Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([NH:27][NH2:28])[CH3:26].CC(O)C>O>[CH2:25]([N:27]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([F:24])[CH:21]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:28]1)[CH3:26]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: CCNN
Solvent: CC(C)O
Solvent: O
Product: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (400 mg), ethylhydrazine (369 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and 10% Pd—C (50% wet, 400 mg) was added. The mixture was stirred at room temperature for 1 h under H2 atmosphere, filtered and evaporated. The residue was suspended in AcOEt/IPE and collected by filtration to give the title compound (220 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:40]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:41])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.), triphenylphosphine (1.5 equiv.) and phthalimide (1.5 equiv.) in THF (0.3 M) at 0° C. was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (1.5 equiv.) dropwise. The reaction was stirred at 0° C. for 2 hours. Concentrated to dryness under vacuo, then purified the crude via silica gel column chromatography eluting with EtOAc and hexanes (1:1 with 5% methanol) to afford the 2-(3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (63% yield). LC/MS=350.3 (M+H), LC=3.936 min.
Reaction SMILES: [C:1]([CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6])#N.[OH-:16].[K+].CC[OH:20]>C1(C)C=CC=CC=1>[C:10]1([CH:3]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:20])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(C#N)c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)CC(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 43.5 g (214 mmol) of ethyl 3-cyano-3-phenylpropanoate and 52.2 g (930.4 mmol) of potassium hydroxide in 670 mL of EtOH is refluxed for 4 hours. After cooling to room temperature, the medium is concentrated under vacuum and then treated with 1 L of 1N HCl, and a precipitate then forms, which is filtered off and rinsed with water (2×50 mL). The solid obtained is taken up in a mixture of 200 mL of toluene and 40 mL of EtOH and concentrated under reduced pressure, and then dried with a vane pump. 37 g of 2-phenylbutanedioic acid are obtained in the form of a solid, which is used without further purification in the following step.
Reaction SMILES: C([N:4]1[C@@H:9]([C:10]([O:12]CC)=[O:11])[C@H:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:22]=[C:23](Br)[S:24][C:6]=2[C:5]1=[O:26])C=C.[CH3:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:8]2[C@H:9]([C:10]([OH:12])=[O:11])[NH:4][C:5](=[O:26])[C:6]3[S:24][C:23]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:22][C:7]2=3)=[CH:20][CH:19]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C=CCN1C(=O)c2sc(Br)cc2[C@@H](c2ccc(Cl)cc2)[C@@H]1C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc3c(s2)C(=O)N[C@@H](C(=O)O)[C@@H]3c2ccc(Cl)cc2)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of ethyl rel-(4R,5R)-6-allyl-2-bromo-4-(4-chlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (505.0 mg, 1.11 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (486 mg, 2.22 mmol) in 1,4-dioxane (14.6 mL, 187 mmol) and water (1.9 mL, 110 mmol) were added tetrakis(triphenylphosphine)palladium(0) (64.2 mg, 0.055 mmol) and cesium carbonate (1.08 g, 3.33 mmol). The mixture was stirred at 80° C. for 16 hr. After the reaction was completed, the solvent was evaporated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% [(60/20/20/20) EA/ACN/MeOH/water)]/EA to give the title compound as a yellow solid (428.7 mg, 73% yield). LCMS: (AA) ES+ , 399/401. 1H NMR (400 MHz, DMSO) δ 8.72 (d, J=6.1 Hz, 1H), 8.45 (d, J=6.6 Hz, 1H), 8.30 (d, J=4.4 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.43 (t, J=10.0 Hz, 2H), 7.21 (dd, J=24.7, 7.7 Hz, 3H), 4.98-4.59 (m, 1H), 4.32 (d, J=2.9 Hz, 1H), 2.69 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.Cl[C:25](OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].[NH2:37][C@H:38]([C:43]([NH2:45])=[O:44])[C:39]([CH3:42])([CH3:41])[CH3:40]>ClCCCl>[NH2:45][C:43]([C@@H:38]([NH:37][C:25]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:16])[CH3:15])[C:6]1=[O:14])=[O:26])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:44]
Reactant: CC(C)(O)CCn1c(=O)[nH]c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](N)C(N)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.8 %

Procedure:
To a solution of 1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.25 g, 1.1 mmol) in 1,2-dichloroethane (30 mL) were added triethylamine (0.52 mL, 3.7 mmol) and 4-nitrophenyl chloroformate (0.27 g, 1.4 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a mixture of L-tert-leucinamide (0.18 g, 1.4 mmol) in 1,2-dichloroethane (5 mL) at 0° C. and stirred at rt. After 14 h, the reaction was quenched by addition of water (50 mL) and filtered and washed with water (30 mL) and dichloromethane (30 mL). The obtained solid was suspended in water (50 mL) and filtered. This procedure was repeated twice followed by recrystallization from methanol. The obtained solid was suspended in water (50 mL) again and filtered and this procedure was repeated twice. Then the solid was dissolved in methanol/dichloromethane and filtered and concentrated in vacuo. The obtained solid was then recrystallized from acetone to give 0.14 g (33%) of the title compound.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][O:11][CH:12]([CH2:22][O:23]CC1C=CC=CC=1)[CH2:13][O:14]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[ClH:42]>CCO.[Pd]>[ClH:42].[NH2:8][CH2:9][CH2:10][O:11][CH:12]([CH2:22][OH:23])[CH2:13][OH:14]
Reactant: c1ccc(COCC(COCc2ccccc2)OCCN(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: NCCOC(CO)CO
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.3 %

Procedure:
Charged a solution of N,N-dibenzyl-2-(1,3-bis(benzyloxy)propan -2-yloxy)ethanamine (2000 g, 4.0 mol, 1.0 eq) in EtOH (10000 mL, 5.0 v), Pd/C (10%, 400 g, 20% wt,) and acetic acid (970 g, 16.2 mol, 4.0 eq) to a 20 L pressure reactor. The resulting mixture was stirred for 10 hours at 80° C. under hydrogen (20 atm). The reaction progress was monitored with NMR. The reaction mixture was cooled to 20˜30° C. and filtered. HCl (36%, 500 ml, 6.0 mol, 1.5 eq) was added to the filtrate, stirred for 10 minutes and concentrated under vacuum to give 572 g (83.4%) of 2-(2-aminoethoxy)propane-1,3-diol hydrochloride as an oil. H-NMR of 3 (300 MHz, D2O, ppm): 3.79 (2H, q), 3.60 (2H, m), 3.50 (3H, m), 3.15 (2H, q).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][CH2:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33]>>[ClH:27].[ClH:27].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]4[CH2:28][CH2:29][CH2:30][NH:31][C:32]4=[O:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C=NCCCCl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCCNC5=O)c4)CC3)cccc2n1
Product: Cl
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the synthesis of cyclic ureas and carbamates (Method G) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and 1-chloro-3-isocyanatopropane.
Reaction SMILES: COC([N:5]([C:13]1[CH:59]=[CH:58][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:44]=[CH:43][C:42]([N:45](C(OC)=O)[C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:41][CH:40]=2)=[O:22])=[O:18])=[CH:15][CH:14]=1)[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])=[NH:7])=O.[OH-].[Li+].[ClH:62]>CO.O>[ClH:62].[CH3:12][O:11][C:9]([NH:8][C:6](=[NH:7])[NH:5][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:43][CH:44]=2)=[O:22])=[O:18])=[CH:58][CH:59]=1)=[O:10]
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(N(C(=N)NC(=O)OC)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=N)Nc1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(NC(=N)NC(=O)OC)cc2)cc1
Yield: 58 %

Procedure:
In a mixture of 1,4-dioxane (3.0 ml) and H2O (3.0 ml) was dissolved (S)-[4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidino-benzoylamino)propyl]-2-oxopiperazin-1-yl]acetic acid hydrochloride (another name: (S)-4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidino-benzoylamino)propyl]-2-oxopiperazine-1-acetic acid hydrochloride) (0.3 g, 0.51 mmol) produced in Working Example 15. To the solution were added gradually, under stirring at 0° C. while keeping the pH at 10 or below, a 2N aqueous solution of sodium hydroxide (2.60 ml, 5.10 mmol) and chlorocarbonic acid methyl ester (0.31 ml, 4.00 mmol). The reaction mixture was stirred for 10 minutes at 0° C., whose pH was adjusted to 4 with a 1N aqueous solution of hydrochloric acid, followed by shaking together with ethyl acetate for extraction. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (CHP-20, 10% CH3CNaq-15% CH3CNaq-20% CH3CNaq-25% CH3CNaq-35% CH3CNaq) to give (S)-[4-[[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]acetyl]-3-[3-[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazin-1-yl]acetic acid (another name: (S)-4-[[4-(1,3-dimethoxycarbonylguanidino)-benzoylamino]acetyl]-3-[3-[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazine-1-acetic acid) (0.26 g, 62% ) as a colorless amorphous powdery product. This product (0.26 g, 0.31 mmol) was dissolved in a mixture of methanol (2.6 ml) and H2O (0.26 ml). To the solution was added, under ice-cooling, lithium hydroxide.1.0hydrate (42 mg, 1.00 mmol). One hour later, the reaction system was adjusted to pH 4 with a 1N aqueous solution of hydrochloric acid, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography [(CHP-20, 5% CH3CNaq-10% CH3CNaq-15% CH3CNaq-20% CH3CNaq) and (LH-20, H2O)] to afford the title compound (0.13 g, 58% ) as a colorless amorphous powdery product.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][NH:10][C:8](=[O:9])[C:7]1[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:34])=[CH:3][C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:5][CH:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A suspension of 4.00 g (11.1 mmol) 4-iodo-N-methyl-6-(4-methyl-piperzin-1-yl)-nicotinamide and 642 mg (0.555 mmol) tetrakis(triphenylphosphine)palladium(0) in 60 ml toluene was dioxygenated with a stream of argon for 30 min. After addition of 11 ml of a 2 N aqueous solution of sodium carbonate and 1.66 g (12.2 mmol) o-tolylboronic acid, the mixture was heated at reflux overnight. Cooling to room temperature was followed by dilution with water and extraction with three 50 ml portions of ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with three 50 ml portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 2.26 g (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][CH:9]=1.[Br:14]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][N:10]=1
Reactant: Cc1ncc(-c2ccccc2Cl)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1-c1cnc(CBr)s1
Temperature: 25 °C

Procedure:
180 mg (0.86 mmol) of the compound from Example 75A together with 229 mg (1.29 mmol) of N-bromosuccinimide and 14 mg (0.09 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 66 mg (27% of theory) of the target compound.
Reaction SMILES: COC=C.C(O)(=O)/[CH:6]=[CH:7]\[C:8](O)=[O:9].CCC[CH2:16][O:17][C:18](/[CH:20]=[CH:21]\[C:22](O)=O)=[O:19].COC=C>>[OH:9][C:8]1[CH:22]=[CH:21][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCCCOC(=O)/C=C\C(=O)O
Agent: C=COC
Product: COC(=O)c1ccc(O)cc1

Procedure:
Monobutylester of the copolymer of methylvinylether/maleic acid, sold under the tradename "GANTREZ ES 425" by G.A.F.: 0.37 g (active material)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH:3]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][CH2:11][CH3:10]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CN
Solvent: CCO
Product: CCCC(NC)C1=C(O)C(=O)c2ccccc2C1=O

Procedure:
3.50 g (20.1 mmol) of 2-hydroxy-1,4-naphthoquinone (lawson) was added to 50 ml of ethanol, and 1.60 g (20.6 mmol) of an aqueous monomethylamine solution (40% by weight) was further added thereto to obtain uniform solution of the amine salt. Then, 1.90 g (26.4 mmol) of butylaldehyde was added thereto, and the mixture was reacted at 25° C. for 1.5 hours. In about 20 minutes, crystals started to precipitate. After completion of the reaction, precipitated crystals were collected by filtration and washed with methanol to obtain 4.43 g (17.1 mmol) of crude crystals of the desired product. The yield was 85.1 mol %.
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:22](=[O:23])[CH2:21][C:20]([CH3:26])([CH3:25])[CH3:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:23]
Reactant: C1COCCOCCNCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCN(C(=O)CC(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].O>N1C=CC=CC=1>[C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)Cl
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
4.2 g (0.025 mol) of 2-nitro-4-methoxy-aniline are dissolved in 30 ml of pyridine, cooled to 0° C. and treated with 3.3 g (0.0275 mol) of valeryl chloride with stirring. After stirring for 1 hour at ambient temperature, the mixture is poured into iced water, the crystals are filtered off under suction and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:33](OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH3:33])[CH3:23])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
4-[2-(2-Methanesulfonylamino-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (470 mg, 1.14 mmol) was dissolved in THF (20 mL) and cooled to 0° C. Sodium hydride (29 mg of 60% dispersion in oil, 1.2 mmol) was added followed by dropwise addition of methyl iodide (78 μL, 1.25 mmol). The mixture was warmed to r.t. and stirred for about 36 hours. Ethyl acetate (20 mL) was added, and the solution was washed with saturated NaHCO3 (5 mL), H2O (5 mL) and brine (5 mL) and then dried over magnesium sulfate. The solvents were removed under reduced pressure to afford the final compound as a clear oil (486 mg, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:18])[N:6]([CH3:17])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[C-:19]#[N:20].[K+]>CN(C)C=O>[CH3:17][N:6]1[C:7]([S:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)=[C:3]([CH2:2][C:19]#[N:20])[N:4]=[C:5]1[CH3:18]
Reactant: Cc1cc(C)cc(Sc2c(CCl)nc(C)n2C)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
In 5.6 ml of dry dimethylformamide was dissolved 280 mg (1.0 mmol) of 4-chloromethyl-1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazole (42c). Added was 98 mg (1.5 mmol) of potassium cyanide, and the mixture was heated at 50° C. for 5 hours. To the reaction mixture, ice-water was added, extracted with diethyl ether, the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain 114 mg of [1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]acetonitrile (42d) (yield 42%).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10])=[CH:5][C:4]([Cl:12])=[C:3]([Cl:13])[CH:2]=1.[C:14]1(N2CCOCC2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1.Cl.C([O:30]C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([CH:1]=[CH:2][C:3]=1[Cl:13])[C@@H:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:14]1=[O:30])[CH2:8][N+:9]([O-:11])=[O:10]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC(C)OC(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 52.3 g (0.24 mol) of 3,4-dichloro-ω-nitrostyrene in 500 ml of methylene chloride is added while stirring and cooling within about 45 minutes to a solution of 40.1 g (0.24 mol) of N-(1-cyclohexen-1-yl)morpholine in 400 ml of methylene chloride under nitrogen so that the temperature does not exceed 0°. The mixture is subsequently stirred at 0° for a further 3 hours. 420 ml of 1N hydrochloric acid are added rapidly while stirring intensively, whereupon the mixture is stirred for a further 30 minutes. The aqueous phase is separated and extracted twice with 500 ml of methylene chloride each time; the organic phase is washed with water, dried over magnesium sulphate and evaporated. The oily residue obtained is taken up in 250 ml of isopropyl ether and left to stand in a refrigerator overnight. There is obtained rac-(2S*)-2-[(R*)-3,4-dichloro-α-(nitromethyl)benzyl]cyclohexanone in the form of colourless crystals of m.p. 109°- 110°.