Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.Cl>CC(N(C)C)=O>[C:17]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=3)[N:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11]=2[C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc2nc(N3CCCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (105 mg, 279 μmol), piperidine (47.6 mg, 55.3 μl, 559 μmol) and triethylamine (84.8 mg, 117 μl, 838 μmol) in DMA (2 ml) was heated to 100° C. in a sealed tube. After 4 h 0.1N HCl was added at room temperature and the mixture was extracted with EtOAc. The combined organic layers were washed with 0.1N HCl and brine and dried with Na2SO4. The remaining brown oil was purified by chromatography (silica gel, DCM/MeOH 98:2 to 95:5). The product fractions were concentrated and the remaining solid was dissolved in EtOAc, filtered through silica gel and evaporated. The remaining residue was finally purified by preparative thin-layer chromatography (DCM/MeOH 95:5) to obtain the title compound (22 mg, 18%) as light yellow solid. MS (ESI): 425.4 (M+H)+.
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(F)c2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid {2-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-yl}-amide (49 mg, 0.12 mmol) in AcCN (2.0 mL) was treated at rt with MnO2 (86 mg, 0.89 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. The solvent was removed under reduced pressure and the residue was dissolved in EA (10 mL), washed with water (10 mL), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=1.03 min; [M+H]+=410.85.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>>[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([I:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[CH:27][CH:28]=1)[CH3:20]
Reactant: O=C(Nc1ccc(Cl)c(I)c1)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(Cl)c(I)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(4-Chloro-3-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(4-chloro-3-iodo-phenyl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after suspension in small volume of EtOAc and filtration. HRMS m/z calcd for C25H24N4O3ClI [M+H]+: 591.0655. Found: 591.0655.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27](C)[C:28](=[O:34])[O:29][C:30](C)(C)C>ClCCl>[CH3:30][O:29][C:28](=[O:34])[NH:27][CH2:26][CH2:25][CH2:24][CH:23]=[O:22]
Reactant: CN(CCCCO)C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)NCCCC=O

Procedure:
To a stirred and cooled (<10° C.) solution of 150 parts of pyridinium dichromate in 1300 parts of dichloromethane was added dropwise a solution of 50 parts of (1,1-dimethylethyl) (4-hydroxybutyl)methylcarbamate in 91 parts of dichloromethane. Upon complete addition, stirring was continued for 3 hours in the presence of 112 parts of molecular sieves of 4A at room temperature. The reaction mixture was filtered over magnesium sulfate, washed with 1,1'-oxydisethane and the filtreate was evaporated. The residue was purified by column chromatography over silica gel using dichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in methylbenzene and the whole was evaporated again, yielding 3.5 parts (6.9%) of (1,1-dimethylethyl) (methyl(4-oxobutyl)carbamate as a residue (interm. 7).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)=[CH:17][O:18][C:14]=2[C:13]([I:8])=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4ccnc(N)c34)ccc21
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(I)cnc(N)c34)ccc21
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of NIS (0.985 g, 4.38 mmol) in DMF (20 mL) was added dropwise to a solution of 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1.505 g, 4.28 mmol) in DMF (20 mL) at −40° C. under Nitrogen. The mixture was stirred and allowed to slowly warm to room temperature for 17 hours. LCMS indicated about 85% conversion, so the mixture was cooled to about −30° C. and another portion of NIS (0.193 g, 0.858 mmol) in DMF (3 mL) was added dropwise. It was then allowed to slowly warm to room temperature and stirred for another 24 hours. The reaction mixture was then poured into water (ca. 200 mL) and the precipitate was collected by vacuum filtration and rinsed with Et2O (50 mL) to give 1,1-dimethylethyl 5-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (2.384 g, 4.00 mmol, 93% yield) as a tan solid. LC/MS (ES) m/z=478 [M+H]+.
Reaction SMILES: IC.[Br:3][C:4]1[C:5]([Cl:14])=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[C:15](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Br:3][C:4]1[C:5]([Cl:14])=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:15])[C:8]=2[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2cc(Br)c(Cl)cc2o1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CI
Product: Cn1c(=O)oc2cc(Cl)c(Br)cc21
Reaction time: 18 h

Procedure:
Iodomethane (0.579 ml . . . , 926 mmol) was added dropwise to a mixture of 5-bromo-6-chlorobenzo[d]oxazol-2(3H)-one (1.15 g, 4.63 mmol), potassium carbonate (1.599 g, 11.57 mmol) in DMSO (5 mL) at room temperature. The resulting mixture was stirred at this temperature for 18 h. Ethyl acetate (40 mL) was added and the mixture was stirred for 30 min and then filtered. The solution was washed with water (10 mL), brine (15 mL) and dried over Na2SO4. After filtration and concentration, a pale white solid was obtained (1.1 g). 1HNMR (400.342 MHz) δ 3.38 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CC(=O)O)c2ccccc21
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)O)c2ccccc21

Procedure:
Methyl (RS)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (50 g, 0.17 mol) was mixed with Candida Antarctica Lipase (CAL, SP-435, Novo Nordisk, Denmark) (2.5 g) and subsequently added 0.1 M phosphate buffer (pH=7.0) (3 L) under vigorous stirring. The resulting mixture was stirred vigorously at 25° C. for 120 h, and the pH was maintained at 7 by the addition of 0.5 N NaOH. After addition of about 0.45 equivalent of base, filtering off the enzyme stopped the reaction. The enzyme was washed with diethyl ether (1 L), and the pH of the aqueous phase was adjusted to 8. The aqueous phase was extracted with diethyl ether (2×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude methyl (R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid, which was used for the synthesis of (−)-(R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (see below). The aqueous phase was cooled by addition of ice, and the pH adjusted to 1.5 with 37% HCl (aq). The aqueous phase was extracted with diethyl ether (3×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude title compound (enantiomeric excess was about 80-85%). A number of precipitations from diisopropyl ether gave the title compound: mp 137-138° C.; enantiomeric excess 96.5%; [α]D=+12.8° (c=0.45, methanol). The chiral analysis was performed on a Ultron ES OVM 150×4.6 mm, flow 1.0 ml/min, eluent 25 mM phosphate buffer (pH≅4.6)/methanol/2-propanol/tetrahydrofuran 90/5/5/0.5, T=30° C. Enantiomeric purities expressed as enantiomeric excess (ee) were calculated from peak areas.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1
Yield: 27.8 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 3-methoxybenzyl chloride (19.6 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL). Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] afforded the desired product (10.2 mg, 27.9% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.35 (apparent d, 1H, J=8.3 Hz), 7.27-7.21 (m, 2H), 6.95 (apparent t, 3H, J=6.9 Hz), 6.82 (apparent dd, 1H, J=2.4, 8.3 Hz), 3.84 (m, 3H), 3.56 (s, 2H), 3.05 (d, 2H, J=10.5 Hz), 2.51 (apparent sept, partially hidden, 4H, J=7.2 Hz), 2.13 (apparent t, 2H, J=9.7 Hz), 1.88 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 367.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from the solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2Z,6E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1735 cm-1, 1677 cm-1, 1630 cm-1, 1448 cm-1, 1368 cm-1, 950 cm-1.
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:27]2)=[CH:24][CH:25]=1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 4-trifluoromethylphenylhydrazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2ncccc2c1
Reactant: c1ccc2ocnc2c1
Product: c1cnc2ccc(OCC3CO3)cc2c1

Procedure:
Compound 79 was prepared in the manner of compound 6 substituting 6-hydroxy-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[NH:7][C:6]2=[O:16].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][CH2:28]1.O>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:7]2[C:6](=[O:16])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:9][C:8]2=[O:15])[CH2:31][CH2:32]1
Reactant: COc1cc2[nH]c(=O)[nH]c(=O)c2cc1OC
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(=O)n(CCN3CCN(c4ccccc4OC)CC3)c(=O)c2cc1OC
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
Two grams of 6,7-dimethoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione was dissolved in 30 ml of dimethylformamide. After adding 1230 mg of sodium hydride thereto under cooling, the mixture was stirred for 10 minutes. Then, 23 grams of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride was added and the stirring was continued at 70° C. for 6 hours. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with chloroform and concentrated. The resultant residue was purified through the silica gel chromatography and crystallized from methanol to obtain 1.4 g of the titled compound (yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Clc1ccc([C@H](OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Reaction time: 7 h
Yield: 93.4 %

Procedure:
In 15 ml of acetone was dissolved 1.33 g (4.39 mmol, optical purity: 99.4% e.e.) of (S)-(−)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine obtained according to Reference example 1, then, 1.03 g (5.28 mmol) of ethyl 4-bromobutanoate and 0.73 g (5.28 mmol) of potassium carbonate were added, and the mixture was refluxed under stirring for 7 hours. Insolubles were filtered off and the filtrate was concentrated under reduced pressure. The resulting slightly yellowish oily product was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol (volume ratio: 30:1) as an eluent. Fractions containing the isolated objective compound were concentrated under reduced pressure to afford 1.71 g of ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]-butanoate as an oily product (Yield: 93.4%, optical purity: 99.4% e.e.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13].[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]2[N:11]([CH3:16])[S:12](=[O:14])(=[O:13])[CH2:15][CH2:2][C:3]=2[CH:8]=1
Reactant: COc1ccc(N(C)S(C)(=O)=O)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCS(=O)(=O)N2C
Temperature: 75 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 291 mg (0.95 mmol) N-(2-Bromomethyl-4-methoxy-phenyl)-N-methyl-methanesulfonamide in 15 ml of DMF was treated with 45 mg (1.14 mmol) 60% NaH and the reaction mixture was stirred at 75° C. for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, dried and evaporated. The residue was passed through a short plug of silica gel eluting with 25% ethyl acetate in hexane. There was obtained 123 mg (57%) of the desired product. Mass spectrum APCI (m/z) 228 (p+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[C:1]([CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2]
Reactant: N#CCCn1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: N#CCCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Yield: 79.9 %

Procedure:
17,9 g (0.08 mol) of the 9-(β-cyanoethyl)-carbazole thus obtained were suspended in 108 ml glacial acetic acid in a three-necked flask equipped with a stirrer, condenser, thermometer and dropping funnel and a mixture of 13.5 ml glacial acetic acid and 6.75 ml 65% nitric acid were added dropwise, while stirring, at 80°C, the nitrile thereby going into solution. The reaction mixture was further stirred for 15 minutes at 80°C, cooled and thereafter added dropwise into 200 ml ice water. The precipitated nitro compound was filtered off with suction, washed with a little water and the crude product recyrstallized from acetone. There were obtained 17.2 g (79.9% of theory) 9-(β-cyanoethyl)-3-nitrocarbazole in the form of yellow-green crystals with a melting point of 225°C.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)=O.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>COC1C=CC(O)=CC=1.N1C=CC=CC=1>[OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1ccc(N)c(O)c1
Agent: COc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(C#N)cc1O
Yield: 58 %

Procedure:
400 g of o-hydroxy-p-cyanoaniline, 4 g of hydroquinone monomethyl ether, 4 litres of acetone, and 360 g of pyridine were mixed and the mixture was cooled externally with a freezing medium. At a point when the internal temperature of the solution had dropped to -10° C., 420 g of methacrylic acid chloride was added dropwise to the mixture with stirring. Thereafter the mixture was treated in the same way as in Synthesis Example 1 to obtain 350 g of o-hydroxy-p-cyanomethacrylanilide. 76.8 g (0.38 mol) of this o-hydroxy-p-cyanomethacrylanilide was dissolved together with 68.4 g (0.60 mol) of ethyl methacrylate, 1.44 g (0.02 mol) of acrylic acid and 0.7 g of α,α'-azobisisobutyronitrile in 300 ml of an acetone/ethanol (1/2) mixed solvent. After replacing the atmosphere with nitrogen gas, the solution was heated at 65° C. for 4 hours to obtain a polymer solution. This polymer solution was poured into 3 litres of aqueous 5% HCl solution and the produced white precipitate was filtered and dried, giving 75 g of a white polymer. Determination of molecular weight of this polymer by the GPC method showed Mn=4,700 and Mw=33,000.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][NH2:13].Cl>[Cu].[OH-].[Na+]>[F:8][C:7]1[C:2]([NH:13][CH3:12])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(F)c1F
Reactant: CN
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Product: CNc1c(F)cccc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2',3'-difluoroacetophenone (30 g), methylamine (33% w/w solution in industrial methylated spirit, 46.5 ml), industrial methylated spirit (20 ml) and copper powder (1 g) was stirred in a sealed pressure vessel overnight at 100°. The reaction mixture was allowed to cool to ambient temperature and the mixture washed out of the vessel with industrial methylated spirit (2×30 ml). A solution of sodium sulphide nonahydrate (3.7 g) in water (39 ml) was added and the mixture heated at 50° for 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed washed with industrial methylated spirit (50 ml). The combined filtrate and washing were evaporated to give an oil which was stirred with hydrochloric acid (5M, 120 ml) for 90 minutes. The mixture was neutralised with aqueous sodium hydroxide (5M, 120 ml) and then extracted with dichloromethane (2×150 ml, then 100 ml). The combined extracts were washed with aqueous sodium chloride (6M, 50 ml), dried over magnesium sulphate and evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) to give the novel compound 3'-fluoro-2'-(methylamino)acetophenone, m.p. 26°-28°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)([C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.BrC1C=CC(C(C2C=CC=CC=2)(C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CN=2)O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Br)cc2)cc1
Product: OC(c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ncc[nH]1

Procedure:
Using the procedure described in Example IB but substituting an equivalent amount of α,α-bis(p-bromophenyl)-1-(toluene-p-sulphonyl)imidazole-2-methanol for the α-(p-bromophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol, α,α-bis(p-bromophenyl)imidazole-2-methanol was obtained. Its melting point was 192°-194° C. after crystallisation from isopropyl alcohol.