Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[O:23]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:31][CH:32]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4phenoxybenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-phenoxybenzylamine using method N. NMR; δH [2H6]—DMSO 9.15,(1H, t), 8.00,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.53,(3H, m), 7.37,(4H, m), 7.11,(1H, m), 7.01-6.96,(4H, m), 4.49,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.76 min, MH+ 476.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:2][CH3:3])=[O:10])[CH2:6]1
Reactant: CCI
Reactant: C=C1CC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)OCC)C1
Reaction time: 16 h

Procedure:
Iodoethane (7.5 mL, 93.0 mol) was added at rt to a mixture of 3-methylenecyclobutanecarboxylic acid (10.0 g, 80.0 mmol) and cesium carbonate (56.0 g, 170.0 mmol) in anhydrous N,N-dimethylformamide (500.00 mL) under an atmosphere of nitrogen. The reaction was stirred for 16 hr then partitioned between diethyl ether (1 L) and brine (1 L). The aqueous layer was extracted with diethyl ether (3×500 mL) and the combined organic phases washed with water (2×1 L), dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, 3H), 2.71-3.27 (m, 5H), 4.15 (q, J=7.07 Hz, 2H) and 4.53-4.96 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:33])[CH:5]=1)([CH3:3])[CH3:2].[C:34]1([CH2:40][O:41][C:42](=[O:49])[C:43]([CH3:48])([CH3:47])[CH2:44][CH2:45]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:45][CH2:44][C:43]([CH3:48])([C:42]([O:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:49])[CH3:47])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(CCO)C(=O)OCc1ccccc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCC(C)(C)C(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (7 g; 14.55 mmol), 4-hydroxy-2,2-dimethylbutyric acid phenylmethyl ester (3.88 g;17.46 mmol), DEAD (3.04 g; 17.46 mmol) was dissolved in 180 ml of THF at 00C and then (Ph)3P (4.575 g; 17.46 mmol) was added at 0° C. The above mixture was stirred overnight at room temperature and concentrated in vacuo, and the residue was purified by column chromatography (2×, silica gel; 12-33% ethyl acetate/hexane;methylene chloride/hexane, 1/4-30/1) to afford 3.65 g (37%) of 4-isopropyl-6-[3-methyl-3-(phenylmethyloxycarbonyl)butoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)2 C(CH3)2CO2Ph) as a solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.Cl[C:17]1[N:22]=[C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]([CH3:42])([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:33])=[N:31][C:26]3=[N:25][CH:24]=2)[CH:20]=[CH:19][N:18]=1>C1COCC1>[N:11]1([C:17]2[N:22]=[C:21]([C:23]3[N:27]4[CH:28]=[CH:29][C:30]([C:32]([CH3:33])([O:34][Si:35]([CH2:36][CH3:37])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH3:42])=[N:31][C:26]4=[N:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: c1c[nH]cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-n4ccnc4)n3)cnc2n1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of LiHMDS (370 μl) in hexanes (1.0M, 370 μmol) was added to a stirred solution of imidazole (25 mg, 0.37 mmol) and 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (from Example 34) (150 mg, 0.37 mmol) in THF (5 ml) at −78° C. under N2. The reaction was allowed to warm slowly to room temperature overnight and was then quenched with NH4Cl solution (10 ml). The organics were extracted with EtOAc (2×25 ml), washed with brine (10 ml) and concentrated under reduced pressure while dry loading onto silica. The residue was purified by column chromatography on silica using 100% EtOAc as the eluent to afford 3-[2-(imidazol-1-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (73 mg, 45%): 1H NMR (400 MHz, d6-DMSO) δ 10.08 (1H, d, J 7.2), 8.93 (1H, s), 8.85-8.78 (2H, m), 8.13 (1H, d, J 1.1), 8.03 (1H, d, J 5.5), 7.72 (1H, d, J 7.2), 7.21 (1H, s), 1.64 (6H, s), 0.96 (9H, t, J 8.0), 0.65 (6H, q, J 8.0); m/z (ES+) 453 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Cl)cc1

Procedure:
Chlorobenzene (0.3 mL), acryloyl chloride (120 mg), and aluminium chloride (115 mg) were reacted in dichloromethane (1 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (390 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]C2C=CC=CC=2)=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:41]1([CH2:47][CH2:48][S:49][CH:50]([C:54]([OH:56])=O)[C:51]([OH:53])=[O:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[OH:56][C:54]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[O:53][C:51](=[O:52])[C:50]=1[S:49][CH2:48][CH2:47][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: COc1ccccc1COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]phenylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 138°-139° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 3.83 (s, 3 H), 5.14 (s, 2 H), 6.68 (s, 1 H), 6.97 (t, 1 H), 7.08 (d, 1 H), 7.20 (m, 7 H), 7.53 (t, 1 H), 7.40 (d, 1 H), 7.76 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[CH2:3]1.C([O:33]OC(C)(C)C)(C)(C)C>C(Cl)Cl>[O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[CH2:3]1
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CS(=O)c3ccccc32)c1
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CS(=O)(=O)c3ccccc32)c1
Reaction time: 8 h
Yield: 29.3 %

Procedure:
Dissolve N-[3-(10-oxo-10,11-dihydro-10λ4-thia-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide (35 mg, 0.085 mmol) in 5 mL of methylene chloride at ambient temperature. Add 300 mg of silica gel followed by t-butylperoxide (0.012 mL, 0.085 mmol). Stir overnight, filter and evaporate. Recrystallize from 1:1 ether:pentane to obtain 10.6 mg of the product as a yellow solid. 1H N (CDCl3) δ8.91 (b, 1H), 7.85 (m, 1H), 7.57 (m, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.25-7.15 (m, 2H), 7.10 (m, 1H), 7.02 (m, 1H), 7.00-6.95 (m, 1H), 6.30 (d, 2H), 6.15 (d, 1H), 5.25 (t, 1H), 4.40 (t, 1H), 2.80 (s, 311). MS [EI+] 424 (M−H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19]CC=C)[C@H:17]([O:23][C@@H:24]2[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:25]2[NH:55][C:56](=[O:58])[CH3:57])[C@@H:16]([CH2:59][O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].N12CCN(CC1)CC2>[Rh].[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@H:18]([OH:19])[C@H:17]([O:23][C@@H:24]2[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C@@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:25]2[NH:55][C:56](=[O:58])[CH3:57])[C@@H:16]([CH2:59][O:60][CH2:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1[C@@H](NC(C)=O)[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(C)=O
Agent: Cl[Rh]
Agent: [Rh]
Agent: C1CN2CCN1CC2
Product: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2NC(C)=O)[C@@H]1O
Reaction time: 8 h

Procedure:
To a solution of benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-D-glucopyranoside (597 mg, 0.65 mmol) in 7:3:1 (v/v/v) ethanol-toluene-water (25 ml) stirred at reflux temperature under an atmosphere of nitrogen are added 1,4-diazabicyclo[2.2.2] octane (75 mg, 0.67 mmol) and tris(triphenylphosphine) rhodium (I) chloride (50 mg). Two further additions of 50 mg of the rhodium catalyst are made at 90 minute intervals, and stirring at reflux temperature under nitrogen is continued overnight. The cooled solution is then evaporated, the residue taken up in chloroform (80 ml), washed three times with water, dried (magnesium sulfate), and evaporated. The residue is then stirred in aqueous (1.5 ml) tetrahydrofuran (15 ml) in the presence of mercuric chloride (750 mg) for 30 minutes at room temperature. The reaction mixture is then evaporated, the residue taken up in chloroform (75 ml), washed twice with 2.5 M aqueous potassium iodide, dried (magnesium sulfate) and evaporated to a residue that is applied to a column of silica gel (40 g) that is eluted with 2:1 chloroform-ethyl acetate. Combination and evaporation of the appropriate fractions affords benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)-6-O-benzyl-2-deoxy-α-D-glucopyranoside; yield 362 mg (63%); m.p. 220.5°-221.5° (methanol), [α]D25 +74° (c, 1.5, chloroform). The 300 MHz nmr spectrum in chloroform-d is in accord with the desired structure.
Reaction SMILES: [OH-].[Na+].O[CH:4]([CH3:30])[CH2:5][N:6]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:7][CH2:8][O:9]S(C1C=CC(C)=CC=1)(=O)=O.O>CO.C(Cl)Cl>[CH3:30][CH:4]1[O:9][CH2:8][CH2:7][N:6]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CC(C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCOC(C)C2)cc1
Reaction time: 1 h

Procedure:
Sodium hydroxide (0.91 g, 0.02 mol) suspended in methanol (15 ml) was added to a stirred solution of Toluene-4-sulfonic acid 2-[(2-hydroxy-propyl)-(toluene-4-sulfonyl)-amino]-ethyl ester (9.69 g, 0.02 mol) in DCM (15 ml). After 1 h, water (50 ml) was added to the solution. The organic layer was collected, dried over sodium sulphate and evaporated in vaccuo to yield a green oily residue. This was purified by chromatographic separation (20% Ethyl acetate:petrol) to yield the title compound as a white solid. (1.70 g, 6.66 mmol, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:47])[C@H:26]([CH:44]([CH3:46])[CH3:45])[NH:27][C:28](=[O:43])[C@H:29]([CH:40]([CH3:42])[CH3:41])[NH:30][C:31](=[O:39])[C@H:32]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])[NH2:33].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][O:24][C:25](=[O:47])[C@H:26]([CH:44]([CH3:46])[CH3:45])[NH:27][C:28](=[O:43])[C@H:29]([CH:40]([CH3:42])[CH3:41])[NH:30][C:31](=[O:39])[C@H:32]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])[NH:33][C:14](=[O:15])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:20][CH2:21][CH2:22][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C=CCOC[C@H](N)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Temperature: 0 °C
Yield: 92.3 %

Procedure:
N-tert-butoxycarbonyl L-prolyl L-proline 2 (3.80 g, 12.2 mmol) and O-allyl L-seryl L-valyl L-valine methyl ester 9 (4.35 g, 12.2 mmol) were dissolved in DMF (25 mL) and the solution cooled to 0° C. HOBt hydrate (1.87 g, 12.2 mmol) was added under stirring. EDC hydrochloride (2.57 g, 13.4 mmol) was added to the reaction mixture in small portions. The reaction mixture was stirred overnight and the solvent evaporated. The residue was taken up in EtOAc (50 mL) and washed with 2M HCl (3×25 mL), 7.5% (w/w) K2CO3 (3×25 mL) and saturated brine (20 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.34 g, 93%); δH (300 MHz; d6-DMSO) 8.10 (1H, d, J 8, NH(Valx)), 7.98 (1H, d, J 8, NH(Ser(All))), 7.60 (1H, d, J 9, NH(Valy), rotomer 1), 7.59 (1H, d, J 9, NH(Valy), rotomer 2), 5.83 (1H, ddt, J 5, 11 and 17, CH═CH2), 5.24 (1H, ddt, J 1, 3 and 17, CH═CHH), 5.14-5.09 (1H, m, CH═CHH), 4.46-4.37 (3H, m, CαH(Pro1)/CαH(Pro2)/CαH(Ser(All))), 4.32 (1H, dd, J 7 and 9, CαH(Valy)), 4.15-4.10 (1H, m, CαH(Valx)), 3.93 (2H, m, J 1 and 5, CH2CH═CH2), 3.67-3.50 and 3.36-3.24 (6H, m, CδH2(Pro1)/CδH2(Pro2)/CH2(Ser(All))), 3.61 (3H, s, OCH3), 2.26-1.71 (10H, m, CH2(Pro)/CH(CH3)2), 1.37 (9H, s, (CH3)3, rotomer 1), 1.30 (9H, s, (CH3)3, rotomer 2), 0.89-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.6, 171.5, 171.3, 171.1, 170.9, 170.4, 169.1, 169.1, 153.3, 152.9, 134.8, 116.5, 78.3, 78.1, 71.1, 69.3, 59.1, 57.4, 57.2, 56.9, 52.9, 51.4, 46.5, 46.4, 46.3, 46.3, 30.9, 30.6, 29.6, 29.5, 29.4, 28.7, 28.5, 28.1, 27.9, 24.4, 24.3, 23.6, 23.0; m/z (ESI) 674.3737 ([M+Na]+; C32H53N5O9Na requires 674.3741)
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Br[C:8]1[N:9]=[C:10]([NH:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:11]2[N:12]([C:14]([C:17]3[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])=[C:19]([CH3:29])[CH:18]=3)=[CH:15][N:16]=2)[CH:13]=1>CS(C)=O>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[CH:28][C:17]([C:14]3[N:12]4[CH:13]=[C:8]([S:4][CH2:1][CH2:2][CH3:3])[N:9]=[C:10]([NH:30][CH2:31][C:32]([OH:35])([CH3:33])[CH3:34])[C:11]4=[N:16][CH:15]=3)=[CH:18][C:19]=2[CH3:29])[CH2:25][CH2:26]1
Reactant: CCCS
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)nc(Br)cn23)ccc1C(=O)NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCSc1cn2c(-c3ccc(C(=O)NC4CC4)c(C)c3)cnc2c(NCC(C)(C)O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80 mg (1.05 mmol) 1-propanethiol in 1.5 mL DMSO were added 50 mg (1.052 mmol) sodium hydride and the mixture was stirred for 2 h at rt. 100 mg (0.21 mmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropyl-2-methylbenzamide were added and the mixture was heated at 120° C. for 2 h. The mixture was filtered and purified by HPLC.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:14][CH:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C1CCCC1O
Reaction time: 20 h
Yield: 47.3 %

Procedure:
A suspension of 0.339 g (3 mmol) of 2-nitroimidazole, 30 ml of ethanol, 3.5 ml of cyclopentene oxide and 0.15 g of potassium carbonate was refluxed with stirring under nitrogen for 20 hr. A clear yellow solution resulted; this was evaporated and the residue dissolved in 50 ml of chloroform and filtered. The filtrate was evaporated to yield 0.28 g (47.3%) of the title compound. It was recrystallized from ethyl acetate, mp 109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:15])[CH:4]=1.[Br:16]N1C(=O)CCC1=O>ClCCCl>[Br:16][C:4]1[C:5](=[O:15])[CH:6]([CH2:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH2:7][C:3]=1[O:2][CH3:1]
Reactant: COC1=CC(=O)C(CC2CCOCC2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: COC1=C(Br)C(=O)C(CC2CCOCC2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (906 mg, 4.7 mmol) in 1,2-dichloroethane (15 ml) at 0° C. in an amber flask was added portion wise over one hour N-bromosuccinimide (890 mg, 5 mmol). The reaction was stirred at 0° C. for a further 90 minutes and then any remaining solid was removed by filtration. The filtrate was evaporated to dryness under reduced pressure, the resultant solid dissolved in warm toluene (50 ml) and washed quickly with ice-cold water (2×20 ml). The organic phase was dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was purified using column chromatography (40% to 80% EtOAc in hexane) to give 2-bromo-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:15])(=O)=O.O>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Cl:15])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g 3-Oxo-heptanoic acid methyl ester were dissolved in 80 ml dry dichloromethane and 2.82 ml sulfurylchloride were added. The reaction mixture was stirred at room temperature for 30 minutes. 20 ml of water were added and the reaction mixture extracted five times with portions of 30 ml of dichloromethane. The combined organic extracts were washed with water and saturated NaHCO3 solution and brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester as raw material. This material was used without further purification. 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester were dissolved in 50 ml ethanol and 6.4 g 4-(Trifluoromethyl)thiobenzamide were added. The reaction mixture was heated under reflux overnight. The solvent was removed under reduced pressure and the residue purified by chromatography with the eluent n-heptane:ethyl acetate=100:1=>60:1. This gives 7.4 g 4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester as yellow oil.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O.[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24]>CC(O)=O>[CH3:19][O:20][C:21](=[O:26])[C:22]1[CH:4]=[CH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:25][C:23]=1[CH3:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: CN(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
4.59 g (16.3 mmol) of the above prepared 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 1.86 g (1.0 eq.) of 3-aminocrotonic acid methyl ester were dissolved in 50 ml of AcOH and heated to reflux for 4 h. After cooling, the bulk of the solvent was evaporated in vacuum, the residue dissolved in AcOEt, and washed with water and brine. Drying over sodium sulfate, evaporation of the solvents and flash chromatography (SiO2, hexane/AcOEt=8/2) delivered finally 2.40 g of the title compound as light yellow waxy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:35][C@H:36]([C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([NH:35][C@H:36]([C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:47][CH2:48]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N1CCN(c2ccccc2)CC1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Product: NC(=O)C[C@H](NC(=O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(c2ccccc2)CC1
Yield: 32.5 %

Procedure:
Condensation of 3-(2,4-dibenzyloxyphenyl)propionic acid (772 mg) and 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-phenylpiperazine (964 mg) was carried out in the same manner as in Example 7 (i) to obtain colorless crystal 1-[3-(2,4-dibenzyloxyphenyl)propionyl-L-asparaginyl]- 4-phenylpiperazine (430 mg). Melting point: 96°-98° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:20][C:21]1[N:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:20][C:21]1[CH:26]=[N:25][C:24]([O:27][CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[CH:23][N:22]=1
Reactant: Oc1cnc(Br)cn1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3cnc(Br)cn3)co2)cc1
Reaction time: 1 h

Procedure:
A mixture of 4-chlormethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.345 g, 1.2 mmol), 5-bromo-pyrazin-2-ol (0.175 g, 1.0 mmol) and cesium carbonate (Cs2CO3) (0.489 g, 1.5 mmol) in DMF (4 ml) is kept at 80° C. for 1 h. After cooling ethyl acetate (40 ml) is added, the mixture is washed with sat. NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexane 1:9->ethyl acetate/hexane 1:2) yielding 2-bromo-5-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl-methoxy}-pyrazine as a white solid. Yield 122 mg (29%).