Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].CS(C)=O.C[O-].[Na+]>CO>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
To a solution of 9.86 g. (50 mmoles) of N-methylsaccharin and 10.8 ml. of methyl chloroacetate (123.8 mmoles) in 50 ml. of dimethylsulfoxide was added at the rate of 0.15 ml./minute 9.2 g. (170 mmoles) of sodium methoxide in 30 ml. of methanol. After the addition was complete an additional 2.7 g. (50 mmoles) of sodium methoxide in 11 ml. of methanol was added at the same rate for a total addition time of about 6 hours.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[CH2:7]([O:11][CH:12]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:8][CH2:9][CH3:10].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:11][CH:12]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]1[N:14]=[CH:15][CH:16]=[C:17]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:19][C:18]=12)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOC(OCCCC)c1ncccc1[N+](=O)[O-]
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOC(OCCCC)c1nccc2c(C)c(C)[nH]c12
Reaction time: 8 h
Yield: 65.7 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 243 ml, 121 mmol) was slowly added at −78° C. to a solution of 2-dibutoxymethyl-3-nitropyridine (11.53 g, 40 mmol) prepared in Step 2 in tetrahydrofuran (100 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution (50 ml) was added thereto. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 8 g of the titled compound as brown oil. The product was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:17][C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:19]
Reactant: CCOC(=O)CCCCCC1CCCCC1=O
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CCCCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(5-carbethoxypentyl)cyclohexan-1-one (Example 15) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: C([C:5]1[C:6]([CH2:18][O:19][SiH](C)C)=[C:7]([N:11]2[CH2:14][C:13]([F:16])([F:15])[C:12]2=[O:17])[CH:8]=[CH:9][CH:10]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>C(#N)C>[OH:19][CH2:18][C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[N:11]1[CH2:14][C:13]([F:15])([F:16])[C:12]1=[O:17]
Reactant: C[SiH](C)OCc1c(N2CC(F)(F)C2=O)cccc1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1N(c2ccccc2CO)CC1(F)F
Temperature: 25 °C

Procedure:
0.19 mmole of compound 3a is dissolved in 1 ml of acetonitrile and this solution is added dropwise to a 40% H2O/HF mixture corresponding to 3 eq. Stirring is maintained for 5 min. at ambient temperature, followed by the neutralization of the excess HF by a 5% aqueous NaHCO3 solution.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.O>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCCl
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
78.25 g of 4-chlorobenzoic acid were suspended in 400 ml of 1,2-dichloroethane. 99.0 g of a mixed acid containing 35.2% of nitric acid and 64.2% of sulphuric acid were added dropwise with stirring over a period of 3 hours at 40° C. After stirring for 2 hours at that temperature, the reaction mixture was poured on to 300 ml of water. The 1,2-dichloroethane was then distilled off and the reaction product filtered off from the residual aqueous suspension, washed with water and dried at 90° C., giving 97.8 g (96.8% of the theoretical) of 4-chloro-3-nitrobenzoic acid melting at 182.9° to 184.0° C. with a purity of 99.5%. The content of unreacted 4-chlorobenzoic acid amounted to only about 0.1%.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]([CH2:23][CH3:24])[CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13].[C:25]([O:29][C:30](=[O:32])N)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:32])[NH:10][CH:11]([CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13])[CH2:23][CH3:24])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCC(N)C(O)c1nc2ccccc2o1
Reactant: CC(C)(C)OC(N)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIPEA (0.35 ml, 2 mmol) and di-tret-butyl dicarbonate (355 mg, 1.63 mmol) were added to a solution of 2-Amino-1-benzooxazol-2-yl-butan-1-ol (320 mg, 1.55 mmol) in dry methylene chloride (10 ml) and stirred at room temperature for 4 hrs. The reaction was quenched with saturated aqueous NH4Cl and the pH was adjusted to neutral. Oraganic layer separated and the aqueous layer extracted with methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give, 1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (500 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Br[CH:13]([OH:15])[CH3:14]>CS(C)=O>[OH:15][CH2:13][CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(O)Br
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCCn1ccc2ccccc21
Yield: 72.6 %

Procedure:
The intermediate product, reported in J. Med. Chem., 1998, 41/10, 1619-1639, was prepared according to the procedure described therein, with the exception of the duration of the reaction time (equal to 30 hours instead of 30 minutes), starting from indole (5.0 g, 42.7 mmol), KOH (3.6 g, 64.1 mmol) and bromoethanol (6.4 g, 51.3 mmol) in 50 ml of anhydrous DMSO, at a temperature of 25-30° C., to obtain 5 g of oily product (yield: 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])([O-:3])=[O:2].[CH2:13]=[O:14]>CN(C)C=O>[OH:14][CH2:13][NH:11][C:9](=[O:10])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6][CH:7]=1
Reactant: NC(=O)c1cncc([N+](=O)[O-])c1
Reactant: C=O
Solvent: CN(C)C=O
Product: O=C(NCO)c1cncc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of 5-nitronicotinamide and 2ml of 37% formalin in 3 ml of dimethylformamide was stirred at 100° C. for 2 hours. After cooling, ice-water was added and the mixture was extracted with ethyl acetate. The extract was chromatographed over silica gel and recrystallized from ethanol to give 0.6 g of the desired product. mp 145° - 146° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:36][OH:37])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, 3-(4′-methanesulfonyl-biphenyl-3-yl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.8:1) as a white foam, MS (ESI+): m/z=485.19 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C@@H:16]1[CH2:20]OS(=O)(=O)[N:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:20])[NH:17][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Agent: Cl
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](C)Nc2ccccn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.16 grams (46.6 millimoles) of 1-(2-methoxyphenyl)piperazine in one portion was added under argon to a solution of 10 grams (46.6 millimoles) of (R)4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide in 200 milliliters of acetonitrile. The mixture became yellow. After 1/2 hour, the reaction mixture was heated to 50° C. for 1 hour and then stirred at room temperature overnight. Then dilute hydrochloric acid was added. The mixture was washed with ethyl acetate, basified to pH 12 and extracted twice with ethyl acetate. The organic phases were washed with brine, dried (Mg SO4) and subjected to evaporation to give 12.053 grams of the title compound which was purified by columning in the system ethyl ether/hexane (1:1) Al2O3 to afford 9.96 grams of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]([NH:12][C:13](=[O:24])[C:14]1[C:15](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16](OC)=O)([CH3:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[NH2:4]>C1(C)C=CC=CC=1>[C:7]([C:6]1([CH3:11])[N:12]2[C:13](=[O:24])[C:14]3[C:15]([C:16]2=[N:4][C:3]1=[O:5])=[CH:20][CH:21]=[CH:22][CH:23]=3)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccccc1C(=O)NC(C)(C(N)=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (from 1.92 g of a 50% suspension of sodium hydride in mineral oil) in 150 ml toluene is heated under reflux. During 20 minutes is then added portionwise 6.13 g (0.02 mole) methyl N-(1-carbamoyl1,2,2-trimethylpropyl)phthalamate to the stirred, refluxing, mixture. Heating is continued for 30 minutes after the addition, the mixture filtered through diatomaceous earth, and the solvent removed in vacuo. The residue crystallizes and is recrystallized from a mixture of acetone-hexane to give 3-t-butyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione, melting point 136.5-137.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8]([C:15]([N:30]([CH3:32])[CH3:31])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21](OC)=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CC(N(C)C)=O>[CH2:8]([C:15]([N:30]([CH3:31])[CH3:32])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:6][CH2:5][CH2:4][CH2:3][OH:7])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCO
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(OC)c(OC)c1)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCO)c(OC)c1)N(C)C
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.40 mol of sodium hydride are suspended in 500 ml of dry dimethylacetamide and 72.3 ml (1.0 mol) of 1,3-propanediol are added dropwise at 0° C. Then 68.3 g (0.20 mol) of 2-benzyl-1-(3,4-dimethoxy-phenyl)-2-dimethylamino-butan-1-one in dimethylacetamide are added dropwise at 0° C. After the solution is stirred at 120° C. for 18 h, the solution is poured into water. The crude product is extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (40:60) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.69 (t, 3H), 1.83-1.92 (m, 1H), 2.04-2.16 (m, 3H), 2.38 (s, 6H), 2.40-2.55 (bs, 1H), 3.18-3.23 (m, 2H), 3.88 (s, 3H), 3.89 (t, 2H), 4.27 (t, 2H), 6.84 (d, 1H), 7.15-7.28 (m, 5H), 7.93 (d, 1H), 8.20 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>>[CH:22]1([O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1
Reactant: OC1C=CCCC1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OC1C=CCCC1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and cyclohex-2-en-1-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].S([O:26][CH3:27])(OC)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:26][CH3:27])=[C:4]([CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][C:7]([OH:12])=[O:8])[CH:3]=1
Reactant: O=C1CC(c2ccccc2)c2cc(Cl)ccc2O1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1C(CC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
6-Chloro-4-phenyl-3,4-dihydrocoumarin (435 g, 1.68 mol. Preparation: T. Manimaran & V. T. Ramakrishnan, Ind. J. Chem. B 18 (1979) 328) is added to a hot solution of sodium hydroxide (140 g, 3.5 mol) in water (500 ml). The solution is chilled to 25° C. and dimethyl sulphate (442 g, 3.5 mol) is added dropwise during 1 h with stirring and cooling at 25°-35° C. The mixture is stirred for an additional 2 h whereupon a solution of 100 g of sodium hydroxide in 500 ml of water is added and the mixture is stirred until a clear solution is obtained. An excess of concentrated hydrochloric acid is added to precipitate the methoxy acid, which separates as an oil which slowly crystallizes. It is filtered off, washed with water and dried. Crystallization from 2-propanol gives colourless crystals of 3-(5-chloro-2-methoxyphenyl)-3-phenyl propionic acid, m.p. 144° C. Yield 455 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:21])=[N:17][N+:18]([O-:20])=[O:19])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:18]([N:17]=[C:16]([NH2:21])[NH:15][C:11]1[CH:10]=[C:9]([CH2:8][NH2:7])[CH:14]=[CH:13][CH:12]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A mixture of the compound (230 mg) obtained in Example 33, methylene chloride (3 ml) and trifluoroacetic acid (1.15 ml) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and 25% aqueous ammonia solution was added to the resulting residue, and the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; methanol) to give 117 mg of the titled compound (yield, 75%).
Reaction SMILES: C(C1(C)N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)C.C(=O)([O-])[O-:16].[Na+].[Na+]>Cl>[NH2:4][C:5]([CH3:11])([CH2:12][CH3:13])[CH2:6][C:7](=[O:16])[CH2:9][CH3:10]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: CCC(=O)CC(C)(N)CC

Procedure:
196.3 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine were added dropwise to 300 ml of concentrated hydrochloric acid at 30° - 40° C, with stirring. When the addition was complete, the mixture was stirred for a further 4 - 5 hours and then neutralized with sodium carbonate and extracted with benzene. The resulting benzene solution was washed with, in turn, a 5% aqueous solution of sodium carbonate and water, and was then dried over potassium carbonate. After removal of benzene, the residue was distilled under reduced pressure, giving 72.4 g of 5-amino-5-methyl-3-heptanone (bp 46° - 48° C/2.5 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Product: Cc1ccc(Cl)c(OCC(O)CNCCOc2cccc(C3=NNC(=O)CC3C)c2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:36]([C:35]5[O:31][N:32]=[CH:33][CH:34]=5)=[O:37])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(NC(=O)c3ccno3)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 540.1 (MH+, 1Cl).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH2:17][O:16][CH2:15][C:14]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:21].[Na+:22]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[CH2:15][O:16][CH2:17][C:18]([O-:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:22]
Reactant: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])COCC(=O)NCCCCCCN1CCCCC1
Yield: 90 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporative distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1 N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)amino-2-oxoethoxy]acetate product with the following spectral characteristics:
Reaction SMILES: [CH2:1]([C:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:11][OH:12])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]I>>[CH2:13]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:11][O:12][CH3:20])[CH2:9][OH:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC(CO)(Cc1ccccc1)Cc1ccccc1
Reactant: CI
Product: COCC(CO)(Cc1ccccc1)Cc1ccccc1

Procedure:
2,2-Dibenzyl-3-methoxy-1-propanol was prepared from 2,2-dibenzyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](Br)[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:40]=[O:41]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([CH:40]=[O:41])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2cc(Br)cs2)cc1CO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2cc(C=O)cs2)cc1CO[Si](C)(C)C(C)(C)C

Procedure:
In a manner similar to that of Example 9(g), by reaction of 34 g (61 mmol) of 5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-bromothiophene with 27 mL (67 mmol) of 2.5 M butyllithium and 5.2 mL (67 mmol) of dimethylformamide, the crude product obtained (33.8 g; Y=99%) is in the form of a brown oil.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17]CC)=O.C(N(CC)CC)C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(O)C>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:15]([C:3]2[N:4]=[C:5]3[N:10]([C:11](=[O:12])[C:2]=2[OH:1])[CH2:9][CH2:8][O:7][C:6]3([CH3:13])[CH3:14])=[O:17])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 35 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
Additional procedure. Ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (50 g, 0.186 mol) and ethanol SDA3A (500 mL) was added to a 1 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Triethylamine (18.86 g, 0.186 mol) was added to the slurry. The resulting solution was heated to 35° C. followed by slow addition of 4-fluorobenzylamine (35.0 g, 0.279 mol). The thick slurry was heated at 78° C. with stirring for 6 h. The reaction mixture was polish filtered and the filtrate reheated to 70° C. The pH was adjusted to about 1.0 by slow addition of 1N HCl (405 mL). The thick slurry was cooled to 20–25° C., the solids filtered off, washed twice with ethanol SDA 3A (each 250 mL) and twice with water (each 500 mL). The white solid was dried in vacuo at 50–55° C. to afford N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide (58.9 g).