Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1](=[O:3])[CH:2]=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2ccccc2c1
Product: CN(C)C=CC(=O)c1ccc2ccccc2c1
Yield: 76 %

Procedure:
2'-Acetonaphthone (10 0 g, 58 mmol, [93-08-3]) was dissolved in 20 mL of N,N-dimethylformamide dimethylacetal [4637-24-5] and the mixture was heated under reflux for 14 hours. The mixture was then cooled, concentrated, and the crystalline residue was recrystallized from cyclohexane to give the title product as orange crystals (9.88 g, 76%). mp 100° -101° . Calc'd for C15H15NO: C 79.97%, H 6.71 %, N 6.22%; found: C 79.71%, H 6.76%, N 6.51%. NMR (CDCl3): 8.40 (s, 1 H); 8.00-7.83 (m, 5 H); 7.54-7.51 (m, 2 H); 5.86 (d, 1 H); 3.33-2.83 (br d, 6 H). Mass spec 226 (M +H+).
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].CC(CCC=C(C)CCC=C(C)C)=CCN1C(=O)C2C(=CC=CC=2)C1=O.P(Br)(Br)[Br:44]>C(OCC)C>[CH2:2]([Br:44])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr

Procedure:
A solution of 2.00 g (9.0 mmol) of (E,E)-farnesol in 20 ml of dry diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 735 1 (4.0 mmol, 0.45 eq.) of PBr3 in 4 ml of dry diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with H2O and separated. The organic phase was washed with 15 ml of NaHC03, 15 ml of H2O, and 15 ml of brine, dried over MgSO4 and evaporated to provide 2.47 g of crude farnesyl bromide as a clear oil.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[C:7]1[C:16]2[O+]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1.[NH4+:29]>O>[C:17]1([C:14]2[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]3[CH2:10][CH2:9][CH2:8][C:7](=[O:6])[C:16]=3[N:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)[o+]c21
Reactant: [NH4+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)nc21

Procedure:
12.44 g of 5,6,7,8-tetrahydro-8-oxo-2,4-diphenyl-1-benzopyryliumtetrafluoroborate (32 mmol) is suspended in 80 ml of distilled water and a solution of 25 g of ammonium carbaminate (320 mmol) in 200 ml of distilled water is added with stirring. After stirring at room temperature for 24 h, the solution is extracted by suction via a nutsche, washed with distilled water and dried by suction. The cream-coloured powder is washed in portions with diethyl ether and dried at 50° C. in a vacuum drying cabinet to constant weight: 8.39 g of ivory-coloured product (87.5%) with a melting point of 177-178° C. (decomposition). IR (ATR): The CO valence vibration band can be seen at 1700 cm−1. 1H-NMR (500 MHz, CDCl3): δ=8.09 (d, 2H, o-H of 2-phenyl), 7.79 (s, 1H, H3), 7.56-733 (m, 8H, arom. H), 2.92 (t, 2H, J=5.75 Hz), 2.83 (t, 2H, J=6.56 Hz), 2.10 (p, 2H, J=5.75 Hz, J=6.56 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([N:1]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
2-Amino-4-nitrophenol (5 g, 32.0 mmol) and 2,5-dimethoxytetrahydrofuran (5.03 ml, 38.4 mmol) were dissolved in glacial acetic acid (100 ml), followed by stirring at the reflux temperature for 10 min. After subsequent cooling to room temperature, the solvent was evaporated under vacuum and the residue was neutralized with an aqueous solution of sodium carbonate, followed by three extractions with ethyl acetate. The organic solvent layers were combined, dried with magnesium sulfate and the solvent was evaporated; thereafter, the residue was purified by being subjected to column chromatography on silica gel using a 2:1 solvent system of n-hexane and ethyl acetate as an eluent; the fractions containing the product were collected and the solvent was evaporated to yield the end compound 4-nitro-2-(1H-pyrrol-1-yl)phenol (3.81 g).
Reaction SMILES: [OH-].[Na+].[C:3]([NH2:7])([CH3:6])([CH3:5])[CH3:4].[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 ml 0.1N sodium hydroxide solution and 6.74 g (92.25 mmol) tert.butylamine are added to 9.23 g (50 mmol) cyanuric chloride in 200 ml toluene and stirred for 1 hour at 20° C. The pH value of the reaction is monitored continuously during this period and if necessary readjusted to pH 11-12 with 1N sodium hydroxide solution. Subsequently the solvent is removed by distillation, the residue is taken up in 150 ml water, extracted twice with 150 ml ethyl acetate each time, the organic phase is dried over magnesium sulfate and the solvent is removed. The residue is dissolved in 200 ml ethyl acetate/petroleum ether (v/v 4/1), insoluble components are removed by filtration and the filtrate is concentrated by evaporation. The crude product is purified by column chromatography (silica gel Merck 60, 5×30 cm, eluant: ethyl acetate/petroleum ether (v/v 4/1).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:42]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyrate (115 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyric acid (108 mg). MS (m/z): 667 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12].CC([O-])=O.[Na+].O>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[C:11]([NH:14][C:15](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=Cc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 20.0 g (112 mmol) 3,4-dichlorobenzaldehyde, 19.7 g (168 mmol) N-acetylglycine and 13.8 g (168 mmol) NaOAc in 80 mL acetic anhydride were heated to 120° C. (oil bath temperature) for 5 h. After the reaction had ended the reaction mixture was cooled using an ice bath and then combined slowly with 60 mL water (slightly exothermic reaction). The reaction mixture was heated to 80° C. for a further 1.5 h, cooled somewhat, then added to a mixture of 400 mL water and 200 mL toluene and stirred overnight at RT. The precipitate was suction filtered, washed with toluene and water, then combined with diethyl ether and suction filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc2c(Cl)ccnc2[nH]1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 4-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.73 g), potassium carbonate (6.4 g), methanol (45 ml), and water (15 ml) was stirred at 90° C. for 2 hours. After the mixture was cooled, the obtained needle crystals were filtered and washed with water to obtain 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (1.85 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[CH3:18]I>C1COCC1>[CH3:18][O:15][CH2:14][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(C2(CO)CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(c2ccc(N)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(4-nitrophenyl)cyclobutyl]methane-1-ol (500 mg) and NaH (60% in mineral oil, 1.2 eq) and MeI (1.2 eq) in THF was stirred at RT overnight then quenched with H2O. The solution was extracted with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was mixed with Pd—C (10%, 100 mg) in EtOH (50 ml) and hydrogenated under H2 atmosphere for 30 min. The reaction was filtered through Celite and evaporated to give 4-[(methoxymethyl)cyclobutyl]phenylamine which used for next step without further purification.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[CH:11]([C:27](=[O:37])[NH:28][CH:29]3[CH:34]4[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]4)[CH2:30]3)[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50]>C1(OC)C=CC=CC=1>[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]([C:27](=[O:37])[NH:28][CH:29]2[CH:34]3[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]3)[CH2:30]2)[CH2:10]1
Reactant: COc1ccc(CS[C@H]2CC(C(=O)NC3CN4CCC3CC4)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CN2CCC1CC2)C1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
770 mg of (4S)-4-(4-methoxybenzylthio)-2-[(3-quinuclidinyl)carbamoyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 6) were suspended in 1.5 ml of anisole, and the suspension was placed on an ice bath. Whilst the suspension was still on the ice bath, 6.5 ml of trifluoroacetic acid and 246 μl of trifluoromethanesulfonic acid were added to it, and the resulting mixture was stirred for 1.5 hours at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane; the produce was then precipitated by the addition of diethyl ether, and the mixture was filtered, to give 813 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].OC(C(F)(F)F)=O.[O:21]1[C:32]2[C:33]3[C:28]([C:29](B(O)O)=[CH:30][CH:31]=2)=[N:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C(OCC)(=O)C.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.O>[O:21]1[C:32]2[C:33]3[C:28]([C:29]([C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[C:4]([CH3:12])[C:3]=4[OH:13])=[CH:30][CH:31]=2)=[N:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: Cc1cc2ccccc2c(Br)c1O
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: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccccc2c(-c2ccc3c4c(ccnc24)CCO3)c1O
Temperature: 110 °C
Yield: 29.1 %

Procedure:
1-Bromo-3-methylnaphthalen-2-ol (5B) (340 mg, 1.43 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid TFA salt (5C) (566 mg, 1.72 mmol), Pd(PPh3)4 (166 mg, 0.14 mmol) and K2CO3 (991 mg, 7.15 mmol) were added to a degassed solution of DMA (6 mL) and water (2 mL) and heated to 110° C. in a microwave for 1 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give 5D (136 mg, 29%). LCMS-ESf+ (m/z): [M+H]+ calcd for C22H18NO2: 328.38. Found: 328.2.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:21]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (3 g, 10.47 mmol) in THF (20 mL) was added to a freshly prepared solution of LDA (prepared from n-butyllithium (26.2 mmol) in hexane and diisopropylamine (3.73 mL, 26.2 mmol) in 7 mL of THF) at −78° C. the reaction was stirred for 1 h, warmed to 0° C. for 5 min, cooled again to −78° C. followed by addition of methyl iodide (2.292 mL, 36.7 mmol). The reaction mixture was allowed to warm to room temperature overnight, quenched with aqueous ammonium chloride, and concentrated under vacuum to remove volatile solvents. The residual aqueous mixture was extracted with ether, and the ether solution was dried and concentrated under vacuum to give the crude product as an oil which was further purified via normal phase chromatography on silica gel (Biotage SP1, 40+S column) to give product (2.7 g; MS: (M+H)+=301.3) as a clear oil.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[OH:18][C:19]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:20]=1[N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([O:31][CH3:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:37][C:34]1[CH:35]=[CH:36][C:19]2[O:18][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([O:31][CH3:32])=[O:30])=[N:21][C:20]=2[CH:33]=1
Reactant: COC(=O)c1ccccc1C=Nc1cc(C)ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1-c1nc2cc(C)ccc2o1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Lead tetraacetate (16.6 g) was added portionwise to a solution of compound B (8.1 g) in chloroform (150 ml) and the mixture was stirred for 2 hours. Insoluble material was removed by filtration and the filtrate was washed with water (3×50 ml), followed by saturated sodium chloride solution (50 ml), and then dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give methyl 2-(5-methylbenzoxazol-2-yl)benzoate (C) (5.2 g), as an oil; NMR: 2.5(s, 3H), 3.85(s, 3H), 7.2(dd, 1H), 7.45(d, 1H), 7.55-7.7(m, 3H), 7.75-7.8(m, 1H), 8.05-8.1(m, 1H).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH:13](OC(=O)C)[C@H:12]([O:19][C:20](=[O:22])[CH3:21])[C@@H:11]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[N:40]1[C:48]([NH2:49])=[C:47]2[C:43]([N:44]=[CH:45][NH:46]2)=[N:42][CH:41]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:20]([O:19][C@@H:12]1[C@H:11]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:10]([C:9]#[C:8][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][C@H:13]1[N:44]1[C:43]2[N:42]=[CH:41][N:40]=[C:48]([NH2:49])[C:47]=2[N:46]=[CH:45]1)(=[O:22])[CH3:21]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Reactant: Nc1ncnc2nc[nH]c12
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C

Procedure:
To a solution of Compound 6 (1.1 g, 2 mmol) in 1,2-dichloroethane (16.5 ml), adenine (0.405 g, 3 mmol) and N,O-bis(trimethylsilyl)acetamide (2.7 ml, 11 mmol) were added, followed by refluxing for 1.5 hours. After the mixture was allowed to cool to room temperature, trimethylsilyl trifluoromethanesulfonate (0.77 ml, 4 mmol) was added dropwise to the mixture under stirring at 0° C. in an argon atmosphere. The mixture was stirred for 15 minutes at room temperature, refluxed for 24 hours, and allowed to cool to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added thereto at 0° C., followed by stirring for 15 minutes at room temperature. Insoluble materials were removed through filtration by use of Celite, and then the organic layer was separated from the filtrate. After an aqueous layer was extracted with chloroform, the organic layer was washed once with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated through distillation under reduced pressure, so as to evaporate the solvent. The residue was applied to a silica gel column (15 g, eluent; ethyl acetate:n-hexane:ethanol=20:20:1), to thereby yield Compound 20 in an amount of 0.69 g (55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1cc(OCC(=O)N2CCNCC2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(OCC(=O)N2CCN(Cc3ccc(C#N)cc3)CC2)cc(OC)c1OC
Yield: 70.5 %

Procedure:
To a solution of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonylpiperazine (0.22 g, 0.70 mmol) in 1% acetic acid in methanol (6 mL) was added 4-cyanobenzaldehyde (0.33 g, 2.5 mmol) and sodium cyanoborohydride (0.093 g, 1.4 mmol). The resultant mixture was stirred at ambient temperature for 1.5 hours and the mixture was then concentrated of volatiles in vacuo. Residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 solution, water, and then brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.21 g of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-4-(4-cyanobenzyl)piperazine, a compound of formula (lb), as a clear oil: NMR (CDCl3) 7.6 (d, 2), 7.4 (d, 2), 6.2 (s, 2), 4.6 (s, 2), 3.8 (s, 6), 3.75 (s, 3), 3.6 (m, 4), 3.5 (s, 2), 2.2 (m, 4) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[N:8]2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH2:14][N:15]3[CH2:16][CH2:17][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20]3)=[N:8]2)=[CH:33][CH:34]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 20 h
Yield: 55.8 %

Procedure:
The product of Example 15 (0.05 g) was dissolved in dichloromethane (5 ml) and sodium triacetoxyborohydride (0.068 g) added. After 20 hours at room temperature, brine and dichloromethane were added, the organic phase was separated, dried and the solvent removed by evaporation to give a residue. Trituration under ether gave the product as a solid (0.028 g), m.p. 104-105° C.
Reaction SMILES: CI.[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:20][N:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:19][CH:18]=1)[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: O=[N+]([O-])c1ccc(CNC[C@H]2CCCO2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C[C@H]1CCCO1

Procedure:
Methyl iodide (0.728 mL, 11.7 mmol) was added to (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 10a2 (1.84 g, 7.80 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in DMF (30 mL). After 4 hrs the reaction was diluted with water and extracted with ethyl ether. The combined extracts were washed with water, dried over MgSO4, and evaporated down to give 1.43 g of methyl-(4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 10a3. Using the procedure of Example 21, Compound 10a3 was used in place of Compound 21a2 and carried forward to prepare 4-({methyl-[(2R)-tetrahydro-furan-2-ylmethyl]-amino}-methyl)-phenylamine Compound 10a.