Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([Cl:33])[CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4cccc(Cl)c4)ncnc32)[C@]1(C)F
Yield: 61.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added 3-chlorobenzylamine (about 1.26 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.30 g) as a colorless gummy mass. Yield: 61.2%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.06-8.01 (m, 4H), 7.58-7.24 (m, 6H), 6.56 (d, 1H, J=22.8 Hz), 6.45 (bs, 1H), 4.84-4.78 (m, 3H), 4.49-4.42 (m, 1H), 2.17 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.46 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 568 (50%), [M+Na]+ 590 (70%); IR cm−: 3782, 3414, 2929, 2294, 2177, 1619, 1274, 1061, 712; HPLC: 96%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Br)[CH:16]=1.C(OCC)C.O>CN(C)C=O>[Br:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCc1cccc(CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
0.57 g of potassium phthlimide was suspended in 20 ml of dimethylformamide, and 2.42 g of α,α'-dibromo-m-xylene was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=10/1] to give 0.52 g of N-(3-bromomethylbenzyl)phthalimide as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CCO>[Br:26][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[N:10][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(C)cc2C)n1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(C)cc2C)n(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 128.9 %

Procedure:
Ethyl 1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H-imidazole-4-carboxylate (1.23 g, 3.47 mmol) was dissolved in EtOH (15 mL) and treated with N-bromosuccinimide (1.25 g, 7.02 mmol). The solution was stirred at rt for 3 h. Water was added. Extraction with dichloromethane, which was then washed with NaCl solution, gave an orange solid (1.94 g). Purification by chromatography over silica gel (20% EtOAc in hexane) afforded a light tan solid (1.028 g, 68%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 2H), 7.03 (d, 2H), 7.00 (m, 1H), 6.86 (m, 2H), 4.44 (q, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, 3H); LC-MS m/z 433.1 (MH+), retention time 3.84 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:19][CH3:20])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: CCO
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 5-bromo-2-benzofurancarboxylic acid (5.01 g, 20.8 mmol) in absolute ethanol (150 ml) was added with concentrated sulfuric acid (15 ml) and the mixture was refluxed under stirring for 2 h. After this time, the volatiles were evaporated off under reduced pressure and the resulting residue was neutralized with a sodium bicarbonate saturated solution and extracted with ethyl ether (4×100 ml). The mixture was dried and the solvent was evaporated off under reduced pressure, to obtain 5.19 g of the title compound as a white solid with melting point 58-60° C. (93% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].N12CCCCC1C=NCCC2>CC(C)=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[O:15][CH:7]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: COC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Agent: C1=NCCCN2CCCCC12
Solvent: CC(C)=O
Product: COC(C)(C)C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
1H-1,2,4-Triazole (2.83 g, 0.041 mole) was added to a stirred solution of 14.6 g (0.041 mole) of 1-bromo-1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone in 100 ml. of acetone at -10° C. To the resulting mixture, 6.09 g (0.041 mole) of 1,5-diazabicyclo[5.4.0]-undec-5-ene was added at a rate to maintain the temperature of the mixture below -5° C. After the addition was complete, the mixture was stirred an additional 30 minutes at 0° C. Then the solvent was evaporated off, the residue taken up in 300 ml. diethyl ether, and the resulting mixture extracted with water. The organic phase was dried using MgSO4 and the solvent evaporated. The residual yellow oil (13 g) was stirred for several minutes with boiling hexane, then filtered to remove insoluble material. Upon cooling the filtrate, 9.0 g (63.8% yield) of 1-(2,4-dichlorophenoxy)-1-(1H- 1,2,4-triazol-1-yl)-3-methoxy-3-methyl-2-butanone, m.p. 53°-54° C., was obtained.
Reaction SMILES: [CH:1]([C:3]1([OH:13])[CH2:8][CH2:7][CH:6]([C:9](C)(C)C)[CH2:5][CH2:4]1)=[CH2:2].[C:14]1(C)C=CC=C[CH:15]=1>>[CH:1]([C:3]([OH:13])([CH2:8][CH2:7][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH3:9])=[CH2:2]
Reactant: C=CC1(O)CCC(C(C)(C)C)CC1
Reactant: Cc1ccccc1
Product: C=CC(O)(CCCC)CCCC

Procedure:
A solution of 2.0 grams of 1-vinyl-4-tert-butylcyclohexanol in 30 ml of toluene containing 40 mg of MTO was refluxed 4 hrs. TLC analysis indicated the presence of some residual starting material, so an additional 10 mg of MTO was added and reflux continued until the starting material was consumed. Workup as in the case of 5-vinyl-5-nonanol above gave 1.25 g (69%) of product as a colorless liquid, bp 90 deg C./15 mm Hg. NMR spectrum was consistent with that expected for the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[CH2:15]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:14]=[CH2:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NCC(C)C)cc1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(CC)cc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (400 mg, 2.256 mmol) in pyridine (5 mL) stirred in air at room temperature was added 4-vinylbenzene-1-sulfonyl chloride (760 mg, 3.75 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes then stood for 16 hours. The solvent was evaporated in vacuo (Vaportec V10) to give the crude product, which was then purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 940 mg, as a colourless gum. LCMS [LCMS1] Rt 1.44 min, m/z (ES+) 344 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.C1(O)C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[K+]>C(OCC)C>[NH:25]([C:13]1[C:12]2[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CN1CCc2nc3ccc(Cl)cc3c(Nc3ccccc3)c2C1

Procedure:
By the method described for Example 14, a mixture of the compound of Example 6 (15.0 g, 0.0562 mol), 10.69 (0.115 mol) of phenol and 10.3 mol (0.115 mol) of aniline is reacted. Thereafter, the reaction mixture is slurried with a mixture of 10% aqueous potassium hydroxide and diethyl ether. The insoluble product is filtered and recrystallized from acetonitrile giving the title compound (13.0 g, 72%), m.p. 137°-139° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12].C(NC(C)C)(C)C.C([Li])CCC>>[CH2:11]([O:13][C:14](=[O:19])[CH:15]([C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)[CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOC(=O)CC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)c1cccnc1)C(C)C
Yield: 44 %

Procedure:
Nicotinic chloride hydrochloride (0.9 g), isovaleric acid ethyl ester (2.3 ml), diisopropylamine (2.1 ml) and butyllithium (1.6M hexane solution, 9.4 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (0.78 g, 44%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:31][CH2:32][C:33]#[CH:34].C(NCC)C.C(#N)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: CC#N
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
Trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (0.935 g, 2 mmoles), prepared as described in example 73, 4-pent-4-ynyl-morpholine (0.37 g, 2.4 mmoles), diethylamine (9 ml) and dry acetonitrile (6 ml), then bis(triphenylphosphine)PdCl2 (0.014 g, 0.02 mmole) and Cul (0.004 g, 0.02 mmole) were charged in a flask under N2 and the mixture was stirred at room temperature overnight, brought to dryness, the residue taken up in ethyl acetate and washed with water. The organic phase was washed with water, anhydrified and concentrated to give an oil which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH3 95:5:0.5) to give an oil which was dissolved in ethyl acetate and precipitated by adding HCl in ethyl ether. There was yielded 0.09 g of the title compound. m.p.: 129-131° C. (dec.).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[C:24](Cl)=[O:25].C(Cl)(=O)[C:28]1[CH:36]=[CH:35][CH:34]=[C:30](C(Cl)=O)[CH:29]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:24]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([O:1][C:28]4[CH:29]=[CH:30][CH:34]=[CH:35][CH:36]=4)=[CH:9][CH:10]=3)=[O:22])[N:15]=2)=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)n1

Procedure:
N,N'-Bis-(4-phenoxyphenyl)-2,6-pyridine dicarboxamide was prepared from p-phenoxyaniline and 2,6-pyridine dicarboxylic acid dichloride. The amide (8.0248 g, 0.016 moles) was polymerized with isophthaloyl chloride (3.2484 g, 0.016) using the procedure of Example 27. The amounts of aluminum chloride, DMF and DCE used were 21.33 g (0.160 moles), 4.71 mL (0.061 mol) and 100 mL, respectively. The off-white fibrous polymer which was obtained had the repeat unit ##STR46##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=3[F:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3F)nc12

Procedure:
From 2,4-difluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.4° (c=1.00, CHCl3), ES-MS m/e (%): 407 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH:25][C:26](=[O:39])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][C:26]([NH:25][C@@H:22]2[CH2:23][CH2:24][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21]2)=[O:39])=[CH:30][C:31]=1[O:37][CH3:38])=[O:6]
Reactant: NNC(=O)c1ccc(O)c(N)c1
Reactant: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Solvent: CC(C)O
Product: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=NNC(=O)c1ccc(O)c(N)c1
Yield: 70.2 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×3 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 157-160° C.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][CH2:16][C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[C:33]([OH:35])=[O:34])=[O:18])=[O:14])=[CH:11][C:10]=1[C:38]([CH3:41])([CH3:40])[CH3:39])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:29]([O:28][C:26]([C@H:23]1[CH2:22][C@@H:21]([C:33]([OH:35])=[O:34])[C@@H:20]([NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:36]=[CH:37][C:9]([OH:8])=[C:10]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:11]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2ccc(OCc3ccccc3)c(C(C)(C)C)c2)[C@H](C(=O)O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2ccc(O)c(C(C)(C)C)c2)[C@H](C(=O)O)C1
Yield: 107.4 %

Procedure:
A suspension of (1R,2S,5R)-2-(2-(4-(benzyloxy)-3-tert-butylbenzamido)acetamido)-5-(tert-butoxycarbonyl)cyclohexanecarboxylic acid (100 mg, 0.17 mmol) and 10% Pd/C (100 mg) in MeOH (10 mL) was exposed to an atmosphere of hydrogen for 14 h. The reaction mixture was filtered through diatomaceous earth, rinsed with MeOH (400 mL) and concentrated in vacuo to provide (1R,2S,5R)-5-(tert-butoxycarbonyl)-2-(2-(3-tert-butyl-4-hydroxybenzamido)acetamido)cyclohexanecarboxylic acid (87 mg, quant.) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.79-7.78 (m, 1H), 7.61-7.58 (m, 1H), 6.80-6.75 (m, 1H), 4.59 (s, 1H), 3.99 (s, 2H), 3.45-2.89 (m, 4H), 2.54 (s, 1H), 2.18-1.25 (m, 6H), 1.42 (s, 9H), 1.41 (s, 9H); MS found: (M+H)+=492.
Reaction SMILES: O1CC1CO[C:5]1[C:13]2[C:9](=NS[N:12]=2)[CH:8]=[CH:7][CH:6]=1>C(O)C.Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C2C(=NSN=2)C=CC=1>[NH2:12][CH:13]1[CH2:5][CH2:6][C:7]2[C:8](=[CH:13][CH:5]=[CH:6][CH:7]=2)[CH2:9]1
Reactant: c1cc(OCC2CO2)c2nsnc2c1
Agent: Cl
Agent: OC(CNC1CCc2ccccc2C1)COc1cccc2nsnc12
Solvent: CCO
Product: NC1CCc2ccccc2C1
Yield: 201.6 %

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-2,1,3-benzothiadiazole (20.8 g), prepared according to the teaching of DE-2,404,858, and 2-aminotetralin (14.82 g) in absolute ethanol (125 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,1,3-benzothiadiazol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 32, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][Si](C(C)(C)C)(C)C)[CH:15]=2)=[CH:8][C:9]=1[Cl:10])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:10][C:9]1[CH:8]=[C:7]([C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 5-[3-(tert-Butyl-dimethyl-silanyloxy)-benzylcarbamoyl]-3-chloro-thiophene-2-carboxylic acid methyl ester (260 mg, 0.59 mmol), lithium hydroxide monohydrate (500, mg, 11.82 mmol), THF (5 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 230 mg (100%). MS m/e 311.9 (M+H+).
Reaction SMILES: CO[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[CH2:22]([Al+]CC(C)C)[CH:23](C)C.C([Mg]Br)=C>C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([NH:5][CH:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([OH:20])[CH:22]=[CH2:23])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)C[Al+]CC(C)C
Agent: C=C[Mg]Br
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.6 %

Procedure:
A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSo4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the pure desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([O:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:12]([O:11][N:8]1[CH2:9][CH2:10][C:5]2([NH:14][C:15](=[O:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:3]2[OH:2])[CH2:6][CH2:7]1)[CH3:13]
Reactant: CCON1CCC(NC(=O)Cc2c(C)cc(C)cc2C)(C(=O)OC)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Temperature: 65 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a solution of 2.3 g of 1-ethoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester in 26 ml of dimethylformamide is added 3 g of sodium methoxide. The reaction mixture is heated to 65° C. and stirred for 5 hours. The reaction mixture is poured into brine, neutralized and extracted with ethyl acetate. The organic phase is washed with brine, dried with sodium sulfate, filtered and concentrated. The residue is subjected to column chromatography (heptane/ethyl acetate 2:1) to yield 510 mg of 8-ethoxy-4-hydroxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one as a solid, mp: >250° C.
Reaction SMILES: C([Mg]Br)(C)C.[CH2:6]([CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16])[CH3:7].C(NC(C)C)(C)C.C[O:25][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH:27]=1.Cl>CCOCC.C1COCC1>[CH2:6]([C:8]1([C:28]2[CH2:29][CH2:30][CH2:31][C:26](=[O:25])[CH:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16])[CH3:7]
Reactant: COC1=CC(=O)CCC1
Reactant: CCC1CCCCN(C)C1=O
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC1(C2=CC(=O)CCC2)CCCCN(C)C1=O
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A 2 molar solution of isopropylmagnesium bromide in ether (70 ml) was treated with 3-ethyl-hexahydro-1-methyl-2H-azepin-2-one (21.7 g, Aust. J. Chem. 1976, 29 2651) in THF (20 ml) and the mixture treated dropwise with diisopropylamine (19.6 ml) (exothermic). The reaction mixture was stirred for 2 hours then treated dropwise with 3-methoxy-2-cyclohexenone (12.6 g) in THF (20 ml). After stirring for 2 hours the reaction mixture was poured onto cold 2 N HCl (250 ml). After 10 minutes the mixture was extracted with dichloromethane (2×300 ml), the combined organic phases washed with saturated aqueous NaHCO3 solution and dried (MgSO4). Removal of the solvents under reduced pressure followed by distillation gave the title compound as a viscous oil (Bpt 155°-160° C./0.1 mm) (13 g). Redistillation (154°-158° C./0.07 mm) gave analytically pure material.