Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)=O.[C:13]([NH2:19])([NH2:18])=[N:14][C:15]([NH2:17])=[S:16]>C(O)C>[NH:14]([C:15]1[S:16][C:2]([CH3:12])=[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=2)[N:17]=1)[C:13]([NH2:19])=[NH:18]
Reactant: Cc1ccnc(C(=O)C(C)Cl)c1
Reactant: NC(=S)N=C(N)N
Solvent: CCO
Product: Cc1ccnc(-c2nc(NC(=N)N)sc2C)c1
Yield: 74.7 %

Procedure:
To a solution of 2-chloro-1-(4-methylpyridin-2-yl)propan-1-one (0.4 g) in ethanol (5 ml) was added 2-imino-4-thiobiuret (257 mg). The mixture was refluxed for 2 hours, and the solvent was evaporated under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, dichloromethane:methanol:triethylamine=80:10:1) to give 2-guanidino-5-methyl-4-(4-methylpyridin-2-yl)thiazole (402 mg).
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][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:33][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)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-methyl-β-D-ribofuranosyl)-purine (61, 505 mg, 1.2 mmol) and cyclopentylamine (1.8 mmol, 178 μL). The mixture was purified by column chromatography (eluens 2% MeOH in CH2Cl2). Yield 364 mg (0.95 mmol, 79%), mp 124–126° C.; Rf 0.15 (eluens 2% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.33 (bs, 1H, NH), 8.30 (s, 1H, H-8), 5.81 (d, 1H, J=4.46 Hz, H-1′), 5.51 (d, 1H, J=3.36 Hz, OH-2′), 5.29 (d, 1H, J=3.32 Hz, OH-3′), 4.59–4.29 (m, 2H, CH, H-2′), 4.41–3.99 (m, 2H, H-3′,4′), 3.56–3.52 (m, 2H, H-5′), 1.94–1.92 (m, 2H, cyclopentyl), 1.71–1.50 (m, 4H, cyclopentyl); MS m/z 384 (M+H)+; Anal. (C16H22ClN5O4.0.1 CH2Cl2) C, H, N.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:49])[CH2:15][C@@H:16]([C:22]1[CH:48]=[CH:47][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:50]O.[Li+].[OH-].Cl>C1COCC1.O>[F:44][C:42]([F:43])([F:45])[C:39]1[CH:40]=[CH:41][C:36]([C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([C@@H:16]([C:17]3[CH:21]=[CH:20][O:19][N:18]=3)[CH2:15][C:14]([OH:49])=[O:50])=[CH:48][CH:47]=2)=[O:46])=[CH:37][CH:38]=1
Reactant: OO
Reactant: O=C(Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(OCc2cccc(NC(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of oxazolidinone 27.4 (71.8 mg, 0.107 mmol) dissolved in THF (10 mL), was added a 30% hydrogen peroxide solution (0.121 mL, 1.07 mmol) followed by a 2M LiOH solution (0.268 mL, 0.535 mmol). The resulting slurry was stirred for two hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH 3. The mixture was then extracted with EtOAc (1×50 mL), and the organic layer was washed with acidic sodium sulfite solution (2×30 mL), brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 27 (25.2 mg). MS ESI (pos.) m/e 511.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1 H, br. s.), 10.51 (1 H, s), 8.75 (1 H, d, J=1.6 Hz), 8.15 (2 H, d, J=8.2 Hz), 7.91 (2 H, d, J=8.2 Hz), 7.87 (1 H, s), 7.74 (1 H, d, J=8.2 Hz), 7.38 (1 H, t, J=7.8 Hz), 7.23 (2 H, d, J=8.6 Hz), 7.19 (1 H, d, J=7.8 Hz), 6.96 (2 H, d, J=9.0 Hz), 6.50 (1 H, d, J=1.6 Hz), 5.08 (2 H, s), 4.48 (1 H, t, J=7.8 Hz), 3.07 (1 H, dd, J=16.4, 8.2 Hz), 2.88 (1 H, dd, J=16.2, 7.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 5-nitroindole (10 g, 61.6 mmol) and acetyl chloride (5.8 g, 74 mmol) in methylene chloride at 0° C. is treated with tin tetrachloride (1M in CH2Cl2, 68 mL), stirred under N2 for 6 h, treated with saturated NaHCO3 to pH 9 and filtered. The filtrate is concentrated in vacuo to give a residue. The residue is dissolved in DMF and filtered. This filtrate is concentrated in vacuo to give the title product, 12.6 g (99% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4](O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27](C(OC(C)(C)C)=O)=[N:28]C(OC(C)(C)C)=O.[ClH:43]>O1CCCC1.O>[ClH:43].[ClH:43].[NH:27]([C@H:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1)[NH2:28]
Reactant: CN1CC[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@H](NN)C1
Reaction time: 1 h

Procedure:
To a mixture of (3R)-1-methylpyrrolidin-3-ol and 35 mL of tetrahydrofuran was added 18.2 g of triphenylphosphine, and a solution of 13.2 g of di-tert-butyl azodicarboxylate in 10 mL of a tetrahydrofuran was added dropwise thereto under ice-cooling, followed by stirring for 1 hour, and further stirring at room temperature for 1 hour. To the reaction mixture was added 40 mL of a 6 M hydrochloric acid, followed by stirring at room temperature overnight. To the reaction mixture was added 40 mL of water, tetrahydrofuran was evaporated under reduced pressure, and then 20 mL of dichloromethane was added thereto and the organic layer was separated. The obtained aqueous layer was washed with 20 mL of dichloromethane twice, and the aqueous layer was evaporated under reduced pressure, and then coevaporated with isopropanol. After forming a precipitate, the obtained solid was collected by filtration and dried under reduced pressure to obtain 7.92 g of (3S)-3-hydrazino-1-methylpyrrolidine dihydrochloride.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:14])=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>O1CCCC1>[N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[O:14][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1Cc2ccccc2C[C@H]1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred solution of trans 3-azido-2-hydroxy-1,2,3,4-tetrahydronaphthalene (95 mg, 0.55 mmol) in tetrahydrofuran (5 mL) at 0° C. under nitrogen was added sodium hydride (60% oil dispersion, 26 mg, 0.66 mmol). Gas evolution was observed and the reaction mixture turned cloudy. After slowly warming up to room temperature for 20 min, t-butyl bromoacetate (0.12 mL, 0.83 mmol) was added. After 2 h, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (7% ethyl acetate in hexane was used) to obtain the title compound (90 mg). 13C NMR (400 MHz, CDCl3) δ 169.59, 133.18, 132.59, 128.88, 128.45, 126.50, 126.37, 81.76, 78.89, 67.99, 61.40, 33.95, 33.51, 28.08. 1H NMR (400 MHz, CDCl3) δ 7.03-7.17 (m, 4H), 4.20 (s, 2H), 3.91 (m, 1H), 3.73 (m, 1H), 3.29 (dd, J=5.7, 16.8 Hz, 1H), 3.16 (dd, J=5.7, 16.8 Hz, 1H), 2.90 (dd, J=8.4, 17.0 Hz, 1H), 2.80 (dd, J=8.4, 17.0 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31].C(=O)([O-])O.[Na+]>COC(C)(C)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([CH:32]2[CH2:37][CH2:36][C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33]2)=[CH:26][C:25]=1[F:24]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccc(F)c(F)c2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=C1CCC(c2ccc(F)c(F)c2)CC1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
4.1 g of potassium t-butylate were added in an inert gas atmosphere to a suspension of 12.2 g of dry methoxymethyltriphenylphosphonium chloride in 125 ml of t-butyl methyl ether and the orange-red suspension was stirred for 30 minutes. A solution of 5.00 g of 4-(3,4-difluorophenyl)cyclohexanone in 75 ml of t-butyl methyl ether was added dropwise at 0°-5° C. within 1 hour. The reaction mixture was stirred at 0°-5° C. for a further 1 hour and at room temperature for 2.5 hours and then treated with 50 ml of saturated sodium hydrogen carbonate solution. The organic phase was washed with water and concentrated. The residue was taken up in 200 ml of hexane and 100 ml of 80 percent aqueous methanol. The hexane phase was washed with two 40 ml portions of 80 percent methanol, dried over sodium sulphate and concentrated. There were obtained 5.6 g of 1,2-difluoro-4-[ 4-(methoxymethylidene)cyclohexyl]benzene.
Reaction SMILES: [C:1]([C:3](=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Mg]Br.N#N>[Cu](I)I.C1COCC1>[C:1]([CH:3]([C:9]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:30])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: Cc1ccccc1[Mg]Br
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: I[Cu]I
Agent: N#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (196 mg, 0.667 mmol), copper iodide (39 mg, 0.3 equiv) and dry THF (4 mL) was degassed and recharged with N2 gas (3×), and cooled to 0° C. A solution of o-tolylmagnesium bromide (2.0 M in ether, 600 μL, 1.8 equiv) was added dropwise. The mixture was stirred 1 h at 0° C. under protection of N2 gas before being warmed to rt slowly and stirred 2 h at rt. LC-MS found the reaction was complete. The mixture was cooled to 0° C. again, quenched with 2% aq HCl to pH=˜5, extracted with EtOAc (3×35 mL). The combined organic layers were washed with satd NH4Cl (10 mL) and brine (10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge, eluted with a 0 to 30% EtOAc in hexanes gradient, to afford tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-o-tolylpiperidine-1-carboxylate (226 mg, 88%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH2:21][CH:18]2[CH2:20][CH2:19]2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Reactant: BrCC1CC1
Product: COC(=O)[C@@H]1C[C@@H](SCC2CC2)CN1C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 409b, (2S,4R)-4-mercapto-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 409a) was reacted with cyclopropylmethyl bromide (CAS Reg. No. 7051-34-5) to give the title compound as colorless liquid. MS (ESI): m/z=316.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:23]>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cc(C)cc(C)c4)c3cc2O1
Yield: 28.5 %

Procedure:
The titled compound (10 mg, 29%, m.p. 268-270° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (26 mg, 0.1 mmol) and 3,5-dimethylaniline (24 mg, 0.2 mmol).
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: CCc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)nc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
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: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CS(C)=O>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NCCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(NCCCN2CCOCC2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 158.4 g 4-(3-aminopropyl)morpholine were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The mixture was extracted several times with methyl tert-butyl ether, and the combined organic phases were reduced to dryness on a rotary evaporator. The product obtained was an orange-brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C@H:14]([O:21][Si](C(C)(C)C)(C)C)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C@H:14]([OH:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:10]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)nc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution tert-butyl(2S,5R)-2-[(6-aminopyridin-3-yl)methyl]-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (40 mg, 0.08 mmol) in THF (0.5 mL) was added 1.0M solution of TBAF in THF (1 mL, 1.0 mmol) and the resulting solution stirred for an hour at room temperature. The mixture was concentrate under vacuum and the residue taken up in dichloromethane (10 mL). The solution was washed with water (5 mL) and brine (5 mL). The organics were then dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified vial preparative TLC plate (1000 μM) eluting with 5% methanol in dichloromethane to afford the title compound as a white foam (25.2 mg, 92%). LC-MS: C22H29N3O3 calculated 338.23 found m/z (ES) 339.2 (MH) and 239.2 (M-Boc)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH:14]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH2:37][CH2:38]O)[C:28]=1[CH3:40])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:14]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[C:28]=1[CH3:40])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1c(C(c2ccccc2)c2ccccc2)c2cc(Cl)ccc2n1CCO
Product: Cc1c(C(c2ccccc2)c2ccccc2)c2cc(Cl)ccc2n1CCOc1ccc(CCC(=O)O)cc1

Procedure:
The methyl ester of the title compound was prepared from methyl 3-(4-hydroxyphenyl)propionate and 2-(3-benzhydryl-5-chloro-2-methyl-1H-indol-1-yl)ethanol according to Step 2 of the procedures for Example 2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCCOC.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([N:32]=O)[CH2:28][CH2:27]1)=O)=[CH:20][CH:19]=[CH:18][CH:17]=2>O>[NH2:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:13])[CH2:27][CH2:28]1
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(=O)N1CCN(N=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]c2ccccc2c1CCN1CCN(N)CC1
Temperature: -5 °C

Procedure:
To a stirred mixture of 9.0 g of lithium aluminum hydride in 400 ml. of 1,2-dimethoxyethane is added 10.52 g (0.35 mol) of 1-(2-methylindol-3-ylglyoxyloyl)-4-nitrosopiperazine slowly to maintain reaction temperature below 35° C. After all the material is added, the mixture is refluxed for 14-16 hours. The reaction mixture is cooled to -5° C. and a solution of 50 ml. of water and 50 ml. of 1,2-dimethoxyethane is slowly added while maintaining the temperature below 15° C. Another 50 ml. of water is added. The mixture is then filtered, the solvent is removed, and the residual solid is recrystallized from hot benzene, producing the pure crystals of 3-[2-(4-aminopiperazin-1-yl)ethyl]-2-methylindole, m.p. 118°-120° C. Analysis: Calculated for C15H22N4 : 71.08% C; 8.21% H; 20.72% N Found:71.11% C; 8.28% H; 20.75 % N.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1>C(Cl)Cl>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH2:23])=[S:25])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cccc(CO)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=S)Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(6-Amino-pyridin-2-yl)-methanol (6-2, 1.00 g, 8.06 mmol) was dissolved in 20 mL anhydrous CH2Cl2 and 5 mL anhydrous DMF under N2. Benzoylisothiocyanate (1.19 mL, 8.86 mmol) was added and the reaction was stirred at room temperature fro 16 h. The reaction was concentrated in vacuo and to the resulting residue was added 24 mL 1M NaOH (aq) and 24 mL TEF. The resulting mixture was heated to reflux for 3 h. The THF was removed in vacuo and a white precipitate formed. The mixture was filtered and washed with water to provide the titled compound as a white solid. 1H NMR(DMSO-d6): δ10.58 (bs, 1H), 10.48 (bs, 1H), 8.84 (bs, 1H), 7.74 (t, 1H, J=8.1 Hz), 7.06 (d, 1H, J=7.5 Hz), 7.01 (d, 1H, J=8.1 Hz), 5.47 (t, 1H, J=5.9 Hz), 4.47 (d, 2H, J=5.7 Hz).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])(O)[O-].[Na+]>ClC1C=CC=CC=1Cl>[C:1]([C:9]1[C:10](=[O:11])[O:12][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:15]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Temperature: 0 °C

Procedure:
To a solution of ethyl benzoylacetate (150 g, 0.88 mmol) in 1,2-dichlorobenzene (150 mL) was added a trace amount of sodium bicarbonate. The reaction mixture was heated to reflux. A distillate of ethanol (approximately 20 mL) was collected. The reaction mixture was cooled to 0° C. Ether (100 mL) was added to induce crystallization. The reaction mixture was kept in the refrigerator overnight. The solid formed was collected and washed with ether: m.p. 171°-173° C.; 1H NMR (250 MHz, DMSO-d6) δ 6.91 (s, 1 H), 7.59 (m, 6 H), 7.87 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(neopentyloxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a white solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (s, 9H), 1.32 (t, J=6.8 Hz, 3H), 2.54 (s, 3H), 3.86 (s, 2H), 4.31 (q, J=6.8 Hz, 2H), 6.88-6.91 (m, 1H), 7.22-7.25 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 317 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(Br)c2)ccc1[N+](=O)[O-]
Yield: 82.6 %

Procedure:
To a 50 ml of anhydrous N,N-dimethylformamide suspension containing 2.5 g of sodium hydride (55% weight) was added 10.0 g of 3-bromophenol, and the mixture was stirred under ice-cooling for 15 minutes. Subsequently, a solution of 16.6 g of N-(5-chloro-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester dissolved in 70 ml of anhydrous N,N-dimethylformamide was added to the mixture in drops, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated, followed by addition of water, neutralization using 3N hydrochloric acid and extraction with ethyl acetate. The extraction solution was washed with saturated saline, and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extraction solution, and the insoluble product which deposited was washed with hexane and filtered, followed by drying under reduced pressure, to give the title compound (20.2 g, 83% yield).