Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:25]([O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:26].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.CN(C=O)C>[CH2:25]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[O:5])[CH2:30][CH2:29]1)[CH3:26]
Reactant: CCOC1CCNCC1
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(OC)c34)ccc2F)CC1
Yield: 74.6 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) (200 mg, 0.61 mmol) and 4-ethoxypiperidine (79 mg, 0.61 mmol) were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was then removed to give a brown solid, which was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (200 mg, 74.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.46-1.62 (1H, m), 1.63-1.82 (2H, m), 1.87-1.96 (1H, m), 3.07-3.18 (1H, m), 3.43-3.59 (5H, m), 3.77-3.82 (3H, m), 3.99-4.11 (1H, m), 4.45 (2H, s), 6.91-7.02 (1H, m), 7.11-7.28 (3H, m), 7.62-7.71 (1H, m), 8.03-8.08 (1H, m), 10.29 (1H, s); m/z (ES+) (M+H)+=440.41; HPLC RT=1.87 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:13](=[O:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:17][Mg]Br.C(OCC)C>>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:13]([OH:15])([CH3:17])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1c(C)c(Br)cc2c1OCC2(C)C
Solvent: CCOCC
Product: Cc1c(Br)cc2c(c1C(C)(C)O)OCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A stirred, cooled (ice bath) solution of 1-(5-bromo-3,3,6-trimethyl-2,3-dihydro-benzofuran-7-yl)-ethanone (Compound 48, 2.0 g, 7.09 mmol), was treated drop wise with a 3M solution of methylmagnesium bromide in diethylether (2.84 mL, 8.51 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was cooled (ice bath), quenched with saturated ammonium chloride solution and extracted with ether. The organic extract was washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to a residue which on flash column chromatography using 7% ethyl acetate in hexanes as the eluent afforded the title compound (I.51 g, 71.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.21 (s, 1H), 4.35 (s, 1H), 4.22 (s, 2H), 2.53 (s, 3H), 1.67 (s, 6H), 1.31 (s, 6H).
Reaction SMILES: C([C@@H:3]1[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:6][C@@H:5]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)=O.CC(O)=[O:40].Cl.CON>C(Cl)Cl.CO>[C@@H:5]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:6][C@H:7]([CH2:8][OH:9])[C@@H:3]([OH:40])[CH2:4]1
Reactant: CC(=O)O
Reactant: Cc1cn([C@H]2C[C@H](C=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: CON
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3′-deoxy-3′-C-formyl-5′-O-tritylthymidine (0.59, 1 mmol, prepared as per Example 4 in CH2Cl2:MeOH (2:1, 30 vol.) was added AcOH (0.5 ml) and methoxyamine hydrochloride (0.189, 2.2 mml) at room temperature. The mixture was stirred for 30 min., concentrated under vacuum and the residue dissolved in MeOH (20 ml). To this solution, concentrated HCl (0.1 ml) was added and stirred for 1 h. The solution was neutralized with NH4OH (≈2 ml) and concentrated under a vacuum to furnish the 3′-C-[(methoxyimido)methyl] derivative of thymidine. 1H NMR (CDCl3) δ 9.67 (s, 1, NH); 7.67 (s, 1, H-6); 7.33 (d, 0.70, H-3″ E isomer), 6.65 (d, 0.30, H-3′ Z isomer); 6.15 (m, 1, H-1′); 3.60-4.12 (m, 3.3, H-4′, H-5′5″, H-3′ Z isomer); 3.91 (s, 0.9, OCH3 Z isomer); 3.82 (s, 2.1, OCH3 oxime E isomer); 3.26 (m, 0.7, H-3′ E isomer); 2.27-2.60 (m, 2, H-2′,2″); 1.91 (2s, 3, C6CH3).
Reaction SMILES: Br(F)(F)F.[Br:5]Br.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].S([O-])([O-])=O.[Na+].[Na+]>>[Br:5][C:12]1[CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc(Br)c1

Procedure:
A vigorously stirred mixture consisting of 0.1 moles (5 ml) bromine-trifluoride and 0.12 moles (6.5 ml) of bromine was added into a brine cooled three-necked flask equipped with a magnetic stirrer and a condenser containing ca. 0.6-0.7 moles of nitrobenzene. The addition was carried out dropwise with vigorous stirring while the temperature was kept between zero and ten degrees centigrate. After the addition was completed the crude reaction mixture was poured into a stirred icy 5% sodium sulfite solution. The organic layer was separated, and the aqueous solution was extracted twice with two portions of 100 ml dichloromethane. The combined organic layer was washed with 5% sodium bicarbonate solution and successively with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent evaporated. The crude reaction mixture was quantitatively analyzed by gas-chromatography internal standard program. The meta-bromonitrobenzene obtained was separated from the starting material by reduced pressure distillation. The yield of meta-bromonitrobenzene obtained, expressed in percentage of pure meta-bromonitrobenzene obtained based on reacted nitrobenzene, is 81%.
Reaction SMILES: [CH3:1][C:2]1([CH3:59])[C:10]2[C:5](=[CH:6][C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)=[CH:8][CH:9]=2)[N:4]([CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[N-:60]=[N+:61]=[N-:62].[Na+].O>CN(C)C=O>[N:60]([CH2:47][CH2:46][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)[CH:6]=2)[C:2]([CH3:1])([CH3:59])[CH2:3]1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCOS(=O)(=O)c2ccc(C)cc2)CC3(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CC3(C)C)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.455 g of tert-butyl 3-{3,3-dimethyl-1-[2-(toluene-4-sulphonyloxy)ethyl]-2,3-dihydro-1H-indol-6-ylmethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5.0 ml of N,N-dimethylformamide is admixed with 0.286 g of sodium azide and stirred at 65° C. over 1.5 hours. The reaction mixture is cooled, admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=6.56.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH:22]([NH:33][CH3:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:16].[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[C:41](Cl)=[O:42]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH:22]([N:33]([C:41](=[O:42])[C:40]1[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:38]([C:37]([F:36])([F:51])[F:52])[CH:39]=1)[CH3:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:16]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCC(Cc1c[nH]c2ccccc12)NC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.16 ml (8.32 mmol) of triethylamine and then a solution of 947 mg (2.38 mmol) of 6-(1H-indol-3-yl)-5-methylamino-hexanoic acid ethyl ester trifluoracetic acid salt in 10 ml of tetrahydrofuran are added dropwise at 0° C. in the course of 30 minutes to a solution of 0.49 ml (2.61 mmol) of 97% 3,5-bistrifluoromethyl-benzoyl chloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, then filtered and washed with 10 ml of tetrahydrofuran. The filtrate is concentrated by evaporation and diethyl ether is added. The mixture is then filtered over silica gel and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a brown oil. MS (EI): 528 (M+.), 483, 398, 257, 241, 130. TLC: ethyl acetate, Rf =0.66.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1OB(O)O.C1(C)C=CC=CC=1>C(O)C.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>[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[F:8]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OB(O)O)c(F)c2)CC1
Reactant: Fc1cc(F)cc(Br)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ccc(-c3c(F)cccc3F)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Difluorobromobenzene (30 g), tetrakis(triphenylphosphine)palladium (0) (1.8 g), ethanol (150 mL), and a 2 mol/L aqueous potassium carbonate solution (155 mL) were mixed with each other and heated to 50° C. A solution prepared by dissolving 2-fluoro-4-(trans-4-propylcyclohexyl)phenylboric acid (49.3 g) in ethanol (300 mL) was added thereto, and stirring was performed at 50° C. for five hours. After the temperature was decreased to room temperature by natural cooling, toluene (300 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with a saturated saline solution (200 mL) twice. Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized using ethanol to obtain 4-[2-fluoro-4-(trans-4-propylcyclohexyl)phenyl]-3,5-difluorobenzene (39.1 g). (2-2) The subsequent processes were performed by the same method as in Example 1 to obtain [3,5-difluoro-4-(2-fluoro-4-(trans-4-propylcyclohexyl)phenyl)phenyl]-(5,6,7-trifluoro-2-naphthyloxy)difluoromethane (20.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6](C2C=C3C(=CC=2)NC(C)(C)C=C3C)[CH:7]=1.FC1C=CC=C([N+]([O-])=O)C=1[I:34].IC1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([I:34])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1I
Reactant: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc([N+](=O)[O-])c3)cc21
Agent: Nc1cc(I)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(5-Fluoro-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 280, structure 4 of Scheme II, where R1 =5-fluoro-3-nitrophenyl) 1-Fluoro-3-nitroiodobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg, 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was placed in an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.Cl[CH2:13][C:14](=[O:16])[CH3:15].[OH-:17].[K+]>C(O)C>[C:14]([C:13]1[O:17][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]=1[CH2:2][CH3:11])(=[O:16])[CH3:15]
Reactant: CC(O)C(=O)c1ccccc1
Reactant: [OH-]
Reactant: CC(=O)CCl
Agent: [K+]
Solvent: CCO
Product: CCc1c(C(C)=O)oc2ccccc12
Yield: 80 %

Procedure:
Reaction of hydroxypropiophenone (II) with chloroacetone (III) using potassium hydroxide in ethanol gives, by Stroemer-Schaefer condensation, 2-acetyl-3-ethylbenzofuran (IVj, R1 -R4 =H, R5 =C2H5, R6 =CH3) in a yield of about 80% (Belgian Patent Specification 553 621; (Chem. Abs. 5, 22016)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][O:21]CC2C=CC=CC=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1.B(Br)(Br)Br.CCCCCC.C(OCC)C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][OH:21])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1COCc1ccccc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1CO
Reaction time: 1 h

Procedure:
A solution of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-benzyloxymethyl-2(1H)-pyridinone (198 mg, 0.51 mmol) in dry methylene chloride (6 mL) was cooled in an ice/acetone bath and 1M boron tribromide/hexane (1.5 mL, 1.5 mmol) was added dropwise to give a white precipitate. This suspension was stirred for one hour and then the reaction was quenched by addition of saturated aqueous NaHCO3 (10 mL). After stirring for 0.5 hours, the product was extracted into CH2Cl2, dried, filtered and the solvent evaporated to give a solid. Trituration with diethyl ether gave product as a tan solid. Recrystallization from ethyl acetate afforded a light yellow solid with m.p. of 155°-156° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]=[C:10]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)[C:9]=1[N+:26]([O-:28])=[O:27].[OH2:29]>Cl>[CH3:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[N:11]=[C:10]([N:20]2[CH2:21][CH2:22][S:23](=[O:2])(=[O:29])[CH2:24][CH2:25]2)[C:9]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1nc(N2CCNCC2)nc(N2CCS(=O)(=O)CC2)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 0.8 gm (0.005 mol) of potassium permanganate in 30 ml of water was slowly added dropwise to a solution of 1.6 gm (0.005 mol) of 6-methyl-5-nitro-2-piperazino-4-thiomorpholino-pyrimidine (m.p. 141°-142°C) in about 60 ml of 0.5 N hydrochloric acid at about 5°C. After stirring the reaction mixture for 1 hour at about 5°C, the precipitated manganese dioxide was removed by means of a sodium bisulfite solution. The reaction product was precipitated by addition of concentrated ammonia, washed with water and dried (m.p. 208°-211°C). Yield: 1.4 gm (79% of theory).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14]Br)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: BrCCOc1ccc(Br)c2ccccc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)c3ccccc23)cc1

Procedure:
The solution of 7.0 g. of 2-(4-bromo-1-naphthyloxy)ethyl bromide and 7.9 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is heated for 18 hours, then cooled and diluted with 50 ml. of water. The precipitate is collected and crystallized from 200 ml. of methylcyclohexane and then from 100 ml. of ethanol, m.p. 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](/[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=2)\[C:17]#[N:18])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(F)cc(F)c2)cc1OC
Yield: 69.8 %

Procedure:
3,5-Difluorobenzaldehyde (1.42 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.10 g, yield: 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[N+]([C:18]1[CH:19]=[C:20]2[C:25](=[O:26])[N:24]([CH3:27])[C:22](=[O:23])[C:21]2=[CH:28][CH:29]=1)([O-])=O>O.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:22](=[O:23])[C:21]3=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: Clc1ccccc1
Product: CN1C(=O)c2ccc(-c3ccc(Cl)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
In a 500 ml three-necked flash equipped with a mechanical stirrer, Dean-Stark trap/condenser, nitrogen inlet, and thermometer was added 25.71 grams (0.20 moles) of p-chlorophenol, 100 ml dimethylsulfoxide, and 150 ml of chlorobenzene. After stirring and nitrogen purging the mixture for 30 min., 15.80 grams of aqueous sodium hydroxide (50.62 wt. %; 0.20 moles) was added. The mixture was heated up to 150° C. with the azeotropic removal of the water of reaction. After the removal of water was complete the temperature was lowered to 60° C. and 41.23 grams (0.20 moles) of 4-nitro-N-methyl phthalimide was added. The mixture was stirred overnight. Upon cooling to room temperature the product precipitated from solution. Filtration, washing the precipitate with water, and recrystallization from isopropanol yielded 50.8 grams of 4-(p-chlorophenyl)-N-methyl phthalimide. The melting point was 131°-132° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH2:22]([O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH:43][C:44]1[CH:45]=[C:46]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])C(OC)=O>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:46]5[CH:51]=[C:52]([O:56][CH3:57])[C:53]([O:54][CH3:55])=[C:44]([O:43][CH2:22][C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[CH:45]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: COc1cc(B(O)O)cc(OCc2ccccc2)c1OC
Reactant: COC(=O)c1cc(O)c(OC)c(OC)c1
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(OC)c(OCc6ccccc6)c5)cn4)CC3)nc2)cc(OCc2ccccc2)c1OC

Procedure:
The procedure described in Example 31 was employed. From 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (115.0 mg, 0.280 mmol) synthesized in Reference Example 1 and 3-benzyloxy-4,5-dimethoxyphenylboronic acid (170.0 mg, 0.590 mmol) synthesized from methyl 3-hydroxy-4,5-dimethoxybenzoate (Indian J. Chem., 21B, 27–29, (1982)) by a similar procedure to that described in Reference Example 8, 1,4-bis[5-(3-benzyloxy-4,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine was obtained as a colorless viscous oil (173.0 mg, yield: 84%). From 1,4-bis[5-(3-benzyloxy-4,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine (157.0 mg, 0.210 mmol), 1,4-bis[5-(3-hydroxy-4,5-dimethoxyphenyl)-2-pyridyl]-hexahydro-1,4-diazepine was obtained as a colorless oil (97.0 mg, yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[SH:10].Br[CH:12]([CH2:17][CH2:18][CH2:19][Br:20])[C:13](OC)=[O:14].O>CN(C)C=O>[Br:20][CH2:19][CH2:18][CH2:17][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=2[S:10]1
Reactant: COC(=O)C(Br)CCCBr
Reactant: Cc1cc(N)c(S)cc1C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)SC(CCCBr)C(=O)N2
Yield: 69.3 %

Procedure:
To a solution of 3.06 g of 2-amino-4,5-dimethylthiophenol in 50 ml of dimethylformamide was added 5.48 g of methyl 2,5-dibromovalerate at room temperature with stirring. The mixture was stirred for 14 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was washed with a mixture of ether and hexane to obtain 4.35 g (69.3%) of 2-(3-bromopropyl)-6,7-dimethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from methanol gave prisms, m.p. 151°-153° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(Cl)Cl.[OH-].[Na+]>O>[CH2:8]1[CH2:9][CH2:10][N:5]([C:1]([N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:2])[CH2:6][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCCCC1)N1CCCCC1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Phosgene was passed for 17 minutes, at the rate of 3 grams per minute, through a mixture of 84 grams (1 mole) of piperidine, 500 ml. of methylene chloride and 100 ml. of water. The pH was maintained in the range of 8-11 by the addition of 50% aqueous sodium hydroxide solution during the latter portion of the phosgene passage. An exothermic reaction occurred which caused refluxing of the mixture. After phosgenation was complete, additional base was added until the pH remained constant at 11 for 5 minutes, after which 200 ml. of water was added and the organic layer was removed, washed twice with aqueous hydrochloric acid solution and filtered. Upon vacuum stripping, the desired bis(pentamethylene)urea was obtained in 96% yield. Its structure was confirmed by proton nuclear magnetic resonance spectroscopy.