Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=NC(=O)c1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-chlorobenzoyl chloride, there is obtained ethyl N-(p-chlorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 106°-107° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[N:18]O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][NH:18][C:12](=[O:20])[C:13]3[S:17][CH:16]=[CH:15][C:14]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O
Reactant: ON=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Solvent: CCOC(C)=O
Product: O=C1NCCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 130 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
In a 250-ml round bottomed flask equipped with a stirbar was placed 4-(3,4-dichlorophenyl)-N-hydroxy-5,6-dihydro-1-benzothiophen-7(4H)-imine (1.25 g, 4.00 mmol) and polyphosphoric acid (40 g, 200 mmol). The resulting mixture was heated at 130° C. under an atmosphere of nitrogen with stirring for ˜4 hours, leaving a dark brown mixture. The mixture was allowed to cool to rt then water and ethyl acetate were added. The mixture was stirred briefly then transferred to a separatory funnel. The organic layer was separated then the aqueous layer was extracted with additional ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to leave crude product as a brown oil. The residue was purified using column chromatography on silica gel (120 g RediSep column, gradient 0% ethyl acetate in dichloromethane to 90% ethyl acetate in dichloromethane over 20 minutes) give the product 1.08 g (86% yield) product as a light tan solid. LCMS: (FA) ES+ 312, 314. 1H NMR (400 MHz, DMSO) δ 8.24-8.12 (s, 1H), 7.65-7.59 (d, J=5.2 Hz, 1H), 7.60-7.51 (d, J=8.3 Hz, 1H), 7.45-7.36 (d, J=2.1 Hz, 1H), 7.11-7.01 (dd, J=8.3, 2.1 Hz, 1H), 6.64-6.51 (d, J=5.2 Hz, 1H), 4.56-4.42 (dd, J=8.8, 5.5 Hz, 1H), 3.25-3.03 (m, 2H), 2.34-2.18 (m, 1H), 2.10-1.95 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27][C:28]1[C:32]([CH:33]=[O:34])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:33]([C:32]1[C:28]([O:27][CH2:2][C:3]2[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])[O:12][C:13]=3[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=2)=[N:29][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)=[O:34]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 3-[4-{(4-chloromethyl-2-methoxyphenoxy)methyl}-5-methyl-1,3-oxazol-2-yl]benzonitrile (4.32 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.0 g), anhydrous potassium carbonate (1.47 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl)-2-methoxyphenoxy}methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (5.30 g, yield 96%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:22][CH2:21][CH2:20][Cl:19])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Cl)ccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc(Cl)ccc2N1CCCCl
Yield: 79.2 %

Procedure:
7-Chloro-4H-benzo[1,4]oxazin-3-one (81MF2271a) (1.74 g, 9.47 mmol), Cs2CO3 (4.63 g, 14.2 mmol) and 3-chloro-1-iodopropane (2.13 g, 10.4 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2271b) (1.95 g, 79%). 1H NMR (CDCl3) δ 7.03-6.96 (m, 3H), 4.59 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3) δ 164.0, 146.0, 129.1, 127.3, 123.0, 117.8, 115.5, 67.7, 42.4, 39.2, 30.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[C:2]=1[C:14]([OH:16])=O.[NH2:17]C(N)=O>O>[C:11]1(=[O:12])[C:3]2[C:2](=[N:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[C:14](=[O:16])[NH:17]1
Reactant: NC(N)=O
Reactant: O=C(O)c1cc2ccccc2nc1C(=O)O
Solvent: O
Product: O=C1NC(=O)c2nc3ccccc3cc21
Yield: 38.2 %

Procedure:
Quinoline-2,3-dicarboxylic acid (1.29 g) and urea (709 mg) were ground together and heated at 170° for 3 h. The cooled mass was treated with water (50 mL) and triturated. The resulting solid was filtered, washed with water, and air dried to give the title compound as a white solid (450 mg). M.p.>300°.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:13][C:14]3[CH:24]=[CH:23][C:17]4[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=4[CH:15]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: c1ncc2nc[nH]c2n1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cncnc43)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a stirred solution of 9H-purine (784 mg, 6.53 mmol) in DMF (16 mL) was added NaH (60% dispersion in mineral oil, 373 mg, 9.33 mmol), portionwise at 0° C. After stirring for 30 min, 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.3 g, 6.22 mmol) was added to the mixture. The reaction mixture was allowed to warm to rt and stir for 3 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (150 mL×4). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light yellow solid (569 mg, 32.7%). 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 7.69 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 5.59 (s, 2H), 2.70 (s, 3H). LCMS (ESI) m/z 298 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[ClH:17].[H][H]>CO.[Pd]>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: [H][H]
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1C2CCN(CC2)C1Cc1cccnc1

Procedure:
2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (20 g, 93 mmol) was suspended in methanol (200 mL) and treated with 46 mL of 6N HCl. 10% Palladium on carbon (1.6 g) was added and the mixture was shaken under 25 psi hydrogen for 16 h. The mixture was filtered through Celite and solvent removed from the filtrate by rotary evaporation, to give crude 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one hydrochloride as a white gum (20 g). This was treated with 2N NaOH (50 mL) and chloroform (50 mL) and stirred for an hour. The chloroform layer was separated and the aqueous phase was treated with 2N NaOH, enough to raise the pH to 10 (about 5 mL), and saturated aqueous NaCl (25 mL). This was extracted with chloroform (3×10 mL), and the combined extracts were dried (MgSO4) and concentrated by rotary evaporation. The residue (18 g) was dissolved in warm ether (320 mL) and cooled to 4° C. The white solid was filtered off, washed with a small portion of cold ether and air dried. Concentration of the filtrate to ˜10% of its former volume and cooling at 4° C. produced a second crop. A combined yield 16 g (79%) was obtained.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CCOC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Ethyl 4-(tert-butyldimethylsilyloxy)-1-methylcyclohexanecarboxylate (Intermediate 66, 1.32 g, 4.39 mmol) was dissolved in THF (25 ml), to which tetrabutylammonium fluoride (TBAF, 1M solution in THF) (7.34 ml, 7.34 mmol) was added. The reaction mixture was stirred at room temperature overnight, then concentrated and the residue was partitioned between EtOAc/water. The aqueous layer was back extracted and combined organics were dried over MgSO4, filtered and concentrated to afford a brown oil. This material was purified via flash column chromatography, eluting with 2-50% EtOAc/Hept. Relevant fractions were pooled and concentrated to afford a clear oil—797 mg (97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])=[O:5].Br.[C:23](O)(=O)[CH3:24].[C:27](O)(=O)C>O>[CH:24]1([CH2:13][O:12][C:10]2[C:9]([O:14][CH3:15])=[CH:8][C:7]([CH3:16])=[C:6]([C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:21])[CH:11]=2)[CH2:23][CH2:27]1
Reactant: CC(=O)O
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC
Agent: Br
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OCC1CC1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2,6-dichloro-4',5'-dimethoxy-2'-methylbenzophenone (Compound 1; 2.5 g, 7.7 mmol), hydrogen bromide/acetic acid (33%, 10 ml) and glacial acetic acid (10 ml) is stirred for 1.5 h at 75° C., poured into water (100 ml) and twice extracted with dichloromethane (50 ml each). The extracts are combined, dried, and concentrated in vacuo. The resulting oil is applied onto the top of a flash chromatography column (silica gel, 30 g). Elution is carried out with toluene and toluene/acetone, 9:1 (500 ml each). The fractions containing the material with an Rf =0.54 (silica gel; toluene/acetone, 9:1) are combined and the solvent is evaporated in vacuo until a final volume of 20 ml is reached. The solution is then extracted three times with aqueous sodium hydroxide (2N; 30 ml each). The aqueous layer is acidified with hydrochloric acid (6M) and the precipitate is collected by vacuum filtration and dried to give Compound 5 as colorless crystals, 1.1 g, (45.9% y) mp 152° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>>[CH:17]1([CH2:16][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)cccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.45 (s, 1H), 4.02 (d, J=6.4 Hz, 2H), 2.48 (s, 3H), 1.18 (m, 1H), 0.56 (m, 2H), 0.34 (m, 2H); MS (ES) m/z 254 (M+1).
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: O=P(O)(O)CCl
Reactant: NCCCCCCCCCCN
Solvent: O
Product: NCCCCCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (5.5 g, 42 mmoles) and 1.10-diaminodecane (44 g, 255 mmoles) were heated under reflux in water (200 cm3) for 20 hours. The water was removed and ethanol (400 cm3) added to the solid residue. The phosphonic acid was filtered off and dried. The crude yield was 11.4 g (87%). A sample was purified by recrystallization from water/ethanol to give N-(10-aminodecyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 238° C.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[Cl:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:29][CH2:28][CH2:27][Cl:26])=[O:4]
Reactant: OCCCl
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OCCCl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Chloroethyl perfluorooctanoate was prepared by adding 162 g (0.375 mol) of perfluorooctanoyl chloride to 32.2 g (0.40 mol) of 2-chloroethanol cooled at 0° C., stirring the resulting mixture at 0° for 2 h, and then stirring for about 2.5 days at 25°. Fractionation of the resulting solution gave 152.6 g (85% yield) of the chloroethyl ester, b.p. 84°-88° at 1.3 kpa (10 mm), 98% pure by GC. IR (CCl4): 2960 (sat'd CH), 1790 (C--O), 1300-1100 cm31 1 (CF, C-O). NMR (CCl4): 1H 4.59 (t, JHH 5.5 Hz, 2H, CH2) and 3.70 ppm (t, JHH 5.5 Hz, 2H, CH2); 19F -81.6 (t of t, JFF 10, 4 Hz, 3F, CF4), -119.0 (t of t, JFF 12, 6 Hz, 2, F, CF2C=O), -122.4 (m, 4F, CF2), -123.3 (m, 4F, CF2), and -126.8 ppm (m, 2F, CF2).
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1)C1CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), Cs2CO3 (0.122 g, 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) was stirred at 70° C. for 2 h. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester as a solid (72 mg, 100%).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:26]([O:36][CH2:37][CH2:38][OH:39])=[C:25]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)[CH:24]=1)C>C1COCC1>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:24]=[C:25]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)[C:26]([O:36][CH2:37][CH2:38][OH:39])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71.6 %

Procedure:
To a flamed dried round bottom flask with dodecyl amine (0.519 g, 2.80 mmol) and THF (8 mL) cooled to 0° C. was added n-BuLi (1.12 mL, 2.5 M in hexane, 2.80 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 40 min. and then cooled to −45° C. To this solution was added dropwise a solution (at 0° C.) of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.302 g, 0.700 mmol) in THF (8 mL) over 5 min. This final mixture was stirred and warmed to room temperature over 30 min. At this point, the reaction mixture was quenched with H2O (3 mL) and diluted with EtOAc (40 mL). The organic layer was washed with 1 N HCl (3×7 mL), brine,(7 mL), and H2O:brine (1:1, 14 mL) and then dried (Na2SO4). After concentration, the residue was purified by flash chromatography (0 to 15% EtOAc/hexane gradient) to afford the product (0.286 g, 72%) as an oily white solid; 1H NMR (DMSO-d6) δ 0.86 (t, J=7.7 Hz, 3H), 1.20-1.37 (m, 18H), 1.46-1.57 (m, 2H), 3.13 (dd, J=6.9, 11.5 Hz, 2H), 3.20-3.33 (m, 4H), 4.46 (t, J=6.2 Hz, 1H), 7.43-7.57 (m, 4H), 7.59-7.63 (m, 2H), 7.68-7.73 (m, 2H), 7.89 (s, 2H), 8.67 (t, J=6.2 Hz, 1H); mass spectrum [(+) APCI], m/z 570 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:10][C:3]1[N:4]=[C:5]([CH3:9])[N:6]=[C:7]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:2]=1[NH2:1]
Reactant: NC1CCOCC1
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
In a 300 mL glass pressure reactor, combine 5-amino-4,6-dichloro-2-methylpyrimidine (20.0 g, 97%, 109.0 mmol), 4-aminotetrahydropyran hydrochloride (21.0 g, 152.6 mmol), di-isopropylethylamine (57.0 mL, 326.9 mmol) and isopropyl alcohol (100 mL). Seal the pressure vessel tightly, start stirring, and adjust the set-point for heat control to 100° C. Stir the mixture at 100° C. for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and add 4-aminotetrahydropyran hydrochloride (2.25 g, 16.3 mmol). Re-seal the vessel, heat the contents to an internal temperature of 100° C., and stir for an additional 24 hours. Cool the reaction mixture to ambient temperature, vent the reactor of pressure, and transfer the contents to a recovery flask. Concentrate the mixture under reduced pressure to approximately ⅓ of its original volume. Add water (200 mL) and ethyl acetate (200 mL) and transfer the resulting mixture to a separatory funnel Separate the layers, re-extract the aqueous layer with ethyl acetate (100 mL) and combine all organics. Wash with water (2×100 mL) and brine (100 mL), then dry the organic layer over anhydrous sodium sulfate. Concentrate under reduced pressure to afford 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine as an off-white solid (25.0 g). MS (m/z): 243/245 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 870.1 %

Procedure:
In analogy to example 1 were reacted 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 1,81 g (2 mmol) of acryloyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 6,5 g (87%) acrylic acid 2,6-di-ethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid. Elemental analysis calculated for C23H35NO3: C 73,95%; H 9,44%; N 3,75%. Found: C 74,43%; H 9,44%; N 3,91%.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>CO.O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(CCSCc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1csc(CSCCN2CCNCC2)c1
Yield: 89.2 %

Procedure:
1 g (3.7 mM) of N-formyl-N'-[2-(2-thienylmethylthio)ethyl]piperazine was dissolved in 10 ml of methanol. Thereto was added a solution of 178 mg (4.4 mM) of sodium hydroxide in 10 ml of water. The mixture was refluxed for 10 hours with heating, to give rise to a reaction After the completion of the reaction, the solvent was removed under reduced pressure. The residue was subjected to extraction with chloroform. The extract was washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel chromatography to obtain 800 mg of N-[2-(2-thienylmethylthio)ethyl]piperazine at a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
To a solution of 91.3 grams (g) (0.56 moles) of 3,4-dichlorophenol dissolved in 500 milliliters (ml) of dimethyl sulfoxide (DMSO) was added 22.4 g (0.56 moles) of sodium hydroxide (NaOH). The slurry was heated at 60° C. for 15 minutes and 100 g (0.55 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 3 hours (hrs). The reaction mixture was cooled and poured into a slurry of 200 ml of 2 normal (2 N) NaOH and 1800 ml of ice and water with the product precipitating. The product was collected by filtration, washed well with water and dried, to obtain 163.3 g of product (96.4% yield), mp 154°-155° C. Recrystallization from 3-methoxy-2-propanol (Dowanol® PM The Dow Chemical Company, Midland, Michigan) afforded purified 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile, melting at a melting point (mp) of 155°-156° C. The prominent infrared bands for 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile were as follows: IR (Nujol) 2250, 1620, 1580, 1520, 1465, 1360, 1270, 1130, 1040 and 895 cm-1.