Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[CH:16]([NH:18][C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:29])[CH:25]=3)[N:20]=1)[CH2:15][CH2:14]2>>[CH:1]([NH:4][C:5]([NH:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([NH:18][CH:16]1[C:17]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[O:8][CH3:7])[CH2:14][CH2:15]1)[CH:28]=[CH:27]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=391.5 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Yield: 99 %

Procedure:
0.278 g (0.00127 mol) of 1-benzylpiperidine-4-carboxylic acid was boiled at reflux in 5 ml of oxalyl chloride for 2 hrs. The excess oxalyl chloride was distilled off. The residue was taken up twice in toluene and concentrated each time. 0.3 g (99%) of 1-benzylpiperidine-4-carboxylic acid chloride was obtained as a pale beige solid. This was dissolved in 20 ml of toluene, treated with 0.265 ml (0.0019 mol) of triethylamine and 0.17 g (0.00165 mol) of benzyl alcohol and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ether/hexane (1:2) as the eluent. 0.246 g (80%) of benzyl 1-benzylpiperidin-4-carboxylate was obtained as a yellow oil. MS: me/e=310 (C2H23NO2+).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=1>C(NC(C)C)(C)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:4]#[C:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(Br)cn1
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylacetylene (73.7 μL), copper iodide (3.16 mg) and tetrakis(triphenylphosphine)palladium (9.59 mg) were added to a solution of ethyl 5-bromopyridine-2-carboxylate (95.5 mg) in diisopropylamine (2 mL) at room temperature, and the mixture was stirred at room temperature for 17 hours and five minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (19.4 mg).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[OH:16][C@@H:9]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccccc1
Agent: Cl
Product: CCOP(=O)(OCC)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added diethyl phosphite (0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, benzaldehyde (0.40 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2 SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain diethyl (S)-hydroxy-phenylmethylphosphonate as a final product in a yield of 39%. The chemical reaction in this Example is shown in chemical formula 33.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:14])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC(=N)C(Cl)(Cl)Cl)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:12][C:11](=[O:13])[C:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(COCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of the N-Boc carboxylic acid 7 (1.6 g, 5.17 mmol) in 15 mL of CH2Cl2 at room temperature was added a 3 eq portion of tert-butyl-2,2,2-trichloroacetimidate (3.4 g). After overnight stirring at room temperature, the solvent was evaporated under reduced pressure. Purification via silica gel column chromatography (15% EtOAc in hexane) afforded 8 as a colorless oil (1.71 g, 90%): 1H NMR (CDCl3) δ 1.44 (9H, s), 1.45 (9H, s), 1.48 (3H, s), 3.66 (1H, d, J=8.8), 3.79-3.82 (1H, broad d), 4.48-4.58 (2H, m), 5.51 (1H, broad s), 7.28-7.35 (5H, m). Anal. (C20H31NO5) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.Cl.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13]>C1COCC1>[OH:8][C:6]1([CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3](=[O:10])[C:4]([CH3:9])=[CH:5]1
Reactant: CC1=CC(=O)C=C(C)C1=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C(C)=C1
Yield: 80 %

Procedure:
Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,6-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.60 g of the desired product (yield 80%).
Reaction SMILES: [CH3:1][P:2]([CH2:12][C:13]([OH:15])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N+](=[CH2:18])=[N-].C(OCC)(=O)C>CCOCC>[CH3:1][P:2]([CH2:12][C:13]([O:15][CH3:18])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: C=[N+]=[N-]
Reactant: CP(=O)(CC(=O)O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)CP(C)(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of [methyl(phenylmethoxy)phosphinyl]acetic acid in ethyl acetate-ether is treated with an excess of diazomethane in ether and stirred for three hours. The excess diazomethane is destroyed by the addition of acetic acid. The solution is washed with sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give an 87% yield of [methyl(phenylmethoxy)phosphinyl]acetic acid, methyl ester as a clear oil (TLC Rf =0.18 (ethyl acetate)).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:49])[N:17]([CH3:48])[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:41])([F:40])[F:39])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:10])C1C=CC=CC=1.[OH-].[Li+]>CO.O>[CH3:48][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:39])([F:40])[F:41])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:49]
Reactant: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)OCc1ccccc1)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
Trans-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid benzyl ester was hydrolyzed with lithium hydroxide in methanol and water. The resulted crude mixture was concentrated and the residue was dissolved in ethyl acetate and water with citric acid as acidifying agent. The organic layer then was concentrated and purified by reverse phase HPLC. The mixture of isomers was obtained as a yellow solid. LCMS calcd for C30H31F3N4O5 (m/e) 584, obsd 585 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=O)[CH2:14][C:15](=O)[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[N:27]=[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[C:15]([CH:16]([CH3:18])[CH3:17])[N:25]=1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)c2ccc(F)cc12
Reactant: N=C(N)N
Agent: O=C(O)O
Product: CC(C)c1cc(-c2ccc(F)c3ccc(F)cc23)nc(N)n1
Temperature: 150 °C
Yield: 34.7 %

Procedure:
1-(4,7-difluoronaphth-1-yl)-4-methylpentane-1,3-dione (0.114 g, 0.5 mmol) was combined with guanidine carbonate (0.180 g, 0.5 mmol) and heated to 150° C. for 6 hours. The reaction was cooled to room temperature and directly purified by column chromatography to give 2-amino-4-(4,7-difluoronaphth-1-yl)-6-isopropylpyrimidine (0.052 g, 34%), m.p. 103°-105° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[H][H]>C(O)C.C(O)=O.[OH-].[Pd+2].[OH-]>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: [H][H]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 4, 0.210 g) in ethanol (6 mL) was added to a flask containing palladium hydroxide (0.020 g) and formic acid (3 drops) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 10% aqueous potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.137 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[CH3:37][O:38][C:39](OC)(OC)OC.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]4[NH:27][C:37]([O:38][CH3:39])=[N:28][C:22]=4[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 1.00 g (2.02 mmol) (R)-2-(3,4-diamino-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.00 mL (15.01 mmol) tetramethoxymethane in 20 mL MeOH was refluxed for 1 h in the presence of 40 mg (0.21 mmol) toluenesulphonic acid hydrate. The mixture was evaporated down i.vac. and the residue was purified by chromatography (Alox, activity grade II-III, DCM/MeOH 20:1).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([C:7]1([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9][C:8]1=[O:15])[CH3:6]>[Cl-].C([N+](CC)(CC)CC)C.CN(C)C=O>[OH:4][CH:2]([CH3:3])[CH2:1][N:11]1[C:12](=[O:13])[C:7]([CH2:5][CH3:6])([CH2:16][CH3:17])[C:8](=[O:15])[N:9]([CH2:1][CH:2]([OH:4])[CH3:3])[C:10]1=[O:14]
Reactant: CC1CO1
Reactant: CCC1(CC)C(=O)NC(=O)NC1=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N(CC(C)O)C1=O
Temperature: 100 °C
Yield: 102.7 %

Procedure:
40.7 g (0.7 mol) of propene oxide are added dropwise over the course of 1 hour to a mixture of 55.3 g of 5,5-diethylbarbituric acid (0.3 mol), 2.77 g of tetraethylammonium chloride (5 mol per cent) and 400 ml of dimethylformamide at 35° C. whilst stirring. Thereafter the mixture is gradually heated to 100° C. After 7 hours' stirring at 100° C. the mixture is worked-up in accordance with example 1. 92.5 g of crude 1,3-di(β-hydroxy-n-propyl)-5,5-diethylbarbituric acid (99.5 % of theory) are obtained. The product boils at 138°-148° C. under 0.08 mm Hg; 75.2 g of pure product 80% of theory) are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)[CH:2]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>CO.C(OCC)(=O)C>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: O=C(O)c1cccc(NCc2cccnc2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccnc4)c3C2=O)C(=O)N1
Yield: 46 %

Procedure:
3-[(Pyridin-3-ylmethyl)-amino]-phthalic acid (3.03 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was slurried in 50% methanol/ethyl acetate (20 ml) for 18 h to give 0.50 g (46%) of product as a yellow solid: mp 231-233° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.03 (t, J=6.6 Hz, 2H), 5.09 (dd, J=5.2 and 12.4 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.64-2.48 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.78, 170.05, 168.65, 167.22, 148.66, 148.27, 145.75, 136.14, 134.79, 134.54, 132.25, 123.58, 117.50, 110.92, 109.82, 48.57, 42.99, 30.96, 22.12; Anal. Calcd. For C19H16N4O4: C, 62.63; H, 4.43; N, 15.38. Found: C, 62.30; H, 4.27; N, 15.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([N:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1>>[CH3:27][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[CH:8][CH:9]=2)[O:26][N:25]=1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: Cc1nc(-c2ccc(O)cc2)cs1
Product: Cc1cc(CCCCCCCOc2ccc(-c3csc(C)n3)cc2)on1

Procedure:
3-Methyl-5-{7-[4-(2-methyl-4-thiazolyl)phenoxy]heptyl}-isoxazole [I; Z=N, Het=4-(2-methyl-4-thiazolyl), R1 and R2 =H, Y=(CH2)7 ] was prepared from 7.3 g of 4-(2-methyl-4-thiazolyl)phenol and 5-(7-bromoheptyl)-3-methylisoxazole according to the procedure of Example 4: yield 10.6 g, m.p. 100-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:15])/[C:5](=[CH:18]\[N:19]([CH3:21])[CH3:20])/[C:6](=[O:14])[CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COC(OC)N(C)C
Product: CCOC(=O)/C(=C\N(C)C)C(=O)C(OCC)OCC
Reaction time: 0.5 h

Procedure:
A mixture of the 4,4-diethoxy-3-oxo-butyric acid ethyl ester (0.500 g, 2.29 mmol, prepared according to the procedure described in JACS, 1919, 41, 812) and dimethylformamide dimethyl acetal (370 μL, 2.78 mmol) in xylenes (5.0 mL) is warmed at reflux. After 30 minutes, The reaction mixture is concentrated in vacuo to afford 2-[1-dimethylamino-meth-(Z)-ylidene]-4,4-diethoxy-3-oxo-butyric acid ethyl ester, which is used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[N:17]1C=CC=C[CH:18]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([C:18]#[N:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(C#N)c2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxynaphthalene-2-carboxylic acid ethyl ester (2.16 g) and pyridine (1.60 mL) in dichloromethane (100 mL) was added trifluoromethanesulfonic anhydride (2.5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added water (30 mL), and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N-methylpyrrolidone (33 mL). To the solution were added zinc cyanide (1.41 g) and tetrakis(triphenylphosphine)palladium (0.58 g), and the resulting mixture was stirred at 110° C. for 40 minutes. After the reaction mixture was cooled to room temperature, water (50 ml) and dichloromethane (50 mL) were added to the reaction solution. The insoluble material was removed by filtering through a Celite pad. The aqueous layer was separated, and the organic layer was filtered through an aminopropyl silica gel (eluent: dichloromethane). The organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), and the mixture was washed with water (30 mL, 5 times). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give 4-cyanonaphthalene-2-carboxylic acid ethyl ester (2.25 g). To a mixed solution of this compound (0.45 g) in tetrahydrofuran (10 mL), ethanol (5.0 mL) and water (5.0 mL) was added lithium hydroxide monohydrate (0.25 g), and the mixture was stirred for 1 hour. To the reaction solution was added water (20 mL), and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/L hydrochloric acid (3.3 mL), and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure at 50° C. to give the title compound (0.37 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2=[N:16]O)([OH:3])=[O:2].[H][H]>CO.N.[Ni]>[NH2:16][CH:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8]1
Reactant: [H][H]
Reactant: CC1(C)CC(=NO)c2cc(C(=O)O)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)CC(N)c2cc(C(=O)O)ccc2O1

Procedure:
35.2 g (0.15 mol) of 6-carboxy-2,2-dimethyl-4-chromanone oxime are dissolved in 300 ml of methanol by addition of 600 ml of concentrated aqueous ammonia and, after addition of a few grams of Raney nickel catalyst, hydrogenated at 80° C. for 10 hours under 100 atm hydrogen pressure. After filtering off the catalyst, approximately ¾ of the solvent is distilled off in a rotary evaporator. The crystalline precipitate of 4-amino-6-carboxy-2,2-dimethylchroman is filtered off.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[OH-].[NH4+:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([S:15](=[O:17])(=[O:16])[NH2:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: [NH4+]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.1 %

Procedure:
16.2 g (1 mol equiv.) 3-Bromo-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was dissolved in 150 mL acetonitrile and cooled to 0° C. Dropwise, 20.8 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. during which a white precipitate was formed. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 14.3 g (94%) N-(2-bromo-4-sulfamoyl-phenyl)-2,2,2-trifluoro-acetamide. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.88 (dd, J=8.2, 1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 11.55 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.1 %

Procedure:
Using the method of Example 5, supra, 1-hexyl glycidyl ether (175 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 95 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 216 (M−121), 163 (11), 121 (22), 114 (14); 1H-NMR (CDCl3) δ7.05 (2H, d, J=8.7), 6.79 (2H, d, J=8.7), 3.77 (1H, m), 3.75 (3H, s), 3.41 (4H, m), 2.97 (2H, broad), 2.79 (1H, dd, J=11.7 and 4.1), 2.64 (3H, m), 1.52 (2H, m), 1.26 (6H, m), 1.04 (3H, s), 1.03 (3H, s), 0.85 (3H, t, J=6.7); 13C-NMR (CDCl3) δ158.1, 131.3, 129.9, 113.4, 73.4, 71.7, 68.9, 55.1, 53.6, 46.3, 44.6, 31.6, 29.5, 26.5, 26.4, 25.7, 22.6, 14.0; FT-IR, cm−1 3405 (broad), 1611, 1512, 1245, 1116, 824.