cl:23][C:20]1[C:19]([C:24]([NH:1][C:2]2[C:3]([NH:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:25])=[CH:18][C:17]([Br:16])=[CH:22][N:21]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CCNc1ncccc1N
Agent: O=C(O)c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCNc1ncccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a cooled solution of 3-amino-2-(ethylamino)pyridine (30.6 g, 223 mmol) in MeCN (740 mL) was added solid NaHCO3 (56.3 g, 669 mmol). After 5 min, crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989, 19, 553-559 (incorporated herein by reference) but with omission of the aqueous work-up] was added (1 equiv., 223 mmol). After 2 h, the reaction mixture was poured over ice/H2O (1.5 L) and the resulting solid was filtered, rinsed with H2O and then hexane. After drying under reduced pressure overnight, the title compound was obtained as a black solid (54.9 g, 69% yield).