Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(I)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (2.99 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (60 wt %) (432 mg) in anhydrous DMF (20 ml) at room temperature, and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.92 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for 8.5 hours. Water was added thereto and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=10/1) to obtain tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (2.87 g). NMR (H1, CDCl3): δ 1.90-2.02 (4H, m), 2.97 (3H, s), 3.80-3.88 (4H, m), 7.14 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=8.5 Hz)
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>CO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccc(F)cc2CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[4-fluoro-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O provided the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][C:32]1[C:27]2[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])[C:28]=2[N:29]=[CH:30][N:31]=1)([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC(C)C)ncnc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and isopropylamine to obtain the title compound (see Table 1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]([C:24]1([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([C:24]1([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC1(C(O)(CCl)Cc2ccccc2Cl)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C(O)(Cc2ccccc2Cl)Cn2cncn2)CCCC1
Temperature: 80 °C
Yield: 35.7 %

Procedure:
13 g (188 mmol) of 1,2,4-triazole and 18 g (130 mmol) of potassium carbonate are initially introduced into 30 ml of absolute dimethylformamide under a nitrogen atmosphere and the mixture is heated to 80° C. At this temperature, a solution of 17.1 g (59.6 mmol) of 1-chloro-3-(2-chlorophenyl)-2-(1-methyl-cyclopent-1-yl)-propan-2-ol in 20 ml of absolute dimethylformamide is added dropwise with stirring. The reaction mixture is then stirred at 80° C. for a further 8 hours. The precipitate is filtered off with suction, and the filtrate is concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed through a silica gel column using dichloromethane/ethanol=99:1 as the eluent. 6.8 g (35.7% of theory) of 1-(2-chlorophenyl)-2-(1-methyl-cyclopent- 1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this way in the form of a solid substance of melting point 110° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][CH2:8][C:10](=[O:11])[CH3:12])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: C=CC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CC(=O)CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.4 g of freshly distilled methyl vinyl ketone are added. An exothermic reaction ensues, the reaction temperature rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 50° and 60°. After cooling to room temperature, the volatile materials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residue is obtained which is dissolved in 50 ml of 2.0 M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water, the white solid is co-evaporated with water (10×50 ml) and then with absolute ethanol (10× 50 ml). Crystallisation of the residue form ethanol yields 3-aminopropyl(3-oxobutyl)phosphinic acid hydrochloride. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W x 8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(3-oxobutyl)phosphinic acid, m.p. 163-5° (decomp.), as a white solid.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].P([O-])([O-])(O)=O.[K+].[K+].[K]>C(#N)C.O>[O:14]=[C:13]1[C@@H:12]2[C@@H:8]([CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:7]1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2CCN3C(=O)OCc2ccccc2)cc1OC
Agent: O=P([O-])([O-])O
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC#N
Product: O=C1N[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
135 g (0.34 mol) of benzyl (1S,5R)-6-(3,4-dimethoxy- benzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate were placed in 1.5 liters of acetonitrile. Thereto there was added a solution of 77 g (0.44 mol) of dipotassium hydrogen phosphate and 128 g (0.47 mol) of potassium peroxodisulphate in 660 ml of water and the mixture was heated to 100° C. The reaction time amounted to 2.5 hours. During this time the pH value of the mixture becomes acidic. This pH was held at about 5 by the portionwise addition of further dipotasium hydrogen phosphate. After completion of the reaction the acetonitrile was removed on a rotary evaporator and the aqueous residue was extracted with 3×250 ml of methylene chloride. The combined organic phases were washed once each time with 500 ml of 3% sodium hydrogen carbonate solution and 750 ml of saturated, aqueous sodium chloride solution and subsequently dried over magnesium sulphate. After concentration there was obtained a brown oil which was purified by chromatography [silica gel, 0.063-0.2 mm particle size, elution with 1) ethyl acetate:hexane =2:1; 2) ethyl acetate].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]4)[CH2:14]3)=[O:12])[S:7][C:6]=2[CH:29]=1>CCN(CC)CC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:14]3)=[O:12])[S:7][C:6]=2[CH:29]=1
Reactant: O=C(c1sc2cc(Br)ccc2c1Cl)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1sc2cc(Br)ccc2c1Cl)N1CC(N2CCNCC2)C1

Procedure:
A solution of compound 11b (0.3 g, 0.59 mmol) in Et3N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 11c, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1F

Procedure:
A suspension of 2,4-difluorobenzoic acid (3.6 g, 22.8 mmol) in dichloromethane (40 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (2.4 mL, 27.5 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes, and then the solution was evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][O:17]C(=O)C)[C:6]=2[N:7]=[CH:8][N:9]=1.CO.N>C(Cl)Cl>[Cl:3][C:4]1[C:5]2[C:12]([I:1])=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: ClI
Reactant: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Agent: N
Solvent: ClCCl
Solvent: CO
Product: OCCOCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Iodine monochloride (0.38 mL) was added dropwise with stirring under a nitrogen atmosphere to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3, 0.82 g) in dry CH2Cl2 (25 mL). The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated at 40 degrees C. under high pressure and the dark purple syrup was placed on the top of a silica gel column. Elution of the column (15×2 cm) with CHCl3 yielded a dark colored syrup, after evaporation of the appropriate UV absorbing fractions, which on trituration with dry ether gave a crystalline product. (0.3 g) as colorless needles. These needles were covered with methanol saturated with ammonia (30 mL) at 0 degrees C., and the reaction mixture stirred at room temperature in a pressure bottle for 20 hours. The solvent was evaporated under high vacuum and the resulting solid was recrystallized from methanol to furnish colorless needles of 9b, 0.21 g (80.75%), mp 154- 155 degrees C. 1H-NMR (DMSO-d6): 8.69 (s, 1, C2-H), 8.14 (s, 1, C6-H), 5.66 (s, 2, N7-CH2), 4.57 (t, 1, J=3.0 Hz, 3.3 Hz, exchangeable with D2O, OH), 3.46-3.33 (m, 4, CH2): UVλmax nm (ε×104); (pH 7) 225 (1.8), 296 (0.9); (pH 1) 233 (2.1), 280 (0.95); (pH 11) 228 (0.8), 280 (0.85).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:17]C)(OC)[CH2:13][OH:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19]I.[OH-].[K+].S(=O)(=O)(O)O>O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[O:17])[CH2:13][O:14][CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(CO)(OC)C1(c2ccc(Cl)cc2)CCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 0.08 h

Procedure:
2-[1-(4-Chlorophenyl)cyclobutyl]-2,2-dimethoxyethanol (1.48 g) and then methyl iodide (1.86 g) were added to a mixture of powdered potassium hydroxide (1.23 g) and dry dimethylsulphoxide (10 ml) which had been stirred for 5 minutes. The mixture was stirred for 30 minutes and was then poured into water (100 ml). The resulting mixture was acidified with concentrated sulphuric acid and extracted with dichloromethane. The extract was washed with water and dried and then evaporated to give 1-[1-(4-chlorophenyl)cyclobutyl]-2methoxyethanone as an oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:32][NH2:33]>C(O)(C)C>[CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15]([NH:32][NH2:33])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(Nc1nc(NN)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Temperature: 70 °C

Procedure:
2-((1-methyl-1-phenylethyl)amino)-4-chloro-5-(4-fluorophenyl)-6-(4-pyridyl)pyrimidine (218 mg, 0.52 mmol) was combined with a solution of hydrazine hydrate (130 mg 2.60 mmol) and isopropylalcohol (ca. 10 mL). The mixture was heated at 70° C. for 4 h. The reaction was cooled to RT, the solvent was evaporated in vacuo and the residue was purified by flash chromatography (2% MeOH:CHCl3) to provide the product as an off-white solid; MS m/z (M+H)+ 415; C24H23FN6 requir. 414.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH3:38])=[CH:6][CH:5]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a mixture of 4-hydroxy-benzoic acid methyl ester (152 mg, 1 mmol) and potassium carbonate (152 mg, 1.1 mmol) add acetonitrile (4 mL). To this mixture add 5-bromomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (Example 4, 314 mg, 1 mmol). Warm the resulting reaction mixture to 60° C., and stir at this temperature for 5 hrs. Cool the mixture to room temperature, dilute with ethyl acetate, wash with water, then brine, dry over MgSO4, filter and concentrate to give the title compound as a white solid (364 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH:26]=[N+]=[N-])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2].[ClH:31]>ClCCl.C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH2:26][Cl:31])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Yield: 81 %

Procedure:
The compound (20) (21.8 mg) obtained in item (9) above was dissolved in dichloromethane (1 ml), and to the resulting solution was added a 1.25M hydrogen chloride solution (0.05 ml) in diethylether at 5° C., and the mixture so obtained was allowed to stand at that temperature overnight. The resulting reaction solution was washed with water and the organic layer obtained was dried over anhydrous sodium sulfate and concentrated to give the titled compound (21) (18.0 mg) as a syrup. Yield: 81%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 128.2 %

Procedure:
Racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester (0.9 g, 3.925 mmol) was dissolved in DCM and 4M HCl in dioxane (9.8 mL) was added. The resulting mixture was stirred at RT for 4 hours before being evaporated. The residue was dried under high vacuum to give 0.65 g of crude racemic trans-3-amino-cyclohexyl-methanol as white foam (>95% yield).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]([NH2:10])[CH2:8][NH2:9].[OH-].[Na+]>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:9][CH2:8][CH2:7][NH2:10]
Reactant: NCCN
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: NCCNCC(O)CO
Yield: 42.9 %

Procedure:
Following the procedure of Surrey et al., J. Am. Chem. Soc. (1952) 74:4102, 3-chloro-1,2-propanediol (8.36 ml, 0.10 mole) was added dropwise over 15 min to stirring ethylenediamine (66.8 ml, 1.0 mole) at room temperature. After the addition was complete, the solution was heated at approx. 60° C. until the 3-chloro-1,2-propanediol was consumed (about 1 hour), as determined by TLC. NaOH (4.4 g, 0.11 mole) was added to the solution and excess ethylenediamine was vacuum distilled off followed by careful fractional distillation to yield 5.76 g (43%) of (36) (b.p. 162° C./2.0 mm).
Reaction SMILES: [F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].[H][H]>CCOCC>[F:1][C@:2]([C:14]([F:15])([F:17])[F:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: CCCCCC=CC[C@@](F)(C(=O)O)C(F)(F)F
Solvent: CCOCC
Product: CCCCCCCC[C@@](F)(C(=O)O)C(F)(F)F
Yield: 84.4 %

Procedure:
In 120 ml of ether was dissolved 10 g (39 mmol) of (R)-2-fluoro-2-(trifluoromethyl)-4-decenoic acid, and 3 g of activated carbon having 5% palladium supported thereon was added to the above-obtained solution. The resulting mixture was vigorously stirred under an atmospheric-pressure hydrogen atmosphere for 96 hours. Subsequently, the reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure, thereby obtaining 8.5 g of (R)-(+)-2-fluoro-2-(trifluoromethyl)decanoic acid having the physical properties as mentioned hereinbefore, in a yield of 85%.
Reaction SMILES: [O:1]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=O)C1C=CC=CC=1.O.[NH2:29][NH2:30].O>O1CCOCC1>[NH:29]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=[O:1])[NH2:30]
Reactant: NN
Reactant: CCOC(=O)N1CCN(c2ccc(NC(=O)Oc3ccccc3)cn2)CC1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of ethyl 4-[5-[(phenoxycarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (0.3 mol crude residue) and hydrazine hydrate (1.5 mol) in 1,4-dioxane (1100 ml) was stirred for 6 hours at room temperature. The reaction mixture was poured into water (4000 ml) and the resulting precipitate was filtered. The filtrate was extracted three times with CH2Cl2 (700 ml each time). The separated organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered and dried (25° C.; 20 hours), yielding 62 g (67%) of ethyl 4-[5-[(hydrazinocarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (interm. 9).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([N:23]3[CH2:27][CH2:28][NH:29][C:30]3=[O:31])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}aniline (1.1 g, 3.26 mmol) and 2-chloroethyl isocyanate (0.369 g, 3.5 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for overnight. Sodium hydride was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the resulting solid was collected and washed with water, diethyl ether, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give the title compound as a solid (1.2 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:22]([N:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:14](=[O:19])[O:15][CH:16]([CH3:17])[CH3:18])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1ccc(NC(=O)OC(C)C)cc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N(C(=O)OC(C)C)C(=O)c2ccccc2)cc1OCC
Temperature: 60 °C
Yield: 80 %

Procedure:
Isopropyl N-(3,4-diethoxyphenyl)carbamate (2.7 g) was dissolved in dimethylformamide (50 ml), and sodium hydride dispersion (50%, 0.5 g) was added thereto. The mixture was heated at 60° C. for 15 minutes, treated with benzoyl chloride (1.4 g) and heated for 30 minutes. The reaction mixture was poured into ice-water and extracted with ether. The extract was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane-acetone as the eluent to give isopropyl N-benzoyl-N-(3,4-diethoxyphenyl)carbamate (Compound No. 99) (3.1 g) in a yield of 80%. M.P., 120°-121° C.