Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:19][CH2:18][C:17](=O)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH:33][CH:17]2[CH2:18][CH2:19][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]
Reactant: CCOc1cccc([C@@H](C)N)c1
Reactant: O=C1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Agent: Cl
Product: CCOc1cccc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)N4CCOCC4)cc3)C2)c1

Procedure:
General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (1R)-1-(3-ethoxyphenyl)-ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 7.33-7.21 (m, 4H), 7.19 (t, J=7.8 Hz, 1H), 6.93-6.86 (m, 2H), 6.74 (dd, J=7.9, 2.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.70 (q, J=6.6 Hz, 1H), 3.57 (br s, 4H), 3.33 (br s, 4H), 3.27-3.20 (m, 1H), 3.03 (t, J=8.3 Hz, 1H), 2.11-2.03 (m, 1H), 1.95-1.88 (m, 1H), 1.78-1.72 (m, 1H), 1.64-1.41 (m, 3H), 1.34-1.28 (m, 3H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1

Procedure:
2.3 g (5 mmol) of the compound from Example I are stirred at 25° C. for 5 h in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid. After concentration, the crude product is chromatographed on silica gel 60 using dichloromethane/methanol (100:5).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzaldehyde (4.38 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess 2,6-dichlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the gummy oil which separates is extracted into ether. The ether extract is washed with brine solution, and dried (Na2SO4). Removal of the ether in vacuo, yields a yellowish residue which after recrystallization from a mixture of n-butyl chloride and petroleum ether (30°-60°C.) gives a white material, 1.75 g., m.p. 140.5°-143°C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1>>[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH:61][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:59][CH:58]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1

Procedure:
The product is prepared according to the procedure described in stage 3 of Example 1, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1, 595 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 182 mg of 1-hydroxybenzotriazole and 0.235 ml of 4-fluoroaniline in place of aniline. 110 mg of N-(4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[OH-].[K+]>ClCCl.C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(Br)ccc2F)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a well stirred solution of (5-bromo-2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone (22.5 g, 72.80 mmol) and triethylsilane (27.9 mL, 20.3 g, 175.0 mmol) in dichloromethane (20 mL) and acetonitrile (60 mL) at 0° C. was added boron trifluoride etherate (32.0 mL, 36.2 g, 255.0 mmol) dropwise. Boron trifluoride etherate was added at a rate so that the internal temperature did not exceed 20° C. The reaction solution was warmed to room temperature and stirred overnight. After a total of 18 hours, a solution of potassium hydroxide (5.0 g) in water (15.0 mL) was added and the resulting mixture was stirred for 2 hours. The organic phase was separated and the aqueous phase was extracted two times with diethyl ether. The combined organic phases were washed once with aqueous 1M sodium hydroxide solution and once with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Upon addition of ethanol to the resulting residue a white solid formed. The solid was collected and dried under high vacuum to afford 4-bromo-1-fluoro-2-(4-methoxy-benzyl)-benzene (20.1 g, 93% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[S:19][C:18]3[N:20]=[CH:21][CH:22]=[N:23][C:17]=3[N:16](COC)[C:15]=2[CH:27]=1)=O.S(Cl)(Cl)=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[N:7]1[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][C:18]4[N:20]=[CH:21][CH:22]=[N:23][C:17]=4[NH:16][C:15]=3[CH:27]=2)[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: COCN1c2cc(C(=O)CNc3ccccn3)ccc2Sc2nccnc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: c1ccn2c(-c3ccc4c(c3)Nc3nccnc3S4)cnc2c1
Yield: 61.6 %

Procedure:
10 ml of a solution of 200 mg of [N-(2-pyridyl)aminometyl](10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone in carbon tetrachloride was stirred at room temperature and 240 mg of thionyl chloride was dropped thereinto. The reaction mixture was distributed into dichloromethane and an aqueous solution of sodium bicarbonate and the organic layer was separated. To the organic layer were added methanol and tetrahydrofuran to give a homogeneous solution. After adding silica gel and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 103 mg of the title compound as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Yield: 92 %

Procedure:
The mixture of 2-bromo-1-fluoro-4-nitrobenzene (5 g), (3-fluorophenyl)methanol (2.86 g) and K2CO3 (9.4 g) in Acetone (50 mL) was refluxed for 4 h. The solid was filtered and the solvent was removed. The obtained yellow solid was recrystallized from EtOAc/Hexane to provide brown solid (6.8 g). Yield: 92%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH3:41])([CH3:40])[C@H:12]3[C@:25]([CH3:28])([CH2:26][CH:27]=2)[CH:24]2[C@:15]([CH3:39])([C@@:16]4([CH3:38])[C@H:21]([CH2:22][CH2:23]2)[C@H:20]2[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]2([C:35]([OH:37])=[O:36])[CH2:18][CH2:17]4)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]>CCOC(C)=O.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:27][CH2:26][C@@:25]3([CH3:28])[C@@H:12]([CH2:13][CH2:14][C@:15]4([CH3:39])[CH:24]3[CH2:23][CH2:22][C@H:21]3[C@@:16]4([CH3:38])[CH2:17][CH2:18][C@@:19]4([C:35]([OH:37])=[O:36])[CH2:31][CH2:30][CH:29]([CH:32]([CH3:34])[CH3:33])[C@@H:20]43)[C:11]2([CH3:41])[CH3:40])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6cccc(C(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](c6cccc(C(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-9-(3-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (20 mg, 0.036 mmol) in EtOAc (3 mL) was added 10% Pd/C (4 mg, 0.0036 mmol). The reaction mixture was stirred at room temperature under 1 ATM of H2 for 36 h. LCMS indicated the reaction was complete and the desired product was formed. The reaction mixture was filtered through a celite pad which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide (3aS,5aR,5bR,7aS,9S,11aS,13aR,13bR)-9-(3-carboxyphenyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid as a white solid (8 mg, 38%). LCMS: m/e 561.45 (M−H)−, 3.53 min (method 5). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.64 (s, 3H), 0.71 (s, 3H), 0.74 (d, J=6.71 Hz, 3H), 0.80-0.86 (m, 3H), 0.92 (s, 3H), 0.93 (s, 3H), 0.95-0.98 (m, 3H), 0.98-1.66 (m, 18H), 1.68-1.82 (m, 3H), 2.07-2.22 (m, 3H), 2.23-2.34 (m, 1H), 2.42 (dd, J=13.12, 2.75 Hz, 1H), 7.36 (t, J=7.48 Hz, 1H), 7.39-7.46 (m, 1H), 7.70-7.80 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C([O-])([O-])=O.[K+].[K+].[CH2:13](O)[CH:14]=[CH:15]C>>[C:1]([O:5][CH2:6][CH:13]=[CH:14][CH3:15])(=[O:4])[CH2:2][OH:3]
Reactant: CC=CCO
Reactant: COC(=O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=CCOC(=O)CO

Procedure:
Methyl glycolate (10.4 g, 114 mmol), crotyl alcohol (100 ml, excess), was refluxed in the presence of K2CO3 (0.8 g) for 1 hr, during which time about 10 ml of the condensate was removed through a Dean-Stock trap. After diluting with hexane (100 ml), the solid was filtered through a short silica gel column (50 g), washed with 1:5 ethylacetate:hexane (250 ml). The combined filtrate and washings was concentrated to 100 ml, and was diluted again with hexane (100 ml), passed through silica gel column and washed. The solution was concentrated to ˜12.5 g of oil, which was vacuum distilled to give crotyl glycolate: 9.3 g (97° C./20 mmHg) as a mixture of cis:trans (1:10). NMR (500 MHz, CDCl3) δ: 1.3 (m, 3H), 4.15 (s, 2H), 4.62 (d, 2H), 5.6 (m, 1H), 5.84 (m, 1H). cis isomer: 1.71 (m, 3H), the rest peaks overlaps with trans isomer.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH3:30])[CH2:20][CH2:19]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[Cl:13][C:14]([Cl:25])([Cl:24])[C@H:15]1[O:22][C:21](=[O:23])[C@H]2[N:16]1[CH2:17]CC2.IC>O1CCCC1.O>[CH3:4][C@@:3]12[CH2:2][CH2:1][CH2:17][N:16]1[C@@H:15]([C:14]([Cl:25])([Cl:24])[Cl:13])[O:22][C:21]2=[O:23]
Reactant: [Li]CCCC
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Solvent: O
Solvent: CI
Solvent: CC(C)NC(C)C
Product: C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
n-Butyllithium (1.31 M, 4.68 cm3, 6.14 mmol) was added dropwise to a stirred solution of diisopropylamine (0.86 cm3, 6.14 mmol) in dry tetrahydrofuran (10 cm3) at −78° C. under an atmosphere of nitrogen. The solution was stirred for 5 min, warmed to 0° C. and stirred for 15 min. The solution was added dropwise to a solution of oxazolidinone 7 (1.00 g, 4.09 mmol) in dry tetrahydrofuran (20 cm3) at −78° C. over 20 min (reaction mixture turned dark), stirred for a further 30 min then iodomethane (0.76 cm3, 12.3 mmol) added dropwise over 5 min. The solution was warmed to −50° C. over 2 h. Water (15 cm3) was added, the solution warmed to room temperature and extracted with chloroform (3×40 cm3). The combined organic extracts were dried (MgSO4), filtered and evaporated to dryness in vacuo to give a dark brown semi-solid. Purification of the residue by flash column chromatography (15% ethyl acetate-hexane) afforded oxazolidinone 8 (0.67 g, 63%) as a pale yellow solid: mp 55-57° C. (lit. Wang 57-60° C.): δH (300 MHz; CDCl3) 1.53 (3H, s, CH3), 1.72-2.02 (3H, m, Proβ-H and Proγ-H2), 2.18-2.26 (1H, m, Proβ-H), 3.15-3.22 (1H, m, Proδ-H), 3.35-3.44 (1H, m, Proδ-H) and 4.99 (1H, s, NCH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][O-:14].[Na+]>CO.CCOC(C)=O>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:3]([CH2:2][O:14][CH3:13])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1cc(Cl)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
To a suspension of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.04 mmol) (A.2.2.1.) in 2.5 mL MeOH was added a solution of NaOMe (1.27 mmol, 0.5M in MeOH). The reaction mixture was heated to 50° C. for 1 h. The mixture was conc. in vacuo, redissolved in EtOAc and it was then washed twice with an aq. soln. of KHSO4, twice with a sat. aq. NaHCO3 soln. and once with brine. The org. layer was dried over MgSO4 and conc. in vacuo to give the desired product as orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Li+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CC(=O)Nc1ccccc1O
Yield: 34.1 %

Procedure:
20 g of o-amino phenol was dissolved in 200 mL of N-methyl-2-pyrrolidone (NMP), and then the solution was ice-cooled. To the solution was added 8.546 g (1.1 times in mol) of lithium chloride. After lithium chloride was entirely dissolved, 17.42 g (1.05 times in mol) of acryloyl chloride was dropped into the solution, and the solution was stirred under ice-cooling for 5 hours. The reaction mixture was poured into 1.8 L of water, and an organic layer was extracted with 700 mL of diethyl ether. The diethyl ether layer was sequentially washed with 0.2 N hydrochloric acid, brine and water, and dried over magnesium sulfate. Diethyl ether was evaporated off under a reduced pressure. 80 mL of diisopropyl ether was added to the solidified residue, and the solution was heated and stirred to wash and filter the residue. The same washing process was carried out once again to obtain 10.2 g of N-(2-hydroxyphenyl)acrylamide as white powder (yield: 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[C:10](=[CH:14][CH:15]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.[CH2:21]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26](=[O:29])[CH2:27][N:28]1[C:16](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=3)[CH:8]=2)[C:11]1=[O:13])[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2)cc1C(=O)O
Reactant: CCCCOC(=O)CN
Product: CCCCOC(=O)CN1C(=O)c2ccc(Oc3ccc(Cl)cc3)cc2C1=O
Temperature: 250 °C
Yield: 65.8 %

Procedure:
A mixture of 500 mg 4-(4-Chloro-phenoxy)-phthalic acid and glycine n-butyl ester (286 mg) was heated at 250° C. for 5 min. The reaction mixture was purified by chromatography with dichloromethane as eluent to give 436 mg the title compound. 1H NMR (200 MHz, DMSO) δ 7.48 (d, J=8.6 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.46 (m, 2H), 7.29 (d, J=9.0 Hz, 2H), 4.46 (s, 2H), 4.16 (t, J=6.2 Hz, 2H), 1.61 (m, 2H), 1.38 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:8][C:9](=[O:63])[C@H:10]([CH2:48][CH2:49][CH2:50][CH2:51][NH:52]C(OCC1C=CC=CC=1)=O)[NH:11][C:12](=[O:47])[C@H:13]([CH:44]([CH3:46])[CH3:45])[NH:14][C:15](=[O:43])[C@H:16]([CH3:42])[NH:17][C:18](=[O:41])[C@H:19]([CH2:37][CH2:38][S:39][CH3:40])[NH:20][C:21](=[O:36])[C@H:22]([CH2:31][CH2:32]C(=O)N)[NH:23][C:24]([O:26]C(C)(C)C)=O)C1C=CC=CC=1.O.CCN(C(C)C)C(C)C.[SH3+]>CN(C=O)C.CC(O)=O.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH:23]1[C:24](=[O:26])[CH2:32][CH2:31][C@H:22]1[C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:8])=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:47])[CH:44]([CH3:45])[CH3:46])=[O:43])[CH3:42])=[O:41])[CH2:37][CH2:38][S:39][CH3:40])=[O:36]
Reactant: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)O)C(C)C
Reaction time: 8 h

Procedure:
A sample of the protected 5-peptide XXIII (0.50 g, 0.55 mmole) was dissolved in DMF (60 ml), H2O (6 ml), DIEA (6 ml) and 10% Pd/BaSO4 (0.10 g) were added and the mixture hydrogenated for 8 hr. On tlc a single spot (RfC, 0.45; RfL, 0.75) was observed. The black solution was filtered on a layer of Celite, the latter washed with DMF and the filtrates evaporated in vacuo to dryness. The residue was dissolved in TFA (20 ml) containing acetyl-DL-methionine n-butyl ester (1.0 g) and kept at room temperature for 1/2 hr. The TFA was removed in vacuo and the residue dissolved in a mixture of EtOAc (20 ml) and H2O (20 ml). The aqueous layer was extracted twice with EtOAc (20 ml each), filtered and lyophilized to give a white powder, 0.40 g. In system C the spot remained near the origin; RfM, 0.45. Trace amounts of impurities, probably the pyroglutamyl derivative and the sulfonium salt could also be detected. A sample (0.10 g) was dissolved in AcOH (ca 2 ml) and heated to boiling for 3 min. After cooling the product was precipitated with ether (20 ml). The pyroglutamyl derivative was collected, washed with ether: 80 mg; m.p. 238°-242° C.; RfC, 0.10; RfM, 0.60. Glu, 0.98; Ala, 0.99; Val, 1.01; Met, 0.96.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[NH:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOC(=O)CCCN
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Product: CCOC(=O)CCCNCC(=O)OC(C)(C)C
Yield: 55 %

Procedure:
By a method substantially equivalent to that described in Example 2-A; 13.6 g (55%) of N(CH2CH2CH2COOEt)Gly-O-t-Bu were prepared from t-butyl bromoacetate and ethyl 4-amino-butyrate hydrochloride.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([B:22]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5 M n-BuLi in hexane (39.8 ml, 59.7 mmol) at −78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at −78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound.