Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:36][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCOC)c(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), trimethyloxonium tetrafluoroborate (275 mg) and 2,6-di-t-butyl-4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–5:1) to give 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine as an yellow oil (60 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)(=[O:41])=[O:40])=[O:31])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of phenyl 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate (203 mg, 0.50 mmol), 5-methylpyridine-2-sulfonamide (86 mg, 0.50 mmol) and DBU (82 μL, 0.55 mmol) in acetonitrile (5 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 145 mg (60%) of the title compound as white solids: MS (ESI) m/z 490 [M+H]+, 488 [M−H]−, 1H-NMR (DMSO-d6) δ 1.18 (3H, t, J=7.5 Hz), 2.37 (3H, s), 2.72-2.90 (4H, m), 3.23 (2H, q, J=6.0 Hz), 6.69 (1H, br), 7.40-7.59 (6H, m), 7.85-7.93 (4H, m), 8.24 (1H, s), 8.55 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].Cl.[CH:14]1[C:19]([O:20][C:21](Cl)=[O:22])=[CH:18][CH:17]=[C:16]([Cl:24])[CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:24])=[CH:15][CH:14]=2)=[O:22])[CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CN[C@H]1CC[C@H](C(=O)OC)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 2.12 g (10.21 mmol) of trans-4-methylamino-cyclohexanecarboxylic acid methyl ester•HCl was dissolved in 30 mL of pyridine, treated at 0° C. with 1.57 mL (11.23 mmol, 1.1 eq) of 4-chlorophenylchloroformate and stirred for 22 h at RT. The solution was evaporated and partitioned between EtOAc (×3)/aqueous 1M HCl. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.41 g (90%) of trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexane-carboxylic acid methyl ester, MS: 326 (MH+, 1Cl).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].FC(F)(F)C(O)=O.CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][C:7]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=[C:3]([CH:1]2[CH2:2][CH2:24][N:23]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22]2)[N:8]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
To a solution of crude 6-ethenyl-2-methyl-3-nitropyridine (440 mg, 2.68 mmol) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (0.268 mL, 3.48 mmol). To this stirred solution was added [(methyloxy)methyl](phenylmethyl)[(trimethylsilyl)methyl]amine (2.74 mL, 10.72 mmol) (carefully) and the reaction mixture was stirred under nitrogen for 1.5 hours. The reaction mixture was diluted with DCM and then treated with saturated sodium bicarbonate solution. The organic phase was separated and passed through a hydrophobic frit. The organic solvent was evaporated in vacuo and the residue was dissolved in DCM (5 mL). This was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane with 0-20% methanol gradient). The appropriate fractions were combined and evaporated in vacuo to give the crude product (201 mg) as a brown liquid. Used directly in next step without further purification. LCMS (2 min, formic) Rt 0.71 min, m/z (ES+) 298 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCc2cccc(O)c2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1CCc2c(C(=O)CCl)ccc(O)c2N1
Reaction time: 15 h
Yield: 37.7 %

Procedure:
13 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of aluminum chloride was added slowly to the mixture followed by stirring for 15 hours at a temperature of 70° to 75° C. The mixture was then steam-distilled to remove nitrobenzene. After allowing the mixture to cool, the precipitated crystals were filtered, washed with hot water and recrystallized from methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 190° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[N:12][CH:13]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1.CC(=O)OCC>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11](=[O:14])[N:12]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:13]=1
Reactant: Cc1cc(Br)cnc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cn(CC2CC2)c1=O
Temperature: 70 °C
Yield: 66 %

Procedure:
Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70° C. for 3 h, EA extractive work up and silica gel chromatography (PE: EA=30:110:1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.39 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.15 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(NC(C)C)(C)C.[Li]>O1CCCC1>[CH2:16]([O:15][C:13](=[O:14])[C:7]1[C:6]([F:8])=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(OCc1ccccc1)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
2,4-Difluoro-1-nitro-benzene (46, 1.4 mL, 13.0 mmol) and benzyl chloroformate (31, 10.42 g, 61.1 mmol) in 20 mL of tetrahydrofuran is cooled to −78° C. and stirred for 1 hour. Lithium diisopropylamine (1.5 g, 14.0 mmol) is added dropwise and the reaction is stirred at −78° C. for 1 hour, then warmed to room temperature over 2 hours. The reaction was purified by silica gel chromatography, eluting with hexane:ethyl acetate 90:10. Appropriate fractions are combined and concentrated under vacuum, then washed with methanol and the solid collected by filtration to provide the desired compound (47, 110 mg).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C)C=O.C1(C)C=CC=CC=1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (8.7 g, 0.043 mol), in dry dimethylformamide (75 ml) was added during 30 min to a stirred suspension of sodium hydride [from a 60% mineral oil dispersion (1.9 g) washed with petroleum ether (3×150 ml)] in dry dimethylformamide (250 ml) maintained at 0° C. under a nitrogen atmosphere. Stirring was continued for an additional 1.5 hours, then benzyl bromoacetate (10.8 g; 0.047 mol) in dry dimethylformamide (75 ml) was added during 45 minutes, the temperature being maintained at 0°. The reaction mixture is then allowed to warm to room temperature while stirring for an additional 18 hours. The dimethylformamide was removed under reduced pressure and the residue partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase was extracted with additional dichloromethane (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give the crude ester-azide as an oil. This material was dissolved in toluene (500 ml) and silica gel (48 g) was added. Filtration and removal of the solvent under reduced pressure gave 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, as an oil, used without further purification in the next synthetic step.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)CCCC>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCO
Product: CC1=CCC(O)(C(C)(C)Sc2ccccc2)CC1
Yield: 52.7 %

Procedure:
To a stirred solution of 76 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 300 ml of n-pentanol were added 2.0 g of 60% sodium hydride and 60 g of thiophenol. After 18 hours reflux, the mixture was vacuum concentrated at 90°-95° C. The residue was dissolved in methylene chloride and washed twice with 2N sodium hydroxide. The dried solution was Claisen-distilled to give 106 g of crude product, b.p. 120°-125° C. (0.1 mm). Recrystallization from 250 ml of hexane gave 69.1 g of the desired product, m.p. 73°-74° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(=O)[C:19]([Cl:21])=[O:20].[Cl-].[Ca+2].[Cl-]>C(Cl)Cl.O>[O:17]=[C:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:19]([Cl:21])=[O:20])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A suspension of 133.3 g of aluminium chloride in 250 ml of methylene chloride was treated dropwise at 20° C. while cooling and gassing with nitrogen with a solution of 174.2 g of 4-phenylcyclohexanone in 250 ml of methylene chloride. The reaction mixture was stirred for a further 30 minutes until a clear solution was obtained. In the meanwhile, a suspension of 133.3 g of aluminium chloride in 500 ml of methylene chloride was treated with 172 ml of oxalyl chloride while gassing with nitrogen. This mixture was subsequently treated dropwise at 20°-25° C. within 1 hour with the above solution of the 4-phenylcyclohexanone-aluminium chloride complex. The reaction mixture was stirred for a further 30 minutes, then cooled to 2° C. and added dropwise within 20 minutes while stirring to a solution of 300 g of calcium chloride in 1 l of water. The mixture was stirred at room temperature for a further 1.5 hours and then poured on to 500 ml of ice/water. The organic phase was separated and washed with 500 ml of semi-saturated sodium chloride solution. The aqueous phases were back-extracted twice with 500 ml of methylene chloride each time. The combined organic phase was dried over sodium sulfate, filtered and concentrated. The oily 4-(4-oxocyclohexyl)benzoyl chloride obtained was dissolved in 400 ml of toluene and this solution was added dropwise to a mixture of 150 ml of methanol, 200 ml of pyridine and 1 l of toluene. The reaction mixture was left to stand overnight and then washed in succession with water, 3N hydrochloric acid, semi-saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated. Recrystallization of the residue from toluene at -25° C. gave 128 g of pure methyl 4-(4-oxocyclohexyl)-benzoate with m.p. 91°-92° C.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O>[Br-:1].[C:24]([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([CH3:15])([CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:26])[CH3:25]
Reactant: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1O
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1OC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 1.0 g of dodecyl(2-hydroxycyclohexyl)-dimethylammonium bromide prepared in Example 3, 5 ml of acetic anhydride and 5 ml of dry pyridine was allowed to stand at room temperature for about 16 hours. Twenty-five milliliters of water was added and the mixture allowed to stand for one hour. The solution was concentrated under reduced pressure at 50° using a rotary film evaporator. Two 20 ml portions of water were added successively to aid removal of pyridine, followed by absolute ethanol for final drying. The residue was 1.11 g of (2-acetoxycyclohexyl)(dimethyl)dodecylammonium bromide. The ir spectrum was consistent with the assigned structure and clearly showed esterification of the hydroxy group to have occurred.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[C:14]([O-])(=[O:17])[CH2:15][OH:16].C=C.[Na+].O>C(O)CO>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:16][CH2:15][CH2:14][OH:17])([O-:3])=[O:2]
Reactant: O=C([O-])CO
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C=C
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
400 ml of ethylene glycol were introduced initially under nitrogen and heated to 65° C. in a 2 l reaction vessel fitted with a stirrer. 162 g of molten 2,4-dinitrochlorobenzene and 586 g of the 12.6% strength mono-sodium ethylene glycolate solution in ethylene glycol obtained in Example 1 were metered in to this mixture simultaneously over the course of 5 hours. The mixture was then stirred for 1 hour at 65° C., and then 600 ml of water was added thereto. The precipitate which formed was filtered off and washed with 1000 ml of water and dried, giving 165.3 g of 2-(2′,4′-dinitro-phenoxy)-ethanol in a purity of 99.2%. Hence, a yield of 96.6% is achieved based on 2,4-dinitrochlorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])([O:27][CH3:28])=[O:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31](=[O:32])[CH2:30][CH2:29][C:25]([O:27][CH3:28])=[O:26])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 24 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 2.1 eq of 3-carbomethoxypropionyl chloride in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride). The resulting product is slurried in ethyl acetate and filtered to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoic acid, methyl ester (24%); mp 157.5°-158° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[F:38][CH:39]([F:48])[CH2:40][NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:41]([CH2:40][CH:39]([F:38])[F:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CNCC(F)F
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN(CC(=O)OCC)CC(F)F)cc1OC
Yield: 51.8 %

Procedure:
The sub-title compound was synthesized by the method of example 9 step (vi) from the product of example 9 step (v) (75 mg) and the product of example 3 step (i) (112 mg). The sub-title compound (44 mg) was obtained as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.37 (1H, dd), 5.77 (1H, tt), 4.97 (2H, br s), 4.28-4.09 (3H, m), 4.00-3.85 (4H, m), 3.86 (3H, s), 3.58 (2H, s), 3.45 (2H, s), 3.11-2.86 (4H, m), 2.36 (3H, s), 1.97 (3H, s), 1.95-1.74 (3H, m), 1.63-1.50 (1H, m), 1.46-1.33 (1H, m), 1.30-1.15 (5H, m), 1.12-0.98 (2H, m), 0.77 (3H, t); LC-MS: m/z 610.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(N(CC)CC)C>[Ni].C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Br)cc1N
Yield: 104.7 %

Procedure:
A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20° C. After this time the theoretical amount of hydrogen had been absorbed (2.5 l), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:22])=[CH:16][CH:15]=1
Reactant: O=C1CCNN1c1ccccc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CCN(C(=S)Nc2ccc(Cl)cc2)N1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 2.11 grams (0.013 mole) of 2-phenyl-3-pyrazolidinone, 2.21 grams (0.013 mole) of 4-chlorophenyl isothiocyanate and 0.5 ml of pyridine in 15 ml of toluene was heated at reflux for 9 hours. The reaction mixture was allowed to cool to room temperature forming a crystalline precipitate. The crystalline precipitate was collected by filtration to yield 3.92 grams of 1-(4-chlorophenylthiocarbamoyl)-2-phenyl-3-pyrazolidinone (mp 136°-139° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[S:24]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]OS(=O)(=O)C)(=[O:27])(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][S:24]([CH3:25])(=[O:27])=[O:26])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 81.9 %

Procedure:
A mixture of 4.0 g (0.012 mole) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 16.3 g (0.062 mole) of diethyleneglycol dimesylate and 3.4 g (0.024 mole) of anhydrous potassium carbonate in 90 ml of anhydrous acetone and 4 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The solvents were removed in vacuo and the residue was treated with 100 ml of 50% ethyl acetate-hexane. Some of the residual starting dimesylate was insoluble and was removed by filtration. The filtrate was concentrated in vacuo and the residual oil was purified by HPLC to give 4.8 g (80% yield) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1.O>C(O)C>[Cl:4][C:5]1[N:10]=[C:9]([NH:3][CH2:1][CH3:2])[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1
Reactant: CCN
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCO
Product: CCNc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 12 h

Procedure:
15 g of a 70% aqueous ethylamine solution is added to 28.9 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (prepared according to Example 1) in 250 ml of ethanol at room temperature. The temperature climbs rapidly to about 35°. The mixture is subsequently stirred at 55° for 12 hours, 25 ml of water are added and the mixture is cooled to 5°. The resulting precipitate is filtered off, washed with 200 ml of water and dried. 2-Chloro-4-ethylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained by crystallization from acetonitrile as colorless crystals having a melting point of 148°.