Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][Mg]Br>O1CCCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:16])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(-c2ccnc(Cl)c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-(4-methoxyphenyl)pyridine (660 mg) and bis(triphenyl-phosphine)nickeldichloride (200 mg) in anhydrous tetrahydrofuran (7.5 mL) is cooled to a temperature close to 0° C. A solution of methylmagnesiumbromide in tetrahydrofuran (2.6 M, 2 mL) is added slowly. The mixture is stirred at room temperature for two hours, concentrated under reduced pressure and dissolved in methyl tert-butyl ether (10 mL). Alkaloids are extracted with a 3N aqueous solution of hydrochloric acid (3 times 10 mL). Extracts are pooled, alkalinised and back extracted with methyl tert-butyl ether (3 times 20 mL) and dichloromethane (30 mL). Organic phases are dried over magnesium sulphate, concentrated under reduced pressure and purified over silica gel (eluent dichloromethane/methanol from 100/0 to 95/5). Fraction containing the expected product are pooled and concentrated under reduced pressure to give 385 mg of 4-(4-methoxyphenyl)-2-methylpyridine as a clear brown powder used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4](O)=O.O.[CH:14]([NH2:16])=[O:15]>>[C:11]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:14](=[O:15])[N:16]=[CH:4]2)#[N:12]
Reactant: N#Cc1ccc(N)c(C(=O)O)c1
Reactant: NC=O
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)ncc2c1
Yield: 44 %

Procedure:
A stirred solution of 2-amino-5-cyanobenzoic acid (2.0 g, 12.3 mmol) in formamide (10 ml) was heated at 190° C. for 7 hours. The dark solution was allowed to cool and poured into water (50 ml). The resulting precipitate was collected by filtration and dried in vacuo at 60° C. to give 6-cyanoquinazolinone (0.93 g, 5.43 mmol, 44%); [2H6]DMSO 12.65 (1H, s), 8.50 (1H, s), 8.28 (1H, s), 8.18 (1H, dd), 7.81(1H, d).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:5][N:4]([C:6](=[O:25])[CH2:7][O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)[CH2:3]1>[Pd].C(O)C>[F:26][C:2]1([F:1])[CH2:5][N:4]([C:6](=[O:25])[CH2:7][O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:3]1
Reactant: O=C(COC1CCN(C(=O)OCc2ccccc2)CC1)N1CC(F)(F)C1
Agent: [Pd]
Solvent: CCO
Product: O=C(COC1CCNCC1)N1CC(F)(F)C1
Reaction time: 3 h
Yield: 32.8 %

Procedure:
Benzyl 4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethoxy)piperidine-1-carboxylate (87) (2.59 g, 7.03 mmol) and palladium on carbon (0.075 g, 0.70 mmol) were added to ethanol (40 mL). This was stirred for 3 hours under an atmosphere of H2 (1.417 g, 703.09 mmol). The reaction was filtered and the solvent evaporated to afford a viscous clear oil. The crude product was purified by distillation at 0.5 mBar, collecting fractions that distilled at 90° C. to afford the desired material as a colourless oil (0.540 g, 32.8% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.49-1.40 (2H, m), 1.94-1.89 (2H, m), 2.65-2.59 (2H, m), 3.10-3.05 (2H, m), 3.44-3.38 (1H, m), 4.13 (2H, s), 4.35 (2H, t), 4.64 (2H, t); NH missing
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.CC([O-])(C)C.[K+].CC(O)(C)C>C1COCC1>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([O:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[N:7]=1
Reactant: OCc1ccc(F)cc1
Reactant: Fc1ccccc1CNc1nc(Cl)ncc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Fc1ccc(COc2ncc(F)c(NCc3ccccc3F)n2)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
A solution of (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine* (0.103 g, 0.40 mmol) in 5 mL of dry THF was treated with 4-fluorobenzylalcohol (0.062 g, 0.49 mmol) and a 1.0 M solution of KOtBu in tBuOH (0.4 mL, 0.4 mmol). The mixture was heated at 80° C. in a sealed vial for 18 h, partitioned between CH2Cl2 and water, and the organic phase was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue purified by flash column chromatography (SiO2, 10→20% EtOAc/petroleum ether) to yield the title compound (0.157 g, 42%) as a white solid: mp 83-84° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=2.8, 1H), 7.45-7.27 (m, 5H), 7.15-6.96 (m, 5H), 5.37 (br s, 1H), 5.29 (s, 3H), 4.74 (d, J=5.9, 3H); MS (ESI) m/z 346 (M+H)+. *Singh, R.; Argade, A.; Payan, D. G.; Clough, J.; Keim, H.; Sylvain, C.; Li, H.; Bhamidipati, S., WO 2004014382 A1 20040219
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][P:16]([O:26][CH3:27])([CH2:18][C@@H:19]([OH:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:28]([CH3:30])[CH3:29])[N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:9]=2)=[CH:4][CH:3]=1>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][CH2:15][P:16]([O:26][CH3:27])([CH2:18][C@@H:19]([OH:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:28]([CH3:30])[CH3:29])[N:11]=[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](O)CP(=O)(C=Cc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C[C@H](O)CP(=O)(CCc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC
Reaction time: 144 h
Yield: 64 %

Procedure:
10% Pd/C (0.026 gm, 0.024 mmol) was added to a methanol solution (30 ml) of (S)-4-[[2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-pyrimidinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester obtained in Example 3 above (0.125 gm, 0.24 mmol) which had been purged with argon for 15 minutes. The solution was then placed under 50 psi of hydrogen on a Parr apparatus and shaken for 6 days. The flask was then taken off the Parr apparatus and the solution filtered through a pad of celite which was washed with methanol. The filtrate was concentrated to give a clear oil which was subsequently purified by flash chromatography on Merck silica gel in 30-70% acetone in hexane. Product fractions were combined and concentrated to afford the title compound as a white solid (0.080 gm, 64%). TLC: Rf =0.41 (50% acetone in hexane).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:23])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>ClCCl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([OH:23])[CH2:14][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:3](=[O:4])[CH2:2][Cl:1])=[CH:11][CH:12]=1
Reactant: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)N(Cc1ccccc1)C[C@@H](O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of chloroacetyl chloride (4.3 g, 3.4 ml, 38 mmol) in dichloromethane (20 ml) was added dropwise over 30 min to the ice-cooled mixture of a solution of (1S)-1-(4-fluorophenyl)-2-(benzylamino)ethanol (8.3 g, 34 mmol) in dichloromethane (100 ml) and 1N aqueous sodium hydroxide solution (40 ml, 40 mmol), and the mixture was stirred for 1 hr at same temperature. The resulting solution was washed successively with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloroacetylamino)ethanol. Potassium hydroxide (2.2 g, 39 mmol) was added to a solution of the obtained compound in isopropyl alcohol (60 ml), and the mixture was stirred for 4 hrs. The solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (6S)-6-(4-fluorophenyl)-4-(benzyl)morpholin-3-one (9.7 g) as a yellow oil.
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:4])[NH2:2].[CH:23](OC)(OC)OC>>[O:4]1[CH:23]=[N:2][N:1]=[C:3]1[C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: COC(OC)OC
Product: O=S(=O)(Nc1cccc2cc(-c3nnco3)[nH]c12)c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A mixture of N-[2-(hydrazinocarbonyl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.28 g) and trimethyl orthoformate (0.13 g) was stirred at 100° C. overnight. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography and the title compound (0.11 g, yield 39%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 271-272° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[CH:9][C:10]#[N:11].[CH:18]1([CH2:21][C:22](Cl)=[O:23])C[CH2:19]1.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[C:9]([C:22](=[O:23])[CH2:21][CH2:18][CH3:19])[C:10]#[N:11]
Reactant: O=C(Cl)CC1CC1
Reactant: CC(C)C(C)NC(=CC#N)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCCC(=O)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 3-(2-chlorophenyl)-3-[(3-methylbutan-2-yl)amino]acrylonitrile (1 g, 4.02 mmol, 1 eq.) in 1,2-dichloroethane (2 ml) were added cyclopropylacetyl chloride (1.71 g, 16.08 mmol, 4 eq.) and pyridine (1.58 g, 20.1 mmol, Seq.) and the solution was heated to 80° C. for 8 h. The reaction was quenched with 1N aq. HCl (20 ml) and extracted with ethylacetate. The organic layers were combined and washed with 1N aq. NaOH (20 ml), dired over MgSO4 and concentration under vacuum. The residual oil was subjected to column chromatography to give 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-oxohexanenitrile (1.012 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15][CH3:16])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[OH:34]O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15]([CH3:16])=[O:34])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: OO
Reactant: CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Solvent: C1CCOC1
Product: CS(=O)c1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Temperature: 73 °C
Reaction time: 12 h

Procedure:
To the title compound from Example 255 (0.18 grams) dissolved in anhydrous THF (10 mL) was added 30% aqueous hydrogen peroxide (3 mL) and the resulting solution was stirred for 12 hours at 73° C. The solution was concentrated in vacuo, diluted with CH2Cl2, and washed with water. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the title compound after preparative plate chromatography (silica gel) using 3% MeOH—CH2Cl2 (0.04 grams, 26%, MH+ 492).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14]([F:16])=[C:13]1[C:8]([CH2:9][CH:10]([CH3:17])[CH2:11][O:12]1)=[CH:7]2.[CH2:18]([Li])[CH2:19][CH2:20]C.CC(C)([O-])C.[K+].C(Br)CC>O1CCCC1>[F:1][C:2]1[C:3]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14]([F:16])=[C:13]1[C:8]([CH2:9][CH:10]([CH3:17])[CH2:11][O:12]1)=[CH:7]2
Reactant: CC1COc2c(cc3cccc(F)c3c2F)C1
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCBr
Product: CCCc1ccc2cc3c(c(F)c2c1F)OCC(C)C3
Temperature: -95 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
The 8,9-difluoro-3-methyl-1,2,3,4-tetrahydro-1-oxaanthracene (1.5 g) obtained in this way was dissolved in 40 ml of tetrahydrofuran and admixed at −75° C. with 7 mmol of n-butyllithium. After stirring for a further 30 minutes, a solution of 7 mmol of potassium tert-butoxide in 20 ml of tetrahydrofuran was added dropwise. After cooling to −95° C., 15 mmol of propyl bromide were added dropwise. After 2 h, the temperature was cooled to −70° C., the mixture was stirred at this temperature for a further 1 h and was then allowed to come to 0° C. overnight. The mixture was added to 200 ml of ice-water and extracted twice with 100 ml each time of tert-butyl methyl ether, and the organic phases were combined, washed with water and saturated sodium chloride solution and dried. The solvent was distilled off under reduced pressure and the brown residue was chromatographed through 500 g of silica gel using heptane/toluene (9:1, v/v). 0.42 g of 8,9-difluoro-3-methyl-7-propyl-1,2,3,4-tetrahydro-1-oxaanthracene was obtained as a colorless syrup.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:19]3[C:20]4[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[C:10]=2[CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:19]3[C:20]4[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[C:10]=2[CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH2:27][CH2:28]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c(CCN3CCN(c4cc(C)ccn4)CC3)c3cccc4c3n2CCC4)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc(N2CCN(CCc3c(-c4ccc(O)cc4)n4c5c(cccc35)CCC4)CC2)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
7.5 g of 2-(4-methoxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 7) were dissolved in 110 ml of acetic acid. 110 ml of 41% strength aqueous hydrobromic acid were added to the solution, and the reaction mixture was heated under reflux for 16 hours. To work up the reaction mixture it was cooled to room temperature, then diluted with 100 ml of water and neutralized by addition of 10% strength aqueous sodium hydroxide solution (pH=6). It was then extracted with dichloromethane, and the organic phase was separated, dried and concentrated. The oily residue which remained was crystallized from ethanol/ether. 5.2 g of 2-(4-hydroxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline having a melting point of 220° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12]Cl)[C:4]=2[CH:3]=1.[CH3:22][CH2:23][N:24]([CH2:27][CH:28]1[NH:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:25][CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12][N:33]3[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]3[CH2:27][N:24]([CH2:25][CH3:26])[CH2:23][CH3:22])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2cc(Cl)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21
Temperature: 50 °C
Reaction time: 32 h

Procedure:
A mixture of 125 g (0.388 mole) of 9-chloro-11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one, 2480 ml of dry dimethyl formamide, 73.0 g (0.429 mole) of D,L-2-[(diethylamino)methyl]piperidine, 60 ml (0.429 mole) of anhydrous triethylamine and 3.0 g of sodium iodide was stirred at an internal temperature of 50° C. for 32 hours and then at room temperature for 15 hours. Insolubles were removed by filtration, and the filtrate was evaporated at the oil pump and at a bath temperature of 45° C. The remaining product was dissolved in 5% hydrochloric acid, and the solution was extracted by shaking twice with 50 ml of dichloromethane each time. The aqueous layer was made alkaline by addition of concentrated potassium carbonate solution, and the liberated base was taken up in dichloromethane, and the solution was treated with 2 g of active charcoal and dried over sodium sulphate. The dark oil remaining after the solvent had been removed by evaporation was purified by column chromatography on 800 g of silica gel (35-70 mesh) using dichloro- methane/methanol/ethyl acetate/cyclohexane/concentrated ammonia 59/7.5/25/7.5/1 (v/v) for elution. The fractions containing the compound which was sought (132 g) were dissolved in dilute aqueous maleic acid solution. The filtered solution was washed four times with 50 ml of ethyl acetate each time, and was then saturated with solid potassium carbonate and exhaustively extracted with dichloromethane. The combined dichloromethane phases were dried over sodium sulphate and evaporated, and 109 g of a partially crystallised oil remained. After recrystallisation twice from 450 ml of acetonitrile each time, using 2 g of active charcoal each time, 63.0 g (36% of theory) of colourless crystals of m.p. 167.5-169° C. were obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][S:6][CH2:7][C:8]1([OH:26])[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([O:15][CH3:16])[CH:9]1[C:17]1([CH3:25])[O:24][CH:18]1[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].[Cl:31][CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34].O>ClCCl>[Cl:31][CH2:32][C:33]([NH:35][C:36]([O:14][CH:11]1[CH2:12][CH2:13][C:8]([CH2:7][S:6][CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[CH2:2][Cl:1])([OH:26])[CH:9]([C:17]2([CH3:25])[O:24][CH:18]2[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:10]1[O:15][CH3:16])=[O:37])=[O:34]
Reactant: O=C=NC(=O)CCl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Solvent: O
Solvent: ClCCl
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
In dichloromethane (1.5 ml) was dissolved 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (300 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (84 μl). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : methyl acetate - hexane=1:2) to give 4-(N-chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (302 mg: yield 79%) as colorless powder.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][N:30]=[C:29]([CH2:32]Cl)[N:28]=2)[CH:24]=[CH:25][CH:26]=1>>[CH:1]1([C:4]2[N:5]([CH2:32][C:29]3[N:28]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=4)[O:31][N:30]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3-(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.66 (m, 2H), 7.55 (d, J=8.5 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 5.65 (s, 2H), 2.15 (m, 1H), 1.16 (m, 2H), 0.91 (m, 2H); MS (ES) m/z 477 (M+1).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH2:7].C([O-])(=O)C.[Na+].[CH3:19][O:20][C:21]([NH:23][C:24](=N)SC)=[O:22]>CO>[CH3:3][N:4]1[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:7]=[C:24]1[NH:23][C:21]([O:20][CH3:19])=[O:22]
Reactant: COC(=O)NC(=N)SC
Reactant: CNC(CN)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC1=NCC(c2ccccc2)N1C

Procedure:
This example illustrates the process of the invention wherein 1-(mono)-alkoxycarbonyl-S-methylisothiourea is used in place of a mixture of the mono- and bis-alkoxycarbonyl-reagents. In this example, a solution containing 2.1 g. of β-methylamino-β-phenylethylamine dihydrochloride, 1.64 g. of sodium acetate and 2.4 g. of 1-methoxycarbonyl-S-methylisothiourea in 20 ml. of 50%, wt., aqueous methanol is gently refluxed for two hours. The resulting heavy slurry is cooled, filtered and the collected solid product then washed with methanol affording 1-methyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole.
Reaction SMILES: [NH:1]([C:8]([CH3:10])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:40]([NH:43][C:44]([C:46]2[NH:47][CH:48]=[C:49]([C:51]3[C:55]([C:56]4[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[C:58]([Cl:64])[CH:57]=4)=[CH:54][NH:53][N:52]=3)[CH:50]=2)=[O:45])[CH2:41][OH:42])[CH:36]=[CH:37][C:38]=1[F:39]>CN(C=O)C>[Cl:32][C:33]1[CH:34]=[C:35]([CH:40]([NH:43][C:44]([C:46]2[NH:47][CH:48]=[C:49]([C:51]3[C:55]([C:56]4[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:5](=[O:7])[CH:2]([NH:1][C:8](=[O:9])[CH3:10])[CH2:3][OH:4])=[C:58]([Cl:64])[CH:57]=4)=[CH:54][NH:53][N:52]=3)[CH:50]=2)=[O:45])[CH2:41][OH:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Reactant: CC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC(CO)C(=O)NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of N—Ac-Ser-OH (0.2 mmol) in DMF (5 mL) was added HOBt (0.4 mmol) and EDCI (0.22 mmol) and stirred for 5 min. To the solution was added benzyl amine 11 (0.2 mmol) and TEA (0.3 mmol). The reaction mixture was stirred for 2 h at room temperature. The crude products were purified from preparatory HPLC to afford the desired product II-20 as a white solid. 1HNMR (CD3OD) 8.5 (br, 1H), 7.6 (s, 1H), 7.5 (m, 1H), 7.4 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (t, 1H), 6.8-6.9 (m, 2H), 5.0 (t, 1H), 4.2-4.4 (m, 3H), 3.6-3.7 (m, 4H), 1.9 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12].Cl[C:23]1C=CC(Cl)=C[C:24]=1NCCN(CC)CC.C(I)C.ClCC(C1C=CC=CC=1)=O>>[CH2:23]([NH:1][CH2:2][CH2:3][N:4]([CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])[CH3:24]
Reactant: NCCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: CCN(CC)CCNc1cc(Cl)ccc1Cl
Agent: O=C(CCl)c1ccccc1
Solvent: CCI
Product: CCNCCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl

Procedure:
When in the procedure of Example 5 an appropriate amount of 2-[N-(β-aminoethyl)-N-(2,5-dichlorophenyl)amino]acetophenone is substituted for N-(2,5-dichlorophenyl)-N',N'-diethylethylenediamine and an appropriate amount of ethyliodide is substituted for 2-chloroacetophenone, 2-[N-(β-ethylaminoethyl)-N-(2,5-dichlorophenyl)amino]acetophenone is obtained.