Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.B(OC)(OC)[O:27]C.N>CCCCCC>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:24])([F:25])[F:14])[C:17]=1[OH:27]
Reactant: COc1cccc(C(F)(F)F)c1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1cccc(C(F)(F)F)c1O
Temperature: -78 °C

Procedure:
A solution containing 160 ml of 1.6 molar butyllithium in hexane, 300 ml oftetrahydrofuran and 40 ml of N,N,N',N'-tetramethylethylenediamine was cooled to -78° C. and 43.3 g of 3-trifluoromethylanisole was added with stirring under nitrogen atmosphere. The solution was allowed to warm up to room temperature and cooled then again to -78° C. after which35 ml of trimethyl borate was added. The solution was warmed up to 20° C. and 50 ml of conc. ammonia solution was added. The solvents were evaporated in reduced pressure and to the residue 60 ml of 98-100% formic acid followed with 25 ml of 35% hydrogen peroxide were added. The solution was extracted with ether-petroleum ether (1:1). The organic phasewas separated and the product was extracted with 2.5 N NaOH-solution. The aqueous phase was acidified with hydrochloric acid and the product was extracted in dichloromethane. The solvent was removed for the most part invacuo after which petroleum ether was added. The crystalline product was filtered, yield 8.5 g (18%), m.p. 51°-53° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@H:9]([CH3:10])[C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@H:9]([CH3:10])[C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:33]([O:36][CH3:37])=[CH:34][CH:35]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4R,5S)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24](OCC)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>C(O)C>[Br:18][C:6]1[CH:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)=[O:25])[O:21][N:20]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Solvent: CCO
Product: COc1ccc(COc2c(Br)cc(-c3noc(C(=O)NCc4cccc(C(F)(F)F)c4)n3)cc2Br)cc1
Yield: 9.7 %

Procedure:
Ethyl 3-(3,5-dibromo-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (2.6 g, 50 mmol) was heated at reflux with 3-(trifluoromethyl)benzylamine (1.75 g, 100 mmol) in ethanol (30 mL) for 7 h. The mixture was cooled and filtered. The solid was washed with cold ethanol and dried to give the title compound (3.1 g) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 3.81 (3H, s), 4.62 (2H, d), 5.04 (2H, s), 6.99 (2H, d), 7.51 (2H, d), 7.61-7.73 (3H, m), 7.79 (1H, s), 8.31 (2H, s), 10.11 (1H, t).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH3:6].[Br:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.Cl>ClCCl>[Br:16][C:17]1[S:18][C:19]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: Brc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (8.9 g) and 4-ethylbenzoylchloride (5.96 g) were added to a solution of 2-bromothiophene (3.2 ml) in dichloromethane (50 ml) at 0° C., and the mixture was stirred for four hours at room temperature. 10% hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (5-bromo-2-thienyl)(4-ethylphenyl) methanone (8.97 g). Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a solution of (5-bromo-2-thienyl)(4-ethylphenyl) methanone in acetonitrile (20 ml) at −40° C., and the mixture was stirred for two hours. Aqueous solution of saturated potassium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-(4-ethylbenzyl)thiophene (6.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][Cl:14]
Reactant: OCc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of 2,4,6-trichlorobenzylalcohol (10.0 g; 47.3 mmoles) in chloroform (100 ml) kept under nitrogen atmosphere, thionyl chloride (6.07 mL, 85.1 mmole) was added slowly at 0° C. over a period of 15 minutes followed by catalytic amount of DMF. The reaction mix was allowed to stir at ambient temp for 3 hours. The reaction mixture was quenched with 50 mL of water; the aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was washed with 5% sodium bicarbonate solution (2×50 ml) followed by brine (50 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. 10.9 g (100.0% of theory) of 1,3,5-trichloro-2-chloromethyl-benzene was obtained in form of a white solid.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:15]([CH:24]([C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(O)C2CCOCC2)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N=[N+]=[N-])C2CCOCC2)o1
Temperature: 0 °C
Reaction time: 22 h
Yield: 69.8 %

Procedure:
6.08 g (22 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 4.43 g (20 mmol, 1 eq) of (5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methanol at 89% in 60 ml of toluene. The reaction medium was cooled to 0° C. and then 3.3 ml (22 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 22 hours. The reaction medium was separated by settling out and the organic phase was washed with water and then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column Analogix SF40-240 g, Spot II) eluted with heptane/ethyl acetate (95/5). 3.09 g of 4-[azido-(5-methylfuran-2-yl)methyl]tetrahydropyran were obtained. Yield=70%.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[N+:29]([O-:31])=[O:30])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[N+:29]([O-:31])=[O:30])[NH:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3n2S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
A mixture of 1-benzenesulfonyl-6-methoxy-2-(4-methoxy-2-nitrophenyl)-1H-indole (2.0 g), tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (11.4 ml) and tetrahydrofuran (40 ml) was stirred for 5 hours at 80° C. The reaction mixture was diluted with water, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.0 g).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C@@H:26]1[CH2:30][S:29][C:28](=[O:31])[NH:27]1)=[O:25]>>[N+:7]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C@@H:26]1[CH2:30][S:29][C:28](=[O:31])[NH:27]1)=[O:25])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: O=C1N[C@H](C(=O)NCCCCO)CS1
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1N[C@H](C(=O)NCCCCO[N+](=O)[O-])CS1
Yield: 20.9 %

Procedure:
Following a procedure similar to that described in Example 16(b), but using 195 mg of nitronium tetrafluoroborate, 157 mg of 2,4,6-collidine and 218 mg of (4R)-N-(4-hydroxybutyl)-2-oxothiazolidine-4-carboxamide [prepared as described in step (a) above], 55 mg of the title compound were obtained as colorless needles, melting at 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C1(C)C=CC=CC=1.[CH2:31]([N:38]=[C:39]=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([NH:38][C:39]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: S=C=NCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (2 ml) and ethanol (2 ml) to prepare a solution. Benzyl isothiocyanate (48 μl) was then added to the solution, and the mixture was stirred at 80° C. for 6 hr. The reaction solution was concentrated, and ether and hexane were added to the residue. The resultant crystal was collected by filtration to give the title compound (46 mg, yield 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(CCCC(F)(F)F)c2ccc(Br)cc2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(CCCC(F)(F)F)c2ccc(Br)cc2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-7,7,7-trifluoro-heptanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 14% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=445.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:5][CH:4]=[CH:3]1.[H-].[Li+].Br[CH2:30][CH2:31][CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43]>CN(C=O)C>[O:43]=[C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41](=[O:42])[N:33]1[CH2:32][CH2:31][CH2:30][O:1][C:2]1[N:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(=O)[nH]3)nc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN4C(=O)c5ccccc5C4=O)n3)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.091 g, 0.26 mmol) in DMF (2 mL) was added LiH (3.2 mg, 0.39 mmol) at 0° C. After stirring for 20 minutes, a solution of 2-(3-bromopropyl)isoindoline-1,3-dione (0.14 g, 0.52 mmol) in DMF (1 mL) was added, and the reaction was warmed up to ambient temperature and stirred for 17 hours. After cooling to 0° C., the reaction was quenched with ice-water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 1.5% MeOH/DCM to yield the desired product (0.117 g, 84% yield). MS (apci) m/z=541.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:33])([CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:10]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(C)(C)NCC(O)c2cc(O)cc3[nH]c(=O)ccc23)cc1

Procedure:
128 mg (0.27 mmol) 7-benzyloxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-1H-quinolin-2-one are dissolved in 12 mL methanol and hydrogenated using palladium on charcoal as catalyst. The reaction mixture is filtered through Celite, eluted with methanol and the filtrate is freed from the solvent. Yield: 65 mg (63%); Rf=0.25 (silica gel, dichloromethane/methanol/ammonia=18:2:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])=[CH:8][CH:9]=1
Reactant: NC(=O)c1[nH]c2cccnc2c1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]c2cccnc2c1-c1ccc(N)cc1
Yield: 74.6 %

Procedure:
0.113 g of Pd/C (10%) is added to a solution of 0.15 g of 3-(4-nitrophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in 10 ml of methanol. After stirring at 22° C. for 3.5 hours under 2 bar of hydrogen, the reaction medium is filtered over silica gel and then concentrated under reduced pressure, to give 0.1 g of 3-(4-aminophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: C(O[C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[O:5])C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[C:4](=[O:5])[CH2:6][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)C1CN(Cc2ccccc2)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that the compound of Example 3 and benzylamine were used.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:7](=[O:25])[N:8]([CH2:21][CH2:22][CH2:23]O)[N:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(Br)([Br:28])=O>O>[Br:28][CH2:23][CH2:22][CH2:21][N:8]1[C:7](=[O:25])[C:6]([Cl:5])=[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]=[N:9]1
Reactant: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCO
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCBr
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To 170 ml of chloroform were added 9.9 g of 4-chloro-5-(4'-chlorobenzyloxy)-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.03 mol) and slowly added 9.4 g of thionyl bromide (0.045 mol) under stirring for about 2 hours at -5° to 5° C. After reaction, the resulting solution was added little by little with water and the chloroform layer was separated. The layer was washed with water and then with aqueous solution of 5% sodium hydrogen carbonate, and further washed with saturated saline and dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The solid product thus obtained was recrystallized from a mixed solvent of n-hexane-benzene to give 5.2 g of 2-(3'-bromopropyl)-4-chloro-5-(4'-chlorobenzyloxy)-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13]C(C#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:19]([C:18]([OH:21])=[O:20])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: N#CC1CCC(OCc2ccccc2)CC1
Agent: Cl
Product: O=C(O)C1CCC(OCc2ccccc2)CC1

Procedure:
The crude 4-benzyloxycyclohexane-1-nitrile (4.0 g) was refluxed with stirring with a mixture of glacial acetic acid (16 ml) and concentrated hydrochloric acid (24 ml) for 20 hours. The reaction mixture was cooled, the solid removed by filtration and washed with water. The product was ground with 2M sodium hydroxide solution (70 ml) and then diluted with water. Unchanged nitrile was removed by filtration and the filtrate acidified with concentrated hydrochloric acid. White crystals separated and were collected by filtration, washed with water and dried to yield 4-benzyloxycyclohexane-1-carboxylic acid m.p. 170°-180° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[N+]([O-])([O-])=[O:18].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:18])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 6-bromo-7-chloro-5-nitroquinoxaline-2(1H)-one (0.025 g, 0.082 mmol, as prepared above) in conc. H2SO4 (0.5 mL) was added KNO3 (0.011 g, 0.11 mmol) and the resulting dark red solution was stirred at room temperature for 65 h. The solution was then cooled in an ice-bath and diluted with ice to a total volume of 5.0 mL. The precipitated solid was filtered, washed with water (2.0 mL) and dried under vacuum to obtain 0.019 g (72%) crude product. It was purified as follows. 0.016 g crude product was taken up in 1N NaOH (1.1 mL). The insoluble solid was centrifuged and the supernatant liquid was acidified with conc. HCl to pH~2. The precipitated solid was filtered, washed with water (1.0 mL), and dried under vacuum to furnish 0.010 g (38%) pure (purity by HPLC>97%) title compound as a cream colored powder; m.p. 338-343° C. (decomposed); 1H NMR (DMSO-d6): δ 7.351 (s, 1H), 12.251 (s overlapped by a br s, 2H); Elemental analysis for C8H3BrClN3O4, calcd: C, 29.98%; H, 0.94%; N, 13.11%, found: C, 29.79; H, 0.77; N, 12.71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:20][C:21]([OH:30])([P:26]([OH:29])(=[O:28])[OH:27])P(O)(=O)O)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:35]>CN(C)C=O.O>[Na+:35].[Na+:35].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:20]([P:26]([OH:29])(=[O:27])[OH:28])[CH:21]([OH:30])[P:26]([O-:27])(=[O:28])[O-:29])=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=P(O)(O)C(O)(Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1)P(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=P([O-])([O-])C(O)C(c1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 154.2 %

Procedure:
A solution of 1.9 g of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid in 5 ml of dimethylformamide is combined with a solution of 0.8 g of sodium bicarbonate in 10 ml of water and stirred for 2 hours at room temperature. Then the thus-precipitated product is vacuum-filtered, washed with a small amount of water, and dried at 110° C., yielding 1.6 g (76%) of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethanediphosphonic acid disodium salt, mp above 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=2)[C:15]([O:17]CC2C=CC=C(Cl)C=2)=[O:16])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)OCc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of (3-chlorophenyl)methyl 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoate from the preparation of Intermediate 84 described above (2.67 g, 6.66 mmol) in 1,4-dioxane (20 ml) and water (10 ml) was treated with lithium hydroxide (419 mg, 9.99 mmol, 1.5 eq). The resulting mixture was stirred at room temperature under argon overnight. A further portion of lithium hydroxide (419 mg, 9.99 mmol, 1.5 eq) was added and stirring continued at room temperature for 2 hours. Stirring continued at room temperature overnight. The solvent was then evaporated to dryness and then partitioned between 2M HCl (100 ml) and diethylether (100 ml). The organic layer was separated and passed through a hydrophobic frit to remove any water and evaporated to dryness to afford the title compound as a white solid (1.98 g) (contains 12% impurity). No further purification carried out. MS (ES−) m/z 275 [M−H]− (C15H1335ClO3).