Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[CH2:16][C:15]2(OCC[O:18]2)[CH2:14][CH2:13]3)[CH2:4][CH2:3]1.Cl>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc3c2CC2(CC3)OCCO2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3c2CC(=O)CC3)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.7 %

Procedure:
3',4'-Dihydro-8'-[4-methyl(piperazin-1-yl)]-spiro-[1,3-dioxolane-2,2'(1H)-naphthalene] (1.0 g, 3.5 mmol) was dissolved in freshly distilled tetrahydrofuran (50 mL) and the solution was cooled to 0° C. To the solution was added 2 M hydrochloric acid (10 mL) and after 5 min the cooling bath was removed. The reaction mixture was stirred at ambient temperature for 3.5 h. Tetrahydrofuran was removed in vacuo and the residue was mixed with methylene chloride (100 mL) and cooled on ice-bath. To the mixture was added 2 M sodium hydroxide (10 mL) and the phases were separated. The organic layer was washed with brine (15 mL) and dried (MgSO4). The solvent was evaporated giving 810 mg (95% yield) of the title compound as a brownish crystalline solid: mp>85° C. (sinters); EIMS (70 eV) m/z (relative intensity) 244 (51, M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].FC1C=C(F)C=CC=1C1C=CC=CC=1.C(Cl)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)([OH:3])[CH3:2])[CH3:46]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Fc1ccc(-c2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
23.2 g. of 4-acetyl-2',4'-difluorobiphenyl, obtainable by reacting 2,4-difluorobiphenyl with acetyl chloride in the presence of AlCl3, and 11.1 ml. of ethyl bromoacetate are dissolved in a mixture of 75 ml. of benzene and 75 ml. of toluene. A 40 ml. portion of the resulting solution is added to 7 g. of zinc powder, previously washed successively with 1% hydrochloric acid, water and acetone and dried and the mixture is warmed to 70° with stirring and under a nitrogen atmosphere. After the reaction has begun, the remainder of the solution is added dropwise, the mixture is heated under reflux for one hour and cooled and 40 ml. of 20% sulfuric acid are added drop-wise in order to decompose the alcoholate Z--C(CH3) (OZnBr)--CH2 --COOC2H5 (Z is 2',4'-difluoro-4-biphenylyl). The organic phase is separated off and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C@H:22]1[NH:27][C:26](=[O:28])[C@@H:25]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[N:24]([CH:33]([C:44]2[N:45]=[C:46]([CH3:49])[O:47][CH:48]=2)[C:34](NC2C=CC=CC=2O)=[O:35])[C:23]1=[O:50]>ClCCl>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]1[C@H:22]1[NH:27][C:26](=[O:28])[C@@H:25]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[N:24]([CH:33]([C:44]2[N:45]=[C:46]([CH3:49])[O:47][CH:48]=2)[C:34]([OH:35])=[O:2])[C:23]1=[O:50]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1coc(C)n1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1coc(C)n1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
Carbonyldiimidazole (352 mg, 1.6 equiv.) was added to a solution of 2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-N-(2-hydroxyphenyl)-2-(2-methyl-1,3-oxazol-4-yl)acetamide (11.8 g pre-dried in vacuo over P4O10 for 24 hours) in dichloromethane (20 mL) and the solution was left at room temperature for 16 hr. The mixture was evaporated and the residue dissolved in acetone (20 ml) and water (20 ml) added, followed by addition of 2NHCl (2 ml) and the mixture left at room temperature for 4.5 hr. This was extracted with ethylacetate (2×30 ml) and the combined organic phase dried via a hydrophobic frit and evaporated. The residue was taken up in ethylacetate (30 ml) washed with 2NHCl (2×10 ml) and then extracted with saturated sodium bicarbonate solution (2×15 ml). The combined aqueous phase was acidifed with 2NHCl and extracted with ethylacetate (2×20 ml) and the combined organic phase washed with brine dried via a hydrophobic frit and evaporated to give {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2-methyl-1,3-oxazol-4-yl)acetic acid (0,355 mg, 73%) as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[S:14][C:15]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=1.CN(C)[CH:30]=[O:31]>C(OCC)C>[F:20][C:19]([F:22])([F:21])[C:18]([C:15]1[S:14][C:13]([CH:30]=[O:31])=[N:17][CH:16]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: OC(c1cnc(Br)s1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a nitrogen purged three-necked flask was added n-butyl lithium in hexane (2.5M, 9.09 mmol, 3.64 mL) and diethyl ether (8 mL). The solution was cooled to −78° C. and 2-(2-bromothiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.03 mmol, 1 g) in diethyl ether (7 mL) added drop wise over a period of 15 minutes. The mixture was stirred at −78° C. for 20 minutes before the drop wise addition of N,N-dimethylformamide (4.54 mmol, 0.332 g) in diethyl ether (4 mL). The mixture was stirred at −78° C. for 1 hour then was allowed to warm to −60° C. and stir for 1 hour. The mixture was slowly quenched with 4M hydrochloric acid at −60° C. and allowed to warm to room temperature. The mixture was extracted with diethyl ether (100 mL), washed with 4M hydrochloric acid (50 mL), followed by water (50 mL) and then brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with a gradient of heptane to 50% ethyl acetate/50% heptane) to afford the title compound (500 mg).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>C(O)(=O)C>[CH3:16][C:15]1[CH:14]=[CH:13][C:11]([NH:12][C:5]([CH3:6])=[O:7])=[CH:10][C:9]=1[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c(C)c1

Procedure:
95 ml of acetic anhydride was added to a stirred solution of 3,4-dimethylaniline in 300 ml of glacial acetic acid at such a rate the temperature of the mixture slowly rose to 60° C. The resulting mixture was stirred while the temperature dropped to room temperature, then evaporated to dryness. A mixture of water and ice was added to the residue, followed by methylene chloride. The resulting mixture was stirred and treated with solid sodium bicarbonate until neutral. The organic phase was separated, and dried (MgSO4), and the solvent was evaporated to give 3,4-dimethylacetanilide (9A).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=O)[CH2:16][CH2:15]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:22][CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH2:19][CH2:18]1
Reactant: NC(=O)C1CCN(CCCCCCCCCCCCO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(CCCCCCCCCCCCO)CC1
Yield: 98 %

Procedure:
Prepared from 1-(12-hydroxydodecyl)-piperidine-4-carboxamide (3.3 g, 10.6 mmol) and LAH (0.8 g, 21.2 mmol) according to general procedure used for Example 8 (Step B) to give 3.1 g of title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][CH:11]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.C(N(CC)C(C)C)(C)C.C[N:80]([CH:82]=[O:83])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9](=[O:31])[NH:10][CH:11]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]([C:24]2[CH:29]=[CH:28][C:27]([C:82](=[O:83])[NH2:80])=[CH:26][CH:25]=2)=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccc(Br)cc2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccc(C(N)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the product from Step 2B (3.5 g, 0.0073 moles), 1,3-bis(diphenylphosphino)propane (305 mg, 0.0073 moles), hexamethyldisilazane (10.8 ml, 0.0146 moles), and N,N-diisopropylethylamine (2.5 ml, 0.0146) in DMF were degassed with nitrogen bubbling for ten minutes. Palladium (II) acetate (162 mg, 0.00073 moles) was added and the mixture degassed for a further five minutes. Carbon monoxide gas was bubbled through the reaction mixture for 5 minutes at room temperature and then for 6 hours at 110° C. After this time, the reaction mixture was cooled and partitioned between dichloromethane (50 ml) and water (50 ml). The aqueous layer was extracted with further dichloromethane (3×50 ml) and the combined organic layers washed with water (100 ml) and brine (100 ml), dried (MgSO4) and vaporated in vacuo. The residue was taken up in a mixture of THF (150 ml) and 2M HCl (30 ml) and stirred at ambient temperature for one hour. The THF was then evaporated in vacuo and the residue partitioned between dichloromethane (50 ml) and 2M NaOH (50 ml). The aqueous layer was extracted with dichloromethane (2×50 ml) and the combined organic layers washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. Purification by chromatography (SiO2, 1% MeOH/CHCl3) gave the title compound. 1H NMR (DMSO-d6) 3.31 (3H, s), 5.07 (2H, s), 5.12 (1H, d), 7.30–7.80 (12H, m), 7.93 (2H, d, J=8.4 Hz), 8.08 (1H, br s), 8.50 (1H, d). MS (ES+) MH+=443
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1cccc(F)c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(C)C/C=C/c1cccc(F)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-fluorophenyl)-4-penten-2-amine (0.83 g, 2.82 mmol) in anisole (11 mL) was treated drop-wise over 30 min with trifluoroacetic acid (13.32 g, 116.8 mmol). The resulting solution was stirred for 45 min at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting residue was cooled (0-5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL) and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was further dried under high vacuum to produce a light-yellow oil. The crude product was purified by column chromatography on silica gel (32 g), eluting with CH3OH—MeOH (3:1, v/v) containing 2% Et3N. Selected fractions containing the product (Rf 0.49) were combined and concentrated on a rotary evaporator to give 0.49 g of a light-yellow oil. The oil was purified by column chromatography on silica gel (31.5 g), eluting with CH3OH—NH4OH (100:2, v/v). Selected fractions containing the product (Rf 0.28) were combined and concentrated on a rotary evaporator to a light-yellow oil. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 262 mg (48.1%) of a light-yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)C.[OH-].[Na+]>C(O)C>[CH2:16]([N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN(CC(=O)O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
[Benzyl-(3-methoxy-benzyl)-amino]-acetic acid ethyl ester (3.0 g, 9.6 mmol) in ethanol (100 mL) was treated with 4N NaOH (20 mL) and the mixture was stirred at ambient temperature for two hours whereupon HPLC analysis showed completion of the reaction. The ethanol was removed on the rotary evaporator, water (˜20 mL) was added to dissolve solids, the pH was adjusted to 4 (6N HCl) with stirring and the precipitate was collected by filtration, washed with water and dried to constant weight in vacuo to give 2.47 g (90%) of [benzyl-(3-methoxy-benzyl)-amino]-acetic acid as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 7.35 (m, 4H), 7.25 (m, 2H), 6.93 (m, 2H), 6.82 (d, J=9 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 2H), 3.30 (br s, 2H, 3.17 (s, 2H); MS (m/e) 286 (M+1); mp 177-179° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.C(N(CC)CC)C>CO>[C:9]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
NH2—(CH2)3—COOH (5.00 g, 48.5 mmol), (BOC)2O (11.6 g, 53.4 mmol) and triethylamine (5.39 g, 53.4 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the resultant solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)3—COOH (6.98 g, 34.4 mmol, yield: 71%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][C:9](=[O:20])[C:8]=3[CH:7]=[CH:6][N:5]2[C:21]=1[CH3:22].[BH4-].[Na+]>CO>[OH:20][CH:9]1[C:8]2[CH:7]=[CH:6][N:5]3[C:21]([CH3:22])=[C:2]([CH3:1])[N:3]=[C:4]3[C:13]=2[NH:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10]1
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)CC(c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)C(O)CC(c1ccccc1)N3
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A suspension of 1 g of 2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one in 15 ml of methanol is treated at room temperature with 450 mg of sodium borohydride in small portions. The resulting yellowish solution is stirred for 2 h and then diluted with ice water. The precipitate which is deposited is filtered off with suction and washed with a little cold 2-propanol. 800 mg of the title compound of melting point 210-12° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Zn]>[CH3:11][C:3]1[C:4]2[N:8]=[CH:7][NH:6][C:5]=2[CH:9]=[CH:10][C:2]=1[C:12]#[N:13]
Reactant: Cc1c(Br)ccc2[nH]cnc12
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: Cc1c(C#N)ccc2[nH]cnc12
Temperature: 120 °C
Yield: 53 %

Procedure:
A mixture of 158 (21 g; 99 mmol), Zn(CN)2 (23.2 g; 198 mmol), Pd(dppf)Cl2 (6.4 g; 9.9 mmol) and zinc (258 mg; 4 mmol) in dry DMF (150 mL) under inert atmosphere was heated at 120° C. for 2 h. The reaction mixture was filtered through a pad of Celite® that was washed with EtOAc. The organics were washed with water, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by SiO2 chromatography eluted with a DCM/MeOH gradient (0 to 10% MeOH) to afford 8.3 g (53%) of 4-methyl-1H-benzo[d]imidazole-5-carbonitrile (160) as a brown solid: MS (ESI) m/z=158 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]([N+:17]([O-])=O)[C:3]=1[CH3:20].O.[Cl-].[NH4+]>CCO.[Fe]>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1
Reactant: Cc1c(Br)cc(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1c(N)cc(Oc2ccc(F)cc2F)cc1Br
Temperature: 85 °C
Yield: 113.9 %

Procedure:
1-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-3-nitro-benzene (7.31 g, 21.2 mmol) was dissolved in 145 mL EtOH and 35 mL water was added, followed by addition of ammonium chloride (3.63 g, 67.9 mmol) and powdered iron (3.56 g, 63.8 mmol). The reaction mixture was placed under nitrogen atmosphere and heated to 85° C. for 2.5 hours. The reaction mixture was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and EtOAc and the organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 7.583 g of 3-bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine, MS(M+H)=314.
Reaction SMILES: [OH:1][CH:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26].C(Cl)(Cl)Cl.C[OH:34]>>[OH:1][CH:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13](=[O:34])[C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26]
Reactant: O=c1c2cccc3c2n(c(=O)n1CC(O)CO)-c1cc(C(F)(F)F)ccc1S3
Reactant: CO
Solvent: ClC(Cl)Cl
Product: O=c1c2cccc3c2n(c(=O)n1CC(O)CO)-c1cc(C(F)(F)F)ccc1S3=O

Procedure:
Reaction of 2-(2,3-dihydroxypropyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl] phenothiazine-1,3(2H)-dione and m-chloroperbenozic acid according to the procedure of Example 6 gave the title compound, m.p. 224°-225° (chloroform-methanol).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([CH2:26][O:27][CH3:28])[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[CH3:28][O:27][CH2:26][C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)C1(CCCCCCCCCCCCC2(COC)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCC1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Reaction time: 8.5 h
Yield: 103.4 %

Procedure:
To a solution of KOH (0.5 g, 9.1 mmol) in 90% ethanol (20 mL) was added product of Example 14 (0.4 g, 1.0 mmol) at 80° C. and stirred at same temperature over for 8.5 h. The crude product obtained upon evaporation of the solvent was diluted with water (5.0 mL), acidified to pH=2 (1N HCl), and extracted with ethyl acetate (50 mL×2). The organic layer was dried over sodium sulphate and concentrated. The residue obtained was washed with n-hexane (10.0 mL×2) and dried under high vacuum to give product as white solid 350 mg (94%). mp. 36.4-37.6° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].BrC1[S:26][CH:27]=[CH:28]N=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[S:26][CH:27]=[CH:28][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2nccs2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 2.37 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide, there is added under nitrogen at less than 30° C., 0.38 g. of sodium borohydride. The mixture is stirred at 20°-30° C. for 1 hour, then 3.2 ml. of 2-bromothiazole is added. The mixture is heated to 130°-135° C. for 1 hour, then cooled and diluted with water. The crude product is filtered off and recrystallized from methanol yielding 1-acetamido-2-nitro-4-(thiazol-2-ylthio)benzene.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>CC(C)=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:27][CH3:28])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 20.0 g of 2-(p-prenylphenyl)propionic acid and 14.0 g of potassium carbonate in 150 ml of acetone was stirred at room temperature for one hour. To the solution was added dropwise a solution of 15.6 g of diethyl sulfate in 50 ml of acetone with stirring at 25° C. After stirring at room temperature for 3 hours, the mixture was refluxed for an additional one hour with stirring. The precipitate which formed was removed by filtration, and the acetone was evaporated. To the residue was added ice-water, and the mixture was extracted with n-hexane. The extract was washed with water, aqueous sodium bicarbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 18.7 g of ethyl 2-(p-prenylphenyl)propionate. b.p. 108° C./0.15 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=3)=[O:13])[CH2:30][CH2:31]2)=[O:25])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(CNS(C)(=O)=O)cc3)CC2)cc1
Yield: 32 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (145 mg) and (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (152 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (84 mg) was obtained.