Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][CH:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16](OC)=[O:17].C(O)(=O)C>C1COCC1.O>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16](=[O:17])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCCC(C)CC(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
Under argon atmosphere, 1.63N n-butyl lithium (65 ml, 106 mmol) was added dropwise at -78° C. to a stirred solution of dimethyl methylphosphonate (13.6 g, 110 mmol) in anhydrous THF (200 ml) and stirring was further continued for 20 minutes. A solution of methyl l-3-methylhexanoate (6.92 g, 48 mmol) in anhydrous THF (20 ml) was added dropwise, and the mixture was stirred at room temperature for one hour. Acetic acid (6.7 ml) was added to neutralize the solution and water (70 ml) was then added. After concentration, the residue was extracted with ether (200 ml×2), and the combined organic layers were washed with brine (40 ml×2), and dried over anhydrous sodium sulfate. Concentration and purification by vacuum distillation gave dimethyl 4(S)-methyl-2-oxo-heptylphosphonate (8.18 g, 34.6 mmol, 72%, b.p.: 114°-115° C./0.25 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[C:22]1=[O:29].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:23]2[CH2:24][CH2:25][N:21]([CH3:20])[C:22]2=[O:29])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: CN1CCC(C(=O)O)C1=O
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCC(C(=O)Nc2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)C1=O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.5179 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (148.3 mg, 1.04 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (297.8 mg, 1.55 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (209.9 mg, 1.55 mmol), N-ethyl-N-isopropylpropan-2-amine (334.7 mg, 2.59 mmol) and THF (25 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 80.4%). LRMS (APCI pos) m/e 512 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.42 (d, 1H), 7.79 (dd, 1H), 7.76 (s, 1H), 7.29 (m, 1H), 7.19 (t, 1H), 6.45 (dd, 1H), 3.43-3.49 (m, 3H), 2.94 (s, 3H), 2.36-2.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]2[CH:14]=[CH:13][C:12](C)=[CH:11][C:10]=2O)=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[Na+].[Na+].O1C2C=CC=CC=2C=N1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=3[O:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=NO)c2ccc(Cl)cc2)c(O)c1
Agent: [Na+]
Agent: c1ccc2oncc2c1
Solvent: O
Product: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1

Procedure:
4'-Chloro-2-hydroxy-4-methylbenzophenone-oxime (0.2g) and anhydrous sodium carbonate (0.2g) were heated together under reflux in triglyome (5ml) for 30 minutes. On cooling, the mixture was poured into water (50ml.) and filtered. On standing a solid separated from the filtrate and was filtered, washed, dried and examined by NMR. The NMR spectrum was consistent with the preparation of the title compound (~30%). T.L.C. also confirmed the presence of the benzisoxazole.
Reaction SMILES: [Br:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])=[CH:7][C:6]=1[S:19](O)(=[O:21])=[O:20].[K].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:37])=O>C(Cl)Cl.C(#N)C>[Br:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])=[CH:7][C:6]=1[S:19]([Cl:37])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)c1cc(OC(F)(F)C(F)(F)Br)ccc1OC(F)(F)C(F)(F)Br
Reactant: O=P(Cl)(Cl)Cl
Agent: [K]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=S(=O)(Cl)c1cc(OC(F)(F)C(F)(F)Br)ccc1OC(F)(F)C(F)(F)Br
Temperature: 75 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A mixture of 5.86 g (0.01mol) of the 2,5-di(2-bromotetrafluoroethoxy) benzenesulfonic acid, potassium salt, 10 mL acetonitrile, 10 mL sulfolane and 6 mL phosphoryl chloride was placed into a 100 mL round-bottom flask, and stirred at 68-82° C. for 1 hour. The mixture was then cooled down to below 5° C. (with the reaction vessel resting in an ice-bath ) and 15 mL ice-cold water was added dropwise. Stirring was continued at a temperature below 10° C. for 20 minutes and the precipitated oily product was isolated by suction and then diluted with 100 mL of methylene chloride. The combined organic layer was washed with saturated aq. sodium chloride in a 500 mL separatory funnel until neutral and dried over sodium sulfate overnight. After the removal of the salt by filtration and the evaporation of the solvents, the crude product was purified by distillation at reduced pressure (10 to 10−2 torr) to collect 102-106° C. fraction at vacuum. A total of 5.00 g (0.0088 mol) of 2,5-di(2-bromotetrafluoroethoxy) benzenesulfonyl chloride was obtained in 88.2% yield.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CCO>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1

Procedure:
2.00 g (7.48 mmol) of commercially available 6-(4-trifluoromethoxy-phenyl)-pyridine-3-carbaldehyde was dissolved in 37 ml of EtOH and treated at 0° C. with 0.283 g (7.48 mmol) of NaBH4. After 10 Min. the cooling bath was removed and stirring continued at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents afforded 2.08 g of pure title compound as off-white solid of mp. 57–58° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)O)c1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, PREPARATION 3, 1.4 g, 4.1 mmol) in THF/water/methanol (4/2/2, 8 mL) is added to lithium hydroxide monohydrate (0.17 g, 4.05 mmol). The mixture is stirred at 20 degrees −25 degrees C. for 1 hour and then solvent is removed under reduced pressure. The residue is dissolved in water (50 mL) and hydrochloric acid (1 N) is added to adjust the pH to about 3. The aqueous mixture is extracted with ethyl acetate and the organic phase is separated and dried over magnesium sulfate to give the title compound. Analytical calculated for C14H18BrNO3: C, 51.23; H, 5.53; N, 4.27; Br, 24.35. Found: C, 51.37; H, 5.56; N, 4.28.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Br[CH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br-:1].[NH:13]1[CH:14]=[CH:15][C:11]([CH2:10][N+:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12]1
Reactant: BrCc1cc[nH]n1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccncc1
Product: [Br-]
Product: c1cc[n+](Cc2cc[nH]n2)cc1

Procedure:
An arylhydrazine, e.g., 3-chloro-5-trifluoromethyl-2-pyridylhydrazine, 2,6-dichloro-4-trifluoromethylphenylhydrazine, or 2,4,6-trichlorophenylhydrazine, was reacted with either ethyl 2-ethoxymethyleneacetoacetate or ethyl 2-dimethylaminomethyleneacetoacetate to produce the corresponding 1-aryl-4-ethoxycarbonyl-1H-5-methylpyrazole. Hydrolysis of the ester group to the acid was followed by reaction of the acid group with thionyl chloride and sulfamide in sulfolane, producing the corresponding 4-cyanopyrazole. Monobromination of the 5-methyl group with N-bromosuccinimide was followed by reaction of the bromomethylpyrazole with pyridine to produce the corresponding N-pyrazolylmethylpyridinium bromide. The pyridinium bromide was then reacted with N,N-dimethyl-4-nitrosoaniline to form the corresponding 5-(4-dimethylaminophenyl-N-oxyiminomethyl)pyrazole. Hydrolysis of this latter intermediate with 6N hydrochloric acid yielded the corresponding 1-aryl-4-cyano-1H-5-formylpyrazole (1), an intermediate also used in the alternative synthesis described below. Reaction of this final intermediate with 2-aminooxypropionic acid yielded the 2-[(1-aryl-4-cyano-1H-5-pyrazolyl)methyliminooxy]propionic acid. Examples 1, 3, and 6 detail this synthetic route for different aryl groups. Ester derivatives were made by reacting the propionic acid compound with methanol, for example, in the presence of p-toluenesulfonic acid (Example 2 and Example 6, Step I) or with 3-chlorophenylmethyl bromide in the presence of potassium carbonate in toluene (Example 4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C1COCC1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:22][CH:23]=1
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(O)c(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.6 %

Procedure:
To a stirred solution of 3-Amino-4-hydroxy benzoic acid (0.136, 0.00089 mols) and pyridine (0.211 g, 0.00267 mols) in 13 ml dry THF is added 4-trifluoromethoxybenzoyl chloride (0.2 g, 0.00089 mols) and the solution is stirred under nitrogen atmosphere at RT for 10 hrs and then refluxed for 3 hrs. The reaction mixture is rotary evaporated and the residue is slurried in water and filtered to get the amide (0.175 g) which is taken for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:30]([O:39][CH2:40]Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[C:30]([O:39][CH2:40][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCCCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCCC(=O)OCOC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
To a round bottomed flask equipped with a reflux condenser and a stirring bar were added piroxicam (1.00 g, 3.0 mmol), potassium carbonate (840 mg, 6.0 mmol), chloromethyl octanoate (870 mg, 4.5 mmol) and acetone (15 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 6 hours additional chloromethyl octanoate (250 mg, 0.75 mmol) and additional potassium carbonate (210 mg, 1.5 mmol) were added and reflux continued for an additional hour. Chromatographed title product was isolated, according to the method of Example 5, as a yellow foam which oiled from toluene/hexane, but crystallized from the oil upon refrigeration (690 mg white crystals, 1.4 mmol, 47%); mp 98°-99° C.; IR (KBr) 1766, 1683 cm-1 ; 1H NMR (CDCl3) delta 0.87 (t, J=8 Hz, 3H), 1.02-1.48 (m, 10H), 2.19 (t, J=6 Hz, 2 H), 3.12 (s, 3H), 5.70 (s, 2H), 7.08-7.17 (m, 1H), 7.67-7.98 (m, 5H), 8.30-8.45 (m, 2H), 9.32 (br s, 1H); precise mass calcd for C24H30N3O6S m/e (P+ +H) 488.1859, found 488.1794.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:30][CH3:31])[C:25]=4[Cl:29])[CH:20]=3)=[O:18])[CH3:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.O>[NH4+].[Cl-].[Fe]>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:30][CH3:31])[C:25]=4[Cl:29])[CH:20]=3)=[O:18])[CH3:16])[CH2:11][CH2:10]2)=[CH:32][CH:33]=1
Reactant: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)ccc2c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccc(N)cc4)CC3)ccc2c1Cl
Product: Cl
Reaction time: 5 h
Yield: 172.3 %

Procedure:
A mixture of reductive iron (0.36 g, 6.47 mmol) in 8.5 ml of 5% NH4Cl, N1-(4-nitrobenzyl)-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine (IV-32) (0.5 g, 0.92 mmol) and water (10 ml) was stirred for 5 hours, and processed according to the procedure of example 12 to give 0.27 g of compound (IV-33), yield 60%, mp 206-8° C., M+ 437.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: COc1ccc(C(C(=O)O)C(C)C)cc1
Product: COc1ccc(C(C(=O)OC(F)c2cccc(Oc3ccccc3)c2)C(C)C)cc1

Procedure:
This compound was prepared from α-isopropyl-(4-methoxyphenyl)acetic acid and α-fluoro-3-phenoxybenzylbromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δppm (solvent CDCl3): 0.72 (3H, d, J=6 Hz, CH3); 1.06 (3H, d of d, J=6 Hz and J=2 Hz, CH3); about 2.25 (1H, m, --CH(CH3)2); 3.17 (1H, d, J=10 Hz, CH); 3.76 (3H, s, CH3O); 7.18 (1H, d of d, J=56 Hz and J=2 Hz, CHF); about 7.2 (13H, m, aromatic protons).
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:6]([O:29]C)=[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([C:20]#[N:21])=[C:9]([CH3:19])[C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrB(Br)Br.O>[Cl-].[Na+].O>[Br:4][C:5]1[C:6]([OH:29])=[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:8]([C:20]#[N:21])=[C:9]([CH3:19])[C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1c(Br)c(C=Cc2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1C=Cc1ccccc1
Temperature: -78 °C
Reaction time: 1.17 h
Yield: 97.3 %

Procedure:
A dichloromethane (1.0 ml) solution of N-(3-bromo-6-cyano-2-methoxy-5-methyl-4-styrylphenyl)-2,2-dimethylpropionamide (I-11) (34 mg, 79.6 μmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (239 μl, 239 μmol) was dropwise added, followed by stirring at −78° C. for 70 minutes. Afterwards, this was heated up to −12° C. and stirred for 1 hour. The reaction liquid was put into cold water (50 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain the entitled compound (32 mg, 96%) as a yellow white semi-solid.
Reaction SMILES: S(=O)(=O)(O)O.C(C1[O:11][C:12]2[C:18]([S:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)(=[O:21])=[O:20])=[C:17]([Cl:29])[CH:16]=[CH:15][C:13]=2[N:14]=1)(C)(C)C>O.O1CCOCC1>[NH2:14][C:13]1[C:12]([OH:11])=[C:18]([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[C:17]([Cl:29])=[CH:16][CH:15]=1
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Yield: 65.4 %

Procedure:
4.27 ml (0.08 mol; 1.20 V) of sulfuric acid diluted in 4.3 ml of water were added dropwise to 3.56 g of 2-tert-butyl-6-chloro-7-(4-methylpiperazine-1-sulfonyl)benzooxazole (0.01 mol; 1.0 eq) in solution in 15 ml of 1,4-dioxane. The reaction medium was refluxed for six and a half hours. The reaction medium was concentrated and 1 N sodium hydroxide was added (to pH 7). The solution was extracted with dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed on silica gel, eluent 95/5 ethyl acetate/dichloromethane. 2.0 g of 6-amino-3-chloro-2-(4-methylpiperazine-1-sulfonyl)phenol were obtained in the form of a thick brown oil. Yield=68%.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH3:18][NH:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=S>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:20]1[N:19]([CH3:18])[C:3](=[O:17])[CH2:4][C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)C[C@](C)(N)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-butyric acid methyl ester (21 mmole) and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (7.22 g) was obtained as white solid. MS (ESI): m/z=361.4 [M−H]−.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[NH2:38][CH2:39][CH2:40][OH:41]>C1COCC1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:25]=[CH:24][C:23]([N:10]3[CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=4)[CH2:12][N:8]([CH2:7][CH2:6][NH:38][CH2:39][CH2:40][OH:41])[C:9]3=[O:37])=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: NCCO
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Solvent: C1CCOC1
Product: O=C1N(CCNCCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl methanesulfonate (12.0 mg, 0.0216 mmol) in THF (0.3 mL) is added 2-aminoethanol (6.53 μL, 0.108 mmol). The reaction mixture is heated at 80° C. for 2 h before removal of the solvent. The residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H25ClF3N3O3 (M+H+) 520.2, found 520.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][NH:14][NH2:15].Cl.O>CCCCO>[CH3:13][N:14]1[C:2]2=[C:3]3[CH:12]=[CH:11][NH:10][C:4]3=[N:5][CH:6]=[C:7]2[CH:8]=[N:15]1
Reactant: CNN
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Cn1ncc2cnc3[nH]ccc3c21
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.37 g, 7.59 mmol, Adesis) and methylhydrazine (0.599 mL, 11.4 mmol) in n-BuOH (7 mL) were heated to about 95° C. After about 15 min, concentrated HCl (0.500 mL, 16.4 mmol) was added and the reaction mixture was heated to about 120° C. After about 4 h, water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was basified with saturated aqueous NaHCO3 to about pH 8 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g column) eluting with a gradient of 5-60% EtOAc in heptane to give 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.960 g, 74%): LC/MS (Table 2, Method d) Rt=1.40 min; MS m/z: 173 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]3[CH2:15][C:10]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)([CH2:11]3)[C:9]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]3=[O:25])=[CH:21][CH:20]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1CC1CCCCC1
Agent: [Pd]
Solvent: COCCO
Solvent: CCOCC
Product: Nc1ccc(C23CC(C2)C(=O)N(CC2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 140°-146° (from ether) Rf (ether)=0.25.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[CH:16]N(C)C)[C:11](=O)[C:10]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]>>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[N:28][C:27]([NH:26][C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[N:29][C:11]=2[C:10]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1CC(=O)N(Cc2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(Cc2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to that described for method I, 1-benzyl-8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-N) and 4-guanidinobenzoic acid were converted to I-6 (26%): MS m/z═471 (M+H)HRMS Calcd. for C26H19ClN4O3: 471.1223, Found 471.1310.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C[O:17][C:18]([NH:20][NH2:21])=[S:19]>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][CH:3]2[CH2:2][S:19][C:18](=[O:17])[NH:20][NH:21]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: COC(=S)NN
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CCl
Solvent: CC#N
Product: O=C1NNC(C=Cc2ccc([N+](=O)[O-])cc2)CS1

Procedure:
A solution containing 11.2 g of 1-chloro-4-(4-nitrophenyl)-2-oxo-3-butene (J. Org. Chem. 28, 2446, 1963) and 6.8 g of hydrazinecarbothioic acid O-methylester in 200 ml of acetonitrile was refluxed for 3 h. The crystals were filtered and washed with acetonitrile and ether. Yield 7.7 g (59%), mp. 231°-240° C.