Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C@@H:12]([CH2:14][CH2:15][CH3:16])[C@@H:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]2.CON.[OH-].[Na+]>Br>[ClH:1].[CH2:14]([C@H:12]1[C:13]2[C:4]([OH:3])=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][C@H:11]1[NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]
Reactant: CCCN[C@H]1CCc2cccc(OC)c2[C@H]1CCC
Agent: Br
Agent: CON
Agent: Cl
Product: CCCN[C@@H]1CCc2cccc(O)c2[C@@H]1CCC
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A solution of 0.57 g (2.0 mmol) methoxy-amine cis(±)-1,2,3,4-tetrahydro-8-methoxy-N,1-di-propyl-2-naphthalenamine hydrochloride in 10 mL 48% hydrobromic acid was refluxed (bath temperature, 120° C.) for eight hours. TLC analysis showed no starting material remaining. The mixture was cooled to room temperature, treated with 20% sodium hydroxide to pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The oil was converted to HCl-salt with excess anhydrous hydrochloric acid and recrystallized from ethyl acetate to give 0.36 g (64%) of pure title compound as a white solid: m.p. 244°-245° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH2Cl2 (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10% solution). The flask was capped and the mixture stirred 4 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) to afford 44.2 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Rf =0.23). (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)N(CCCCl)C1=O

Procedure:
A mixture of 5,5-dimethylhydantoin (5.25 g), 1-bromo-3-chloropropane (8.5 mL), and Cs2CO3 (20.78 g) in 40 mL DMF was allowed to react overnight. The reaction was poured into 125 mL H2O, extracted with ether, and the combined extracts dried over MgSO4. The crude extract was filtered, then reduced in vacuo to yield a clear oil. The residue was chromatographed (50% EtOAc in hexanes) to yield 3-(3-chloropropyl)-5,5-dimethylimidazolidinedione as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:17])=[C:11]([N+:1]([O-:4])=[O:2])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1
Reactant: O=c1cc(O)c2ccc(Br)cc2o1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1oc2cc(Br)ccc2c(O)c1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (27 ml) was added to a stirred suspension of 7-bromo-4-hydroxycoumarin (m.p. 247.5°-248.5°; 4.18g) in chloroform (400 ml) at room temperature over 1.5 hours. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (100 ml) added to the residue. Filtration gave the product, m.p. 155°-7°, (C9H4NO5Br requires C, 37.79; H, 1.41; N. 4.90; Br, 27.94. Found: C, 37.46; H, 1.45; N, 4.78; Br, 27.93).
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C([O:22][C:23]([C:25]1[C:26]2[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=2[S:28][C:29]=1[NH2:30])=O)C>>[CH2:1]([N:5]1[C:23](=[O:22])[C:25]2[C:26]3[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=3[S:28][C:29]=2[N:30]=[C:6]1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)CC2
Reactant: CCCCNC(=O)c1cc(OC)c(OC)c(OC)c1
Product: CCCCn1c(-c2cc(OC)c(OC)c(OC)c2)nc2sc3c(c2c1=O)CC(C)CC3

Procedure:
According to the method described for the compound No. 1 using N-butyl-3,4,5-trimethoxybenzamide a nd 2-amino-5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester as starting materials.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([C:14](=[O:30])[N:15]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=3[CH3:29])[C@H:16]2[CH2:18][CH3:19])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+].CO>C1COCC1.CCOC(C)=O>[CH2:18]([C@@H:16]1[N:15]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=2[CH3:29])[C:14](=[O:30])[N:13]2[CH2:12][CH2:11][C@@H:10]([OH:9])[C@@H:17]12)[CH3:19]
Reactant: CC[C@H]1[C@@H]2[C@H](OC(=O)c3ccccc3)CCN2C(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc(C#N)c(Cl)c1C
Yield: 89.6 %

Procedure:
Compound 87A (64 mg, 0.15 mmol) was dissolved in 1.5 mL of THF, treated with 1N KOH in anhydrous methanol (0.32 mL, 0.32 mmol) at rt for 2 h. Diluted the reaction mixture with 30 mL EtOAc, washed with saturated aqueous NaHCO3 solution (10 mL), brine (10 mL×2), dried over MgSO4, filtered and concentrated. The resulting mixture was purified by reverse phase HPLC (Phenomenex Luna 30×250 mm S5 C18, 30 min. gradient time, 25 mL/min, 30-100% B solvent, A=10% MeOH/water, B=90% MeOH/Water), provided the title compound (43 mg). Analytical HPLC retention time 2.947 min (purity 98%). Condition: YMC Combiscreen ODS-A C18 4.6×50 mm column, 4 min gradient, 4 mL/min flow, 0-100% B solvent, A=10% MeOH/water+0.1% H3PO4, B=90% MeOH/Water+0.1% H3PO4. MS (ES) m/z 320.24 [M+H]+, HRMS calcd for [M+H] 320.1166, found 320.1152.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:29])[N:22]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl 1H-tetrazole in 25 mL of acetonitrile was added at ambient temperature and pressure 0.54 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 0.3 mL of DBU. The reaction mixture was stirred for three hours, added to 25 g of ice and acidified to pH 3 with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried to yield 0.74 g of the desired product, melting point at 213°-216° C. Infrared absorption spectra showed peaks at 1710, 1605 and 1570 cm-1, consistent for the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]([C:40]1[CH:41]=[CH:42][C:43](=[C:45]([CH3:47])[CH3:46])[CH:44]=1)([CH3:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>C1COCC1.CCOCC.O>[CH3:39][C:34]([C:40]1[CH:41]=[CH:42][CH:43]([C:45]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:47])[CH3:46])[CH:44]=1)([CH3:33])[CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)=C1C=CC(C(C)(C)CC(C)C)=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(C)(C)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 2.16 g (7.8 mmol) of 3,6-di-tert-butylfluorene in 35 ml of THF, 5.0 ml (8.2 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 2.16 g (10.6 mmol) of 3-(1,1,3-trimethylbutyl)-6,6-dimethylfulvene in 10 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 5 days. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.80 g (5.80 mmol) of a white solid (yield: 74%). The analyzed values are given below.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:22]=[C:21]3[C:16]([N:17]=[C:18]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[C:19]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[C:20]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[C:21]3[C:16](=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:22]=3)[N:17]=[C:18]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C:19]=2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc3nn(C4CCNCC4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.62 g, 1.1 mmol, obtained in example 20) in CH2Cl2 (19 mL) under argon atmosphere and cooled to 0° C., trifluoroacetic acid (1.8 mL) was added. It was stirred at room temperature for 2.5 h. The solvent was evaporated. The residue was dissolved in CHCl3 and washed with 1 N NaOH and brine. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 319 mg of the title compound (yield: 62%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29](=O)[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-isopropoxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 5 days to afford the title compound as a yellow solid (94 mg, 25%). LC/MS (Method B) 3.12 min, [M+1]+ 450.
Reaction SMILES: [CH2:1]([O:13][C:14](=[O:20])[C@H:15]([C@@H:17]([CH3:19])[OH:18])[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](=[O:24])([O-])O.[Na+].Cl>O1CCOCC1.O>[CH2:1]([O:13][C:14](=[O:20])[C@H:15]([C@@H:17]([CH3:19])[OH:18])[NH:16][C:21](=[O:24])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCOC(=O)[C@@H](NC(=O)CCCCCCCCCCC)[C@@H](C)O
Temperature: 90 °C

Procedure:
The L-threonine dodecyl ester (8.8 g) was dissolved in 1,4-dioxane (60 ml) and water (50 ml), and sodium hydrogencarbonate (3 g, 35.7 mmol) and N-succinimidyl laurate (6.48 g, 21.8 mmol) were added. The cloudy mixture was refluxed at approximately 90° C. for 1 hour and then left to cool. At 50° C., the mixture was adjusted to pH 2-3 using 10% HCl and cooled to 15 to 20° C. in an ice bath. At approximately 40° C. the product begins to precipitate out. The crude product is filtered off, washed with water and recrystallized from methanol. Yield: 7.75 g (16.5 mmol, 78% over 2 steps) of colourless crystalline needles (HPLC>99%). m.p.: 97-98° C., 1H-NMR (CDCl3)δ=0.86 to 0.90 (6H, mn), 1.23 (3H, d, 6.4 Hz), 1.24 to 134 (34H, m), 1.60 to 1.70(4H, m), 2.00 (1H, d, 5.8 Hz), 2.43 (2H, dd, 2*7.4 Hz), 4.16 (2H, t, 6.8 Hz), 4.30 to 4.37 (1H, m), 4.61 (1H, dd, 8.8 Hz, 2.6 Hz), 6.15 ppm (1H, d, 8.8 Hz); 13C-NMR (CDCl3)δ=173.7 (s), 171.3 (s), 68.3 (d), 65.9 (t), 57.0 (d), 36.7 (t), 31.9 (2C, t), 29.7 (2C, t), 29.6 (5C, t), 29.5 (t), 29.4 (2C, t), 29.3 (t), 29.2 (t), 28.5 (t), 25.8(t), 25.7 (t), 22.7 (2C, t), 20.0 (q), 14.1 ppm (2C, q); elemental analysis: calc.: C 71.6%, H 11.8%, N 3.0%, O 13.6%; found: C 71.8%, H 11.2%, N 2.9%, O 13.5%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[N:6][CH:7]=1.BrBr.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>C(O)(=O)C.C(OCC)(=O)C.O.[OH-].[Na+]>[Br:1][C:2]1[C:3]([CH2:8][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cc1ncncc1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: BrBr
Agent: [K]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ncncc1Br
Yield: 88.3 %

Procedure:
5-Bromo-4-methylpyrimidine (2.90 g, 16.8 mmol) in acetic acid (40 mL) was stirred with bromine (3.18 g, 20.2 mmol) at 80° C. for 40 minutes. After completion of the reaction, the reaction solution was cooled, diluted with ethyl acetate and neutralized with water and 1 M aqueous sodium hydroxide, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1). The resulting product (3.69 g) was dissolved in 60 mL of dimethylformamide and heated with potassium phthalimide (2.84 g, 15.3 mmol) at 80° C. for 1 hour with stirring. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform) to give the desired product (4.3 g, 80% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 87.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.02 g) as an oil. ESMS: MH+ 490.4
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12].C(OCC)(=O)C.Cl>CO.O>[OH:3][CH:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(CCCCCC(O)CCCCCC(C)(C)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Under nitrogen atmosphere, sodium borohydride (0.06 g, 1.6 mmol) was added to a stirred solution of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (1.18 g, 3.4 mmol) in methanol (50 mL) at 0° C. The reaction progress was monitored by thin layer chromatography (silica; hexanes:ethyl acetate=50:50). Additional sodium borohydride was added after 1 h (0.48 g, 13 mmol). After 8 h, the reaction mixture was hydrolyzed with water (50 mL) and acidified with concentrated hydrochloric acid (3 mL) to pH 1. The solution was diluted with water (50 mL) and extracted with dichloromethane (4×25 mL). The combined organic layers were washed with saturated sodium chloride solution (2×30 mL), dried over magnesium sulfate, concentrated in vacuo, and dried in high vacuo to give 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (0.7 g, 60%) as a very viscous oil. NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.42 (br. s, 3H), 3.59 (br. s, 1H), 1.65-1.00 (m, 20H), 1.18 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.5, 71.8, 42.1, 40.5, 37.0, 29.8, 25.2, 25.1, 24.9, 24.8. HRMS (FAB): Calcd. for C19H37O5 (MH+): 345.2635. found: 345.2646. HPLC: 83.8% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[H-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.7 g (6.3 mL; 51 mMol) of N-hydroxyethyl-morpholine in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2.5 h. After stirring another hour at rt, the reaction mixture is poured onto 200 mL of water and stirred. The precipitated crystals are filtered and dried at 60° C. under vacuum to obtain 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine. Title compound: ES-MS: 253 [M+H]+; single peak at tR=4.8 min (System 2).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.I.[ClH:28]>CCOCC.CO>[ClH:28].[ClH:28].[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Agent: Cl
Agent: I
Solvent: CO
Solvent: CCOCC
Product: N=C(Nc1ccc2ccn(CCCN3CCCC3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reaction performed as described in Example 40, compound 150. Following isolation of the HI salt by precipitation (193.5 mg), the salt was dissolved in ethanol. Treated amberlite resin (3.00 g) was added to the solution, and the mixture stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated to afford a yellow oil. The material was absorbed onto silica gel and purified by silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane). The resulting yellow oil was found to be the desired product, compound 154, by 1H-NMR. The oil was dissolved in anhydrous dichloromethane (5 mL) and transferred to an argon purged reaction vial. The solution was treated with 1M hydrochloric acid in ether (3 mL) and the salt oiled out immediately. The reaction was stirred for 10 minutes and filtered. The vial and the filter were washed with ethyl acetate and the filtrate discarded. The yellow-brown oil which remained in the reaction vial was dissolved in methanol and the solution poured through the filter. The filter was washed with methanol and all organics combined and concentrated to afford a yellow oil. Additional drying under high vacuum afforded a yellow solid, compound 155. Yield: 116 mg of yellow solid. 1H-NMR (DMSO-d6) δ 7.73-7.72 (d, J=3.6 Hz, 1H), 7.60-7.59 (d, J=4.5, 1H), 7.46-7.43 (d, J=8.1 Hz, 1H), 7.21-7.20 (d, J=3 Hz, 1H), 7.11-7.08 (t, J=4.8 Hz, 1H), 6.92 (s, 1H), 6.60-6.57 (dd, J=1.2, 8.4 Hz, 1H), 6.34-6.33 (d, J=3 Hz, 2H), 4.16-4.12 (t, J=6.9 Hz, 2H), 2.46 (s, 4H), 2.36-2.31 (t, J=6.6 Hz, 2H), 1.93-1.83 (quintet, J=6.7 Hz, 2H), 1.67 (s, 4H). MW 353.