Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>C1COCC1>[CH3:10][C:8]1[CH:9]=[C:4]([B:12]([OH:17])[OH:13])[CH:5]=[C:6]([CH3:11])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mg turnings (1.44 g, 59.43 mmol) were covered with dry THF (18.8 ml) in a dried, N2 filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 ml) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reaction mixture was heated at reflux for 1-2 h until most of the Mg had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to a N2 filled flask containing triisopropyl borate (24.9 ml) at -70° C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. The solution was extracted into Et2O and the Et2O fractions were combined, dried over MgSO4 and the solvent was removed in vacuo to yield 2.41 g (29.7%). mp 249-251° C.; 1H NMR (CDCl3) 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD3OD) 21.36, 133.28, 134.39, 137.48.
Reaction SMILES: [H-].[Na+].[C:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[C:19]1([CH2:25][C:26](OC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1.CCOCC>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:3](=[O:5])[CH2:4][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a suspension of 60% sodium hydride (1.07 g) in THF (15 mL) at 0° C. was added a solution of 4-acetyl-1-(t-butoxycarbonyl)piperidine from Step B2 (3.03 g, 13.3 mmol) and methyl phenylacetate (6.01 g, 39.9 mmol) in THF (6 mL) over 20 min. The reaction was stirred for another 4 h as it was allowed to warm to rt. The mixture was diluted with ether (30 mL) and poured into 1N HCl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The crude product was purified by FC (20% ethyl acetate in hexanes) to give the title compound (3.02 g). Rf: 0.30 (20% ethyl acetate in hexane). The 1H NMR data was the same as that obtained from the product of Method A.
Reaction SMILES: ClC(OCC)=O.[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]1=[O:17].C(N(CC)CC)C.[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH2:35]>C(Cl)(Cl)Cl>[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH:35][C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([OH:7])[C:9]1=[O:17]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Reaction time: 0.2 h

Procedure:
1.2 ml of ethyl chloroformate are placed in 12 ml of chloroform, whereupon there are added dropwise at -30° within 30 minutes 2.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.74 ml of triethylamine dissolved in 50 ml of chloroform. After stirring at a temperature between -2° and -10° for 12 minutes, 2.07 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 10 ml of chloroform are added dropwise. The mixture is left to stand at room temperature overnight. Thereupon, the mixture is evaporated and the residue (6 g) is chromatographed on 120 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with acetonitrile and ethanol has a melting point of 128°-130° after repeated chromatography on aluminum oxide and recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3(O)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3c(Cl)cccc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc2sc(C3=CCNCC3)cc12
Temperature: 23 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene (0.290 g, 0.79 mmol) in methylene chloride (4.0 ml) was treated with 1.5 ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. The reaction was concentrated to a foam under reduced pressure and the residue chromatographed (silica gel, chloroform/methanol 95:5) to give 0.175 g (88%) of a tan powder. FDMS m/e=250 (M+ of free base)
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4]>O>[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([O-:8])=[O:7])[CH3:4].[Na+:2]
Reactant: CCCCC(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]

Procedure:
A solution of 120 g (3.0 moles) of sodium hydroxide was dissolved in 500 ml of distilled water. 2-Ethylhexanoic acid (491 g. 3.3. moles) was added with stirring to form sodium 2-ethylhexanoate. In a separate container 200 g (0.5 mole) of chromium nitrate nonahydrate was dissolved in 500 ml of distilled water. The chromium nitrate solution was slowly added to the sodium 2-ethylhexanoate solution with good stirring. When the addition was complete, 500 ml of hexane were added and stirring was continued for 10 minutes. The layers were separated and the hexane layer containing the aquated chromium III tri-2-ethylhexanoate was washed with dilute sodium hydroxide solution, water, dilute sodium carbonate solution and finally with distilled water. The hexane solution was then dried over anhydrous magnesium sulfate. Most of the hexane was removed under reduced pressure and the resulting concentrate was slowly added to 500 ml of acetone. The resulting blue granular solid was filtered and air dried to yield 130 g (54%) of aquated chromium tri-2-ethylhexanoate. Molecular weight determination indicated that the compound is polymeric in nature, probably due to the oxygen bridging of chromium atoms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC.Cl.[CH3:38][NH:39][O:40][CH3:41]>C1COCC1>[CH3:41][O:40][N:39]([CH3:38])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 127.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol) in THF (100 mL) was added DCC (7.11 g, 34.5 mmol), Et3N (5.18 g, 51.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol), the reaction was stirred at RT for about 16 hr. Concentrated under reduced pressure to remove solvent, the residue was portioned between EA (100 mL) and water (50 mL), the aqueous was further extracted with EA (50 mL×3). The combined organic phases were washed with brine (20 mL), concentrated under reduced pressure to remove solvent, then purified by column chromatography on silica gel (200-300 mesh, CH2Cl2/MeOH=20/1) to give the crude product (˜8.0 g) as a colorless oil. MS (ESI) m/e [M+23]+ 266.9, [M−55]+ 189.0.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1([F:10])[CH2:6][C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC(F)(F)C(=O)O1

Procedure:
2,2-Difluorosuccinic acid (120 g, 0.78 moles) and trifluoroacetic anhydride (540 mL) are refluxed (bath temperature 80° C.) for 2 hours. Most of the trifluoroacetic acid is distilled utilizing a short Vigreux column, the final traces are removed under vacuum (12 mm Hg, 50° C.) and finally by stripping twice with carbontetrachloride. The oily residue solidifies on scratching with petroleum ether. Filtration and washing with petroleum ether yields 2,2-difluorosuccinic anhydride as slightly violet crystals: 98 g (92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.C(O)(=O)C>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Yield: 71 %

Procedure:
A mixture of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (0.5 g, 1.62 mmol), iron powder (0.35 g, 6.26 mmol), acetic acid (0.72 mL, 11.34 mmol) in methanol (6 mL) is heated at 66 C for 1 h. After it is evaporated to dryness, ethyl acetate is added, and then the mixture is filtered through a pad of Celite. The filtrate is evaporated to yield 0.32 g (72%) of the title compound as an orange gum. NMR (CDCl3) spectrum of the product showed it is pure.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[C:1]1([CH2:7][CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: [Pd]
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14].Cl>C(#N)C>[F:8][C:9]([F:19])([F:20])[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:14]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 1.5 °C

Procedure:
Glycine 0.763 g (10.16 mmol) was suspended into acetonitrile 20 ml and 2M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) was also added. After chilling at 0-3° C., 2.12 g (10.16 mmol, 1.0 eq.) of 3-(trifluoromethyl)-benzoyl chloride was diluted with 4 ml acetonitrile and was added dropwise slowly to reaction mixture. After one hour agitation at same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solution obtained as above was brought all together, dried with anhydrous magnesium sulfate and concentrated removing its solvent under decompression. Residues was solidified with tolene, filtered, washed with normal hexane and 2.28 g (91%) target compound as white solid was yielded.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].CCO.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:15][OH:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P2O5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8°-169.4° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 97 %

Procedure:
A solution of 1.4 g (3.1 mmole) of 7[3-t-butoxycarbonylamino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyic acid in 25 ml of trifluoroacetic acid was stirred at room temperature until gas evolution ceased. The solvent was removed in vacuo and the residue dissolved in 1 N sodium hydroxide. The solution was diluted to 100 ml with water and acidified to pH 5.5 with 6 N hydrochloric acid. The precipitate was removed by filtration, washed with water, ethanol, and ethyl ether. The residue was dried in vacuo to give 1.05 g (97%) of the title compound, mp 290°-292° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:9].ClCl>O>[NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccncc1N
Reactant: Cl
Agent: ClCl
Solvent: O
Product: Cc1ccnc(Cl)c1N
Temperature: 20 °C
Reaction time: 0.42 h

Procedure:
3-Amino-4-methylpyridine (21.6g, 0.2 mole) was suspended in 75 ml of water at room temperature. The mixture was dissolved by the addition of 25 ml conc. hydrochloric acid. The solution was cooled to 20° C. and 15.6 g (0.22 mole) of chlorine gas was introduced through an inlet tube reaching below the surface of the reaction mixture over 25 minutes. The mixture was stirred under a nitrogen purge for an additional 30 minutes, then cooled to 10° C. and basified by the addition of 70 mL of a 12.5 N. sodium hydroxide solution. Additional water (100 mL) was added to maintain efficient agitation of the mixture. The precipitate was collected, washed with water and dried to give 14.5g of the title product. The aqueous phase was extracted with 3 times 100 mL of methylene chloride. The organic phases were washed with water, dried over magnesium sulfate, and concentrated to give an additional 9.4g, mp 62-64° C. Total yield, 23.9g (84%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:44](Cl)([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>N1C=CC=CC=1>[CH2:1]([O:19][CH2:20][CH:21]([O:43][S:44]([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
In 9 ml of pyridine was dissoved 5.0 g (8.52 mmole) of 3-O-octadecyl-1-O-tritylglycerol, and after 1.95 g (10.22 mmole) of tosyl chloride was added to the solution, the mixture was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of water and 50 ml of dichloromethane, and after shaking throroughly, the dichloromethane layer was separated out. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (50 g), with n-hexane.ethyl acetate (193:7) used as an eluent, to give 5.3 g (yield of 83.9%) of colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.7 %

Procedure:
A solution of 5-bromoindole (5.02 g, 25.6 mmol) in DMF (50 mL) was cooled in an ice bath. Sodium hydride (2.30 g of 60% dispersion in oil, 57.5 mmol) was added. After stirring for 40 minutes under nitrogen at room temperature, the reaction mixture was again cooled in an ice bath and benzyl bromide (6.7 mL, 56 mmol) was added. The reaction mixture was stirred for 2 hours, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using hexane as an eluant. Dyring at 60° C. for 35 minutes yielded the title compound as a white solid (5.69 g, 78%), mp 93–95° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ7.7 (d,1H, J=1.8 Hz), 7.55 (d, 1H, J=3.1 Hz), 7.4 (d, 1H, J=8.7 Hz), 7.15–7.30 (m, 6H), 6.45 (dd, 1H, J=3.2 Hz and 0.6 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21].O1CCOCC1>ClCCl>[ClH:21].[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (58.82 g, 208.3 mmol) in anhydrous dichloromethane (100 mL) was added hydrogen chloride in 1,4-dioxane (260 mL, 1040 mmol, 4M). The reaction mixture was stirred vigorously at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was left standing overnight at room temperature. The residue was triturated with ether (250 mL). The ether was decanted and dichloromethane was added followed by sonication in a warm bath. The solvent was removed under reduced pressure and the resulting solid was placed under high vacuum at 40° C. for 1 h to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (48.41 g). The material was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.75-2.05 (m, 8H) 3.04-3.17 (m, 2H) 3.19-3.28 (m, 3H) 3.35-3.66 (m, 4H); MS (ES+) (M+H) 183.3.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 106.2 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 500 g (3.42 mol) of diethyl oxalate, 31.3 g (0.23 mol) of trimethylolpropane and 1 g (0.0053 mol) of p-toluenesulfonic acid monohydrate, and mixed at 130° C. for 5 hours. After removing 32.3 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 106.1 g of crude triethoxalyltrimethylolpropane (yield 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>C1COCC1.CCO>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 60 mg, 0.171 mmol) in 2 ml of THF and 7 ml of EtOH at 0° C. was added NaBH4 (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h. The reaction was quenched by slow addition of cold water. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1
Reaction time: 23 h

Procedure:
From benzyl alcohol (50 ml) and 5-amino-4-oxopentanoic acid hydrochloride (10.0 g; 60 mmol). After 23 h at 90°, excess benzyl alcohol was distilled off at 90° (bath temperature) and 0.33 mm Hg. The yield was 8.1 g (53%) of tan powder.