Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[O:13].[ClH:14].NO.C(=O)([O-])[O-].[Ba+2]>C(O)(C)C>[Cl:14][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[O:13]
Reactant: CC(C)OC(=O)C1SCC(C)C1=O
Reactant: Cl
Agent: NO
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)O
Product: CC(C)OC(=O)C1SCC(Cl)C1=O

Procedure:
A mixture of 505 g (2.5 mol) of i-propyl 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylate, 497 g (7.2 mol) of hydroxylamine hydrochloride, 753 g (3.8 mol) of barium carbonate and 2.5 litres of isopropanol is heated under reflux for about 12 hours. The mixture is subsequently filtered off with suction, the filter cake is washed with hot isopropanol and the filtrate is concentrated using water pump vacuum. The residue is taken up in 2 litres of diethyl ether, washed twice with water, dried over magnesium sulphate and filtered. The solvent is carefully distilled off from the filtrate using water pump vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C.N1CCOCC1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:11]=[C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[NH:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1nc2ccccc2[nH]1
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(C=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C

Procedure:
3-Fluorobenzoyl chloride was added to a mixture of 2-methylbenzimidazole, triethylamine and dioxane, followed by heating under reflux for 3 hours and cooling to room temperature. Morpholine was added, followed by stirring under heat at 70° C. for 1 hour and work-up to obtain 1-(3-fluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([OH:32])=O>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([NH2:7])=[O:32]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, DMSO-d5) δ 7.73 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.32 (br, 2H), 4.66 (d, J=16.0 Hz, 1H), 4.45 (d, J=16.0 Hz, 1H), 4.21 (t, J=9.6 Hz, 1H), 3.83-3.76 (m, 1H), 3.57 (dd, J=10.2, 6.8 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 399.0 (M+1).
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.C(O[CH:11]=[CH:12][C:13]#[N:14])C>>[CH:3]([C:4]1[N:6]=[C:13]([NH2:14])[CH:12]=[CH:11][N:5]=1)([CH3:1])[CH3:2]
Reactant: N=C(N)C1CC1
Reactant: CCOC=CC#N
Agent: Cl
Product: CC(C)c1nccc(N)n1

Procedure:
This compound was made in analogy to example 2, step A] from cyclopropylcarbamidine hydrochloride (3 g) and 3-ethoxyacrylonitrile (2.5 mL) to give 2-isopropyl-pyrimidin-4-ylamine (1.36 g) as a light yellow foam. MS (ESI): 138.1 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:32])[CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+]>C1COCC1.O>[N:23]1[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][C:22]=1[CH2:21][C:20]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[CH:11]=[CH:12]2)=[O:32]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)O)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.3 %

Procedure:
To a solution of 3-[5-(2-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoic acid ethyl ester (50 mg, 0.12 mmol) in THF (1.0 mL) was added a solution of NaOH (18 mg, 0.45 mmol) in H2O (0.15 mL), and stirred at ambient temperature for 14 h. Solvents were evaporated. To the resulting residue was added 1N HCl until the solution reached a pH of 5. The mixture was extracted with EtOAc/DCM (9:1) several times until the aqueous layer was free from product by TLC. The extracts were combined, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with MeOH/DCM (2.5, 5, and 7.5%) to afford the title compound (38 mg, 81% yield) as a pale brown solid. 1H NMR (CDCl3) δ 7.79 (d, 1H, J=1.9 Hz), 7.57 (d, 1H, J=7.3 Hz), 7.45 (d, 1H, J=8.9 Hz,), 7.34 (d, 1H, J=3.2 Hz), 7.23 (dd, 1H, J=2.0, 8.8 Hz), 6.69 (d, 1H, J=7.3 Hz), 6.46 (d, 1H, J=3.2 Hz), 3.83 (s, 0.9H), 3.81 (s, 0.5H), 3.49 (t, 2H, J=5.6 Hz), 2.89 (d, 2H, J=7.2 Hz), 2.83 (t, 2H, J=6.1 Hz), 2.67-1.86 (m, 4H), 1.19-0.99 (m, 2H), 0.86 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calculated for C24H29N4O3 421.2 (M+H); found 421.3.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7](/[CH:8]=[N:9]/[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[OH:26][CH:22]1[C:19]2[C:10](=[CH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:18]=2)[NH:9][CH:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)[C:23]1([CH3:25])[CH3:24]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(/N=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Yield: 19.6 %

Procedure:
To a solution of (E)-methyl 4-(4-nitrobenzylideneamino)benzoate (284 mg 1 mmol) and yttrium(III) trifluoromethanesulfonate (62 mg, 0.1 mmol) in tetrahydrofuran (5 mL) was added isobutyraldehyde (72 mg, 1.5 mmol). The resultant mixture was stirred at room temperature for 16 h. Thin layer chromatography showed the starting material was completely consumed. The reaction mixture was quenched with water and separated. The aqueous solution was extracted with dichloromethane and he combined organic layers were dried over anhydrous sodium sulfate. Solvent was removed in vacuo to give the crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 70 mg of methyl 4-hydroxy-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 20%.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=4[F:39])=[O:30])=[CH:24][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O>C1COCC1>[F:39][C:33]1[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:32]=1[NH:31][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:13]3[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=3)[CH:20]=2)=[CH:27][CH:26]=1)=[O:30]
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (800 mg, 1.39 mmol) in 10 ml of THF was added 2M HCl (1 ml, 1 mmol). The mixture was stirred at room temperature under nitrogen for 1.5 hours, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as off-white solid. Yield: 680 mg, 98%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOc1ccccc1

Procedure:
To a chilled (-2° C.) mixture of 9.7 g of 6-(phenoxy)-1-hexanol in 250 ml of dichloromethane containing 11.1 g of triethylamine is added 6.95 g of methanesulfonyl chloride. The product is isolated as described in Example 2 to give the product as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]=[O:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][OH:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1CO
Yield: 94 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carboxaldehyde that was obtained in Example 10 (10b) (1.5 g, 5.8 mmol) in methanol (10 mL) were slowly added sodium borohydride (0.22 g, 5.8 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, the solvent was evaporated in vacuo. Subsequently, a solution of the residue obtained in ether was poured into water (20 mL) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:4 to 3:7) as the eluent to afford the pure title compound (1.4 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([O:6][CH2:7][C:8]2[S:12][C:11]([NH:13][C:14]([C:16]3[CH:32]=[CH:31][C:19]([O:20][C@@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[CH:18][CH:17]=3)=[O:15])=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(COC4CCCC4)s3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnc(COC2CCCC2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
0.446 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenoxy]cyclohexanecarboxylate (0.97 mmol, 1 eq.) is placed in 10 mL of THF with stirring, at room temperature, 0.111 g of lithium hydroxide monohydrate (2.64 mmol, 2.7 eq.) dissolved in 10 mL of water is added and the mixture is stirred for 36 hours and left to stand for 48 hours. Aqueous 1N hydrochloric acid solution is then added to acidic pH. The precipitate formed is filtered off and washed with water and with ethanol. 0.320 g of cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]-cyclohexanecarboxylic acid is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1([C:22]#[N:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(F)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(F)cc2F)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To 4-Cyano-4-(2,4-difluorophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.720 g, 2.42 mmol) in 5 ml of dichloromethane, 2 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.484 g (90%) of 4-(2,4-difluorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][NH:48]3)[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: COCC(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COCC(=O)N1CCC[C@@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Methoxyacetic acid (27 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (103 mg) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was triturated with 1:1 ether/hexanes and filtered to give the title compound as a white solid (97 mg, 82%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 4.0 (m, 3H), 3.95 (s, 3H), 3.50 (m, 21), 3.20 (m, 2H), 2.0-1.85 (m, 4H); Mass spectrum MH+ 475.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.O(CCCCO)C1C=CC=CC=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[O:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cncc(OCCCCOc2ccccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: OCCCCOc1ccccc1
Agent: [Al+3]
Product: c1ccc(OCCCCOc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-(4-phenoxybutoxy)pyrazine (1.99 g, 7.14 mmol; obtained according to the procedure of example 50, step 1, starting from 4-phenoxy-1-butanol*), piperazine (1.84 g, 21.4 mmol) and K2CO3 (0.99 g, 7.14 mmol). The yield of the title compound was 1.52 g (65%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 329 (M+H)+. HRMS m/z calcd for C18H24N4O2 (M)+ 328.1899, found 328.1894. *Prepared by reduction (LiAlH4) of the corresponding acid (cf J. Org. Chem. 1965, 30, 2441-2447; ibid. 1968, 33, 2271-2284).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].C(N(CC)CC)C>C(O)CCC>[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1cccc(O)c1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCCO2)c1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 3-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-butanol for 3 hours. After removal of the n-butanol by vacuum evaporation water was added to remove the n-butanol residues. The resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>99%. 1H-NMR (400 MHZ, DMSO): 1.57m (2H); 1.70m (1H); 1.95m (2H); 2.27qq (1H, Ja=11.7 Hz, Jb=4.0 Hz); 3.66m (1H); 4.0d (1H); 4.63bs (2H); 5.67dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.58dd (1H, Ja=8.2 Hz, Jb=1.5 Hz); 6.73 (d, 1H, J=7.7 Hz); 7.07t (1H, J=7.7 Hz); 8.21s (1H); 8.33bs (1H); 8.36bs (1H); 9.26s (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1)#N.[H-].[Cl-].[Na+].[OH:16]S(O)(=O)=O>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH:4]1([CH2:3][CH:1]=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: N#CCC1=CCc2ccccc21
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CCC1C=Cc2ccccc21

Procedure:
3-Cyanomethylindene (3.84 g, 0.025 mol), prepared as described in example 14, was dissolved in a mixture of hexane and THF and stirred under nitrogen at -78°. Dissobutylaluminum hydride (DIBAL) (19.2 ml of a 1.5M solution in toluene; 0.029 mmol) was added and the mixture stirred at ambient temperature 2.5 hours. Saturated sodium chloride solution (220 ml) was added and the mixture stirred another 20 minutes. 5% H2SO4 (90 ml) was added and the solution immediately extracted with ether. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 8% Et2O in hexane. The product fraction was evaporated to dryness to provide 2-(1H-indene-1-yl)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][C@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@H:12]2/[CH:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][CH:30]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[C:35]([C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]\[C@@H:12]2[CH2:13][C@@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH2:15][N:11]2[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[CH:34][CH:33]=1)([OH:37])=[O:36]
Reactant: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of (2S,4R)-1-(4-chlorophenyl-sulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-2-(4methoxycarbonylphenyl)vinyl]pyrrolidine (15.0 g) in a mixture of methanol (100 ml) and 1N aqueous sodium hydroxide (75 ml) was stirred at 50° C. for 4 hours and the volatile solvent was evaporated in vacuo. The residual aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid. The white precipitate was collected by filtration and washed with water to give (2S,4R)-2-[(Z)-2-(4-carboxyphenyl)vinyl]-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)pyrrolidine (14.50 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[C:19]1([C@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([NH:27][C@@H:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:26])=[O:17])=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and (R)-1-phenyl-ethylamine.
Reaction SMILES: [CH:1]1[C:6]([NH:7][CH2:8][S:9]([O-:11])=[O:10])=[CH:5][CH:4]=[C:3]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH2:22][S:23]([O-:25])=[O:24])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:2]=1.[Na+].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]2N=C(N)N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.OS(O)(=O)=O>>[CH:19]1[C:18]([NH:21][CH2:22][S:23]([OH:25])=[O:24])=[CH:17][CH:16]=[C:15]([S:12]([C:3]2[CH:2]=[CH:1][C:6]([NH:7][CH2:8][S:9]([OH:11])=[O:10])=[CH:5][CH:4]=2)(=[O:14])=[O:13])[CH:20]=1
Reactant: O=S([O-])CNc1ccc(S(=O)(=O)c2ccc(NCS(=O)[O-])cc2)cc1
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]3N=C(N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)(O)O
Product: O=S(O)CNc1ccc(S(=O)(=O)c2ccc(NCS(=O)O)cc2)cc1

Procedure:
Similarly, repeating the above procedure but replacing the sulfoxone sodium and sodium ascorbate with 50 mg/ml streptomycin sulfate, synthetic lipid vesicles are obtained encapsulating such material, for use as an antibacterial preparation for applications to plants.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1)=[O:2].CCOCC>O1CCOCC1.Cl>[NH2:24][C@@H:22]([CH3:23])[C:21]([NH:20][C@@H:18]([CH3:19])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:34])=[O:33])=[O:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of material from Example 73 (213 mg, 0.427 mmol) in Dioxane (10 mL), is added HCl, 4.0M in dioxane (92 mL, 368 mmol) and HCl, 1.0M in Et2O (10.4 mL, 10.4 mmol). The resulting suspension is stirred at room temp 4 h and then the solvent is evaporated off under a gentle stream of N2. The resulting residue is suspended in CH2Cl2 (60 mL) and the solvent is removed in vacuo (repeat 4 times) to give the title compound (quantitative yield) as an off white solid, as an HCl salt. LC/MS (Condition A): ret. T=1.35 min, (M+H)+ 399.20.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=1[C:2](=[O:3])[CH3:1])[CH3:18]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(O)c1C(C)=O

Procedure:
A mixture of 2,6-dihydroxyacetophenone (40 g), ethyl bromoacetate (48 g) and potassium carbonate (58 g) in acetone (500 ml) was refluxed for 3 hours. The mixture was cooled and filtered. The solution was evaporated to dryness and the crude solid extracted with boiling hexane. Upon cooling, the title compound was obtained.