Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].CO.[CH2:7]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH3:10]>O1CCOCC1>[CH2:15]([N:14]1[CH2:13][CH2:12][N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:1]1=[O:2])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCNCCNCCCC
Reactant: O=CC=O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCN1CCN(CCCC)C(=O)C1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To 10 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of methanol is rapidly added 11.9 g (69.0 mmoles) of N,N'-di(n-butyl)ethylenediamine. The solution is rapidly brought to reflux and heating is maintained for 5 minutes. The dark brown solution is then allowed to cool to room temperature at which time fine white crystals precipitate from the brown oil. The oil is diluted with 100 ml of 1,4-dioxane and the solid is removed by filtration. The dioxane solution is concentrated under aspirator vacuum and distilled in a short path distillation apparatus to give 4.5 g of 1,4-di(n-butyl)piperazin-2-one in the form of a brown oil (31 percent yield).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:24]1[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4].[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[OH:27])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1O

Procedure:
A solution of 1.5 g. (0.005 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 10 ml. of methylene chloride was slowly added over a 1 hour period to a stirred solution of 0.6 g. (0.006 mol.) of phenol and 0.1 ml. of boron trifluoride etherate in 15 ml. of methylene chloride. After 3 hours the reaction mixture was chromatographed on 50 g. of silica gel and eluted with methylene chloride containing increasing amounts of ethyl acetate to give N-t-butoxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester and N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester.
Reaction SMILES: C1(N([C@H]2CC[C@H](COC)CC2)C(=O)NC2SC(SC[C:17](O)=[O:18])=CN=2)CCCCC1.[CH:30]1([NH:37][C@H:38]2[CH2:44][CH2:43]C[C@H:41]([CH2:45][O:46][CH2:47][CH3:48])[CH2:40][CH2:39]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:51][C:52](=[O:63])[C:53]([S:56][C:57]1[S:61][C:60]([NH2:62])=[N:59][CH:58]=1)([CH3:55])[CH3:54])C>>[CH:30]1([N:37]([C@H:38]2[CH2:39][CH2:40][C@H:41]([CH2:45][O:46][CH2:47][CH3:48])[CH2:43][CH2:44]2)[C:17](=[O:18])[NH:62][C:60]2[S:61][C:57]([S:56][C:53]([CH3:55])([CH3:54])[C:52]([OH:51])=[O:63])=[CH:58][N:59]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CCOC[C@H]1CCC[C@H](NC2CCCCCC2)CC1
Product: CCOC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(trans-4-ethoxymethyl-cycloheptyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](=[O:17])(O)[O-:15].[K+].C(O[C:23](=O)[CH3:24])(=O)C>O>[C:2]1([C:1]2[O:15][C:14](=[O:17])[C:10](=[CH:11][C:2]3[CH:1]=[N:9][CH:10]=[CH:23][CH:24]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Solvent: O
Product: O=C1OC(c2ccccc2)=NC1=Cc1cccnc1

Procedure:
2-Phenyl-4-(3-pyridylmethyl)oxazolone. A mixture of 180 g of N-benzoyl glycine, 40 g of potassium bicarbonate and 400 ml of acetic anhydride was stirred until solution occurred. 3-Pyridylaldehyde (100 ml) was then added and the mixture stirred for 1 hr with maintenance of the temperature at 20°-25° C. by means of a cold water bath. The mixture was poured into 2 liters of hot water and the precipitate collected by filtration and dried to afford 2-phenyl-4-(3-pyridylmethylene)-2-oxazolin-5-one, mp 164.5° C. The material was hydrogenated in tetrahydrofuran solution over 20% palladium-on-carbon. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the azlactone as a tan foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][N:5]=1)([OH:3])=[O:2].C(N([CH2:18][CH3:19])CC)C.Br[CH:21]([O:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([CH:21]([O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH:21]([C:22]([O:24][CH2:18][CH3:19])=[O:23])[O:27][CH2:28][CH3:29])=[O:11])=[CH:6][N:5]=1)=[O:3])[O:27][CH2:28][CH3:29])=[O:23])[CH3:26]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(Br)OCC
Solvent: ClCCl
Product: CCOC(=O)C(OCC)OC(=O)c1ccc(C(=O)OC(OCC)C(=O)OCC)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,5-Dicarboxy-pyridine (1.67 g, 0.01 mol) is suspended in 40 ml of dichloromethane. 2.8 ml of triethylamine are added dropwise, followed by 4.02 g (0.02 mol) of ethyl 2-bromo-2-ethoxy-acetate. The solution is stirred at room temperature for 2 h. After this period, the dichloromethane solution is filtered, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is purified by silica gel column chromatography (dichloromethane/ethyl acetate) to yield the title compound as a resin; IR (NaCl film): 1730 (CO), 1765 (CO) cm-1.
Reaction SMILES: [CH:1](N1[CH2:17][CH:16]([OH:18])C1)([C:8]1C=CC=C[CH:9]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.FC(F)(F)C1C=CC=C[C:22]=1[CH:23]([OH:31])C1C=CC(C)=CC=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:23]([O:18][CH2:16][CH3:17])(=[O:31])[CH3:22].[CH3:9][CH2:8][CH2:1][CH:2]([CH3:7])[CH3:3]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CCCC(C)C
Product: CCOC(C)=O

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)-4′-methylbenzhydrol (149) (15 mmol) using the procedure described for compound (3). Flash column chromatography [SiO2; ethyl acetate-iso-hexane (5:95)] afforded a yellow gum (4.41 g) which was used in the next step without further purification.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[CH:8]1([C:14]2[CH:45]=[CH:44][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:27]=[C:28]([N:31]([CH2:33][C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=5)[CH3:32])[S:29][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>O.CO>[CH:8]1([C:14]2[CH:45]=[CH:44][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:27]=[C:28]([N:31]([CH2:33][C:34]5[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=5)[CH3:32])[S:29][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(C(=O)O)cc1)c1nc(-c2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
Tetrahydrofuran (250 ml), methanol (250 ml) and a 2N-aqueous sodium hydroxide solution (95.0 ml, 190 mmol) were added to methyl 4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (50.0 g, 94.9 mmol) obtained in Example 2(4), and the mixture was heated under reflux for 40 min under an argon atmosphere. Water (310 ml) was added to the reaction mixture and the mixture was cooled to room temperature. 2N-Hydrochloric acid (95.0 ml, 190 mmol) was added dropwise and the mixture was stirred for 90 min. The resulting crystals were collected by filtration, washed with water (700 mL) and dried to give the title compound (48.5 g, yield 99.7%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:18])[N:7]2[C:12]=1[C:11]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:10]=1[CH2:9][CH2:8]2.Cl[C:26](OC1C=CC=CC=1)=[O:27].[NH2:35][CH2:36][C:37]#[N:38].C(=O)([O-])[O-]>O1CCOCC1.N1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][N:7]3[C:12](=[C:3]([CH2:2][NH:38][CH2:37][C:36]#[N:35])[CH:4]=[C:5]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:6]3=[O:18])[C:11]=2[CH:13]=1.[Cl:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][CH2:8][N:7]3[C:12](=[C:3]([CH2:2][O:1][C:26](=[O:27])[NH:38][CH2:37][C:36]#[N:35])[CH:4]=[C:5]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:6]3=[O:18])[C:11]=2[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CCN
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccc(Cl)cc1-2
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Product: N#CCNCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 0.676 g of 6,7-dihydro-1-(hydroxymethyl)-3-phenyl-10-chloro-4H-benzo[a]quinolizine-4-one in 18 ml of dioxane was treated with 0.6 ml of phenyl chloroformate and 0.42 ml of pyridine and stirred at room temperature for 3 hours. 1.03 g of aminoacetonitrile were then added and the mixture was stirred at 100° until carbonate was no longer present according to thin-layer chromatography. After evaporation, the residue was taken up in chloroform, washed twice with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Chromatography over silica gel [elution agent toluene/dioxane (9:1)] gave [[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]acetonitrile of m.p. 181°-183° (from methanol) as well as in a second fraction (10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl-(cyanomethyl)carbamate of m.p. 166°-167° (from toluene).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][CH2:32][OH:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][CH:32]=[O:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Combine a solution of oxalyl chloride (0.238 mL, 2.72 mmol) in dichloromethane (25 mL) with dimethyl sulfoxide (0.322 mL, 4.54 mmol) at −78° C. and stir. After 15 minutes, add a solution of (S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.60 g, 1.82 mmol) in dichloromethane at −78° C. via cannula and stir at −78° C. After one hour, add triethylamine (1.27 mL, 9.08 mmol) and warm to room temperature overnight. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the title compound: mass spectrum (APCI): m/z=129.1 (M+1-2BOC).
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].[OH-].[K+].[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16]1>CO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:21]1[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A solution of 5-nitroindole (38) (0.2 g, 1.233 mmol) in dry methanol (5 mL) was treated with KOH (0.56 g) at room temperature. After stirring for 10 min., 1,4-cyclohexanedione monoethylene ketal (0.48 g, 3.083 mmol) was added and the resulting solution was refluxed for 36 h. The reaction was brought to room temperature and solvent was evaporated. The crude product was diluted with water (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by flash-column chromatography (ethyla acetate) to obtain compound 78 (0.25 g, 68%) as a solid. mp 175-177° C.; 1H NMR (CDCl3) δ 1.91 (t, 2H, J=6.6 Hz), 2.49 (brs, 2H), 2.49-2.66 (m, 2H), 3.96-4.00 (m, 4H), 6.12 (t, 1H, J=3.9 Hz), 7.22 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.1, 9.0 Hz), 8.36 (brs, 1H), 8.78 (d, 1H, J=2.1 Hz); ESI-MS m/z (%): 301 (M+, 100).
Reaction SMILES: [CH2:1]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=O)[CH2:2][CH2:3][CH2:4][CH3:5].C([NH2:20])C1C=CC=CC=1>[Pd]>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:6]([NH2:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)CCCCC
Reactant: NCc1ccccc1
Agent: [Pd]
Product: CCCCCC(N)CCCCC
Reaction time: 5 h
Yield: 75.4 %

Procedure:
Diamylketone (12 g) was hydrogenated at 50 psi in the presence of 10% Pd/C (1.5 g) and benzylamine (8.31 g) at room temperature for 6 hours. Further catalyst (1.5 g) was added and the mixture was hydrogenated at 40° for 5 hours. The reaction mixture was filtered and evaporated to dryness (combined with the product from a previous 12 g hydrogenation). The oil was purified by column chromatography to give 6-undecylamine as an oil (9.1 g, 38%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[CH2:25]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]([F:11])([F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:35][CH:36]=2)=[CH:45][CH:44]=1)=[O:47])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccccc1N
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3C(F)(F)P(=O)(OCC)OCC)cc2)cc1
Reaction time: 0.25 h

Procedure:
Tto a solution of [(2-amino-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester NVP-VAV664 in CH2Cl2 are added 5 equivalents of pyridine followed by 1 equivalent of 4′-octyloxy-biphenyl-4-carbonylchloride at rt and the mixture obtained is stirred for ca. 10 to 20 minutes. To the mixture obtained EtOAc is added and and the mixture obtained is extracted with NaHCO3. From the organic phase obtained solvent is evaporated and the evaporation residue is subjected to column chromatography. (Difluoro-{2-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-methyl)-phosphonic acid diethyl ester is obtained in the form of a colourless powder.
Reaction SMILES: N1CCOCC1.[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S-:23])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([NH2:32])=[O:31]>C1COCC1>[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S:23][CH2:29][C:30]([NH2:32])=[O:31])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c([S-])c1C#N
Reactant: NC(=O)CBr
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 25 °C
Yield: 360.4 %

Procedure:
To a solution of 0.940 g (2.28 mmol) of the above morpholine salt in THF (15 mL), cooled to 0° C., was added 0.315 g (0.280 mmol) of 2-bromoacetamide as a solid in one portion. The mixture was stirred and allowed to slowly warm to room temperature over a 2 h period during which time salts precipitated from solution. The mixture was filtered through diatomaceous earth to remove solids and the filter pad was washed with EtOAc. The mixture was concentrated under reduced pressure to provide 0.385 g (44%) of 2-{4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl}-acetamide as an orange foam.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]([C:23]1[CH:31]=[CH:30][C:26](C(Cl)=O)=[CH:25][CH:24]=1)#[N:22].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[C:26]2[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:31][CH:30]=2)[C@H:8]([C:18]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COCCN
Product: C=CCON=C1C[C@@H](C(=O)NCCOC)N(C(=O)c2ccc(C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2-methoxyethylamine the title compound was obtained in 44% purity by LC/MS. MS(ESI+): m/z=371.0.
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([NH2:20])[N:17]=[C:18](Cl)[C:3]=2[N:2]=1.Cl.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C(N(CC)CC)C>C(O)C>[NH2:20][C:16]1[N:15]=[C:4]2[C:3]([N:2]=[CH:1][N:5]2[C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])=[C:18]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([I:22])[CH:24]=2)[N:17]=1
Reactant: NCc1cccc(I)c1
Reactant: Nc1nc(Cl)c2ncn(C3OC(CO)C(O)C3O)c2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(NCc2cccc(I)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
A mixture of 2-amino-6-chloropurine riboside (purchased from Aldrich Chemical Co., 80 mg, 0.26 mmol), 3-iodobenzylamine hydrochloride (71.5 mg, 0.265 mmol), and triethylamine (0.11 ml, 0.79 mmol) in ethanol (1.6 ml) was heated for 24 h at 80° C. After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1) to yield 2-amino-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (99 mg, 75%) as a colorless solid: m.p. 152°-154° C.; 1H NMR (DMSO-d6) d 3.52 (m, 1H, H-5'a), 3.63 (m, 1H, H-5'b), 3.89 (m, 1H, H-4'), 4.10 (m, 1H, H-3'), 4.50 (m, 1H, H-2'), 4.60 (br s, 2H, CH2), 5.08 (d, J=4.6 Hz, 1H, exchangeable with D2O, 3'-OH), 5.35 (m, 2H, exchangeable with D2O, 5'- and 2'-OH), 5.73 (d, J=6.2 Hz, 1H, H-1'), 5.83 (br s, 2H, exchangeable with D2O, NH2), 7.11 (pseudo t, J=7.9 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.70 (s, 1H, H-2"), 7.94 (s, 1H, H-8).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH2:12][NH2:13].C(OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[C:4]1([C:3]2[O:2][CH:1]=[N:12][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: c1ccc(-c2nnco2)cc1
Temperature: 80 °C

Procedure:
Benzoic acid methyl ester (1.01 g, 7.34 mmol) and hydrazine monohydrate (10 mL) were dissolved in EtOH (20 mL) then heated in a sealed tube to 80° C. for 23 hours. The reaction was allowed to cool and then triethylorthoformate (25 mL) and p-toluenesulfonic acid (0.100 g, 0.526 mmol) were added, the tube was re-sealed, and the reaction was heated to 120° C. for 26 hours. The reaction mixture was then submitted to standard aqueous workup and purified on silica gel (0-70% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: C([O-])(=[S:3])C.[K+].Cl[CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.[Na+].[Cl-].[C:20]([O:23]CC)(=O)[CH3:21]>C(#N)C>[C:20]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:3])(=[O:23])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)CC(=O)CC(=S)OC(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
2.40 g (21.0 mmols) of dry potassium thioacetate were added to a solution, cooled to 0° C., of 3.85 g (20.0 mmols) of tert.-butyl 4-chloroacetoacetate in 40 ml of anhydrous acetonitrile and the mixture was stirred at this temperature for 30 minutes. Thereafter, the mixture was poured into a mixture of NaCl solution and ethyl acetate, the organic phase was separated off and extracted with 2×30 ml of ethyl acetate and the extracts were washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 95:5), 3.87 g (83%) of the title compound were obtained as a colorless oil, RF :0.2 (toluene:ethyl acetate 95:5).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:20])([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1)[CH3:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CCOC(C)=O>[C:1]([O:7][C:8]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:23](=[O:24])[CH2:22][Cl:21])([CH3:20])[CH3:9])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)OC(C)(C)C1NCCc2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC(C)(C)C1c2ccccc2CCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-methyl-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl pivalate (2.79 g) was dissolved in a 1:4 mixed solvent (30 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of chloroacetyl chloride (0.9 mL) in EtOAc (6 mL) was added dropwise to the reaction liquid under ice-cooling, followed by stirring at room temperature for 2 hours and extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-[2 (chloroacetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-methylethyl pivalate (3.01 g).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2C)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]phenol (137 mg, 0.38 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (170 mg, 0.5 mmol, 1.4 eq). The resulting mixture was stirred for 30 min at room temperature, then ethyl 2-bromoacetate (77 mg, 0.46 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 2.5 h and then diluted in water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (120 mg, 70%).