Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.C([NH2:39])=O.CO[Na].O>CN(C=O)C.CO>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([N:8]2[C:9]3[C:10](=[O:28])[N:11]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C:22]5=[O:27])=[CH:17][CH:16]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([NH2:39])=[O:3])=[N:7]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Reactant: NC=O
Agent: CO[Na]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Method B. A solution of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 977 mg, 2.0 mmol) in DMF (5 mL) was treated with formamide (901 mg, 0.8 mL, 20 mmol, 10.0 equiv) at room temperature, and the resulting reaction mixture was cooled down to 0–5C before being treated dropwise with a solution of MeONa (864 mg, 0.92 mL, 4.0 mmol, 2.0 equiv) in methanol at 0–5C. The resulting reaction mixture was stirred at 0–5° C. for 30 min before being gradually warmed up to room temperature for an additional 3 h. When HPLC and TLC showed the reaction was complete, the reaction mixture was slowly poured into water (20 mL). The resulting mixture was then stirred at room temperature for 1 h to precipitate the desired product. The solids were collected by filtration, washed with water (2×10 mL) and methyl tert-butyl ether (2×10 mL), dried in vacuo at 40–45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (62, 653 mg, 919 mg theoretical, 71%) as off-whit crystals. This product was found to be identical with the material prepared from method A.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:23])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:24].[OH:25]O>CS(O)(=O)=O>[C:1]1([NH:7][C:8]([NH:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([O:23][OH:25])=[O:24])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O
Reactant: O=C1CCCCCCCCCCCN1C(=O)Nc1ccccc1
Agent: CS(=O)(=O)O
Product: O=C(NCCCCCCCCCCCC(=O)OO)Nc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
31.6 g (0.1 mol) of N-phenylcarbamoyllaurolactam are dissolved in 50.0 g of methanesulfonic acid (98% strength by weight), 3.6 g (0.2 mol) of water are added and the mixture is heated at 80° C. for 30 minutes. After cooling the reaction mixture to 25° C., 17.0 g (0.25 mol) of hydrogen peroxide (50% strength by weight) are added dropwise such that the internal temperature can be kept between 22 and 25° C. After stirring at 25° C. for 20 minutes, 100 ml of water are added and the precipitated peroxycarboxylic acid is filtered off with suction. The filter cake is washed free of mineral acid with water and dried at 40° C. in a water pump vacuum.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:16](Cl)(=[O:18])=[O:17])[C:9]=2[CH3:20])[CH2:5][C:4](=[O:21])[C:3]=1[C:22](=[O:25])[CH2:23][CH3:24].Cl.[NH3:27]>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:16](=[O:18])(=[O:17])[NH2:27])[C:9]=2[CH3:20])[CH2:5][C:4](=[O:21])[C:3]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(=O)(=O)Cl)c2C)CC1=O
Reactant: N
Agent: Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 3-hydroxy-5-(2,4,6-trimethyl-3-chlorosulphonylphenyl)-2-propionylcyclohex-2-en-1-one (1.3 g) and aqueous ammonia (50 ml, 25%) was stirred at 20° C. for 1 hour. The mixture was acidified with dilute hydrochloric acid and the product was extracted into dichloromethane (2×100 ml). The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator to give 3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)-2-propionylcyclohex-2-en-1-one (1.1 g, 81%) as a pale brown foam. Proton magnetic resonance spectrum (CDCl3 ;δ in ppm): 1.17 (3H, t):2.42 (3H, s); 2.63 (3H, s); 2.72 (3H, s); 2.8-4.0 (7H, m); 4.98 (2H, s); 6.96 (1H, s); 18.27 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:18].O1CCCC1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([O-:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:18]
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)[O-])C1
Temperature: 45 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
To a solution of #169 (75 mg, 0.32 mmol, 1 eq.) in methanol (0.3 mL) was added a solution of lithium hydroxide (13.8 mg, 0.572 mmol, 1.8 eq.) in water (0.4 mL). Next, tetrahydrofuran (0.45 mL) was added and the reaction was stirred at 45° C. for 18 hours. The reaction was concentrated in vacuo and the material was azeotroped (3×) with toluene (4 mL) to obtain #171 (77 mg, 100%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol) in CH2Cl2 (10 mL) and NEt3 (0.4 mL) was added bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.028 mmol), copper (1) iodide (2 mg) and 1-octyne (0.25 mL. 1.7 mmol). The reaction mixture was stirred and refluxed under N2 atmosphere for two days and then cooled to room temperature. After washing with aqueous 10% NaOH (1X), the organic layer was dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc, 10: 1 to 10:2) to afford an oil (255 mg, 79%): 1H NMR (CDCl3, 300 MHz) δ0.88 (t, 3H, J=2.5 Hz), 1.20-1.38 (m, 4H), 1.42 (d, 4H, J=2.5 Hz), 1.44 (s, 9H), 1.90 (m, 1H), 2.00 (m, 1H), 2.40 (t, 2H, J=7.0 Hz), 3.12 (q, 4H, J=7.5 Hz), 3.32-3.44 (m, 2H), 3.90 (br, 1H), 4.08-4.20 (m, 2H), 7.10 (s, 1H), 8.08-8.30 (m, 2H); MS (CI/NH3) m/z 387 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][P:19]1(=[O:26])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CN(C=O)C>[CH3:10][C:9]([CH3:11])([CH3:12])[C:8]#[C:7][C:5]1[S:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][CH:22]2[CH2:23][CH2:24][P:19]([O:18][CH3:17])(=[O:26])[CH2:20][CH2:21]2)[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: COP1(=O)CCC(=O)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCP(=O)(OC)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A solution of methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (474 mg, 2 mmol) and 1-Methoxy-1-oxo-1λ5 phosphinan-4-one (390 mg, 2.4 mmol) in THF (1 mL) and DMF (1 mL) was treated with dibutyltin dichloride (60 mg, 0.2 mmol). After 5 min, phenylsilane (272 μL, 2.2 mmol) was added, and the mixture was stirred for one hour at room temperature and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with 5% LiCl and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using EtOAc:Hexanes as eluent to provide 650 mg (85%) of title compound: MS (m/z) 384.0 [M+H]+; HPLC retention time: 4.463 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[CH3:12])(=[O:5])[CH3:4].O>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[CH3:12])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1sc(O)nc1C
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1nc(O)sc1C(=O)CBr
Yield: 49.8 %

Procedure:
A solution of bromine (19.2 g) in methylene chloride (10 ml) was dropwise added to a solution of 5-acetyl-2-hydroxy-4-methylthiazol (15.7 g) in a mixture of methylene chloride (300 ml) and acetic acid (50 ml) at 40° C. to 44° C. with stirring. After being stirred at the same temperature for 30 minutes, the reaction mixture was poured into water (300 ml). The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-(2-bromoacetyl)-2-hydroxy-4-methylthiazole (11.75 g). mp 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].N1C=CC=CC=1.[N+:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[S:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)(=[O:26])=[O:27]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CNc1ccccc1Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(c1ccccc1Cl)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-N-methylaniline (4.96 mmol, 1.1 eq., 702 mg) and pyridine (5.86 mmol, 464 mg) in 20 mL of methylene chloride was added 3-nitrobenzenesulfonyl chloride (4.51 mmol, 1.0 g) in one portion. The reaction mixture was stirred 16 hr and diluted with methylene chloride and water. The aqueous layer was separated and extracted once with methylene chloride. The combined organic layers were extracted once with a saturated solution of aqueous sodium carbonate, once with water, and then dried over sodium sulfate. The crude product was purified using flash chromatography (10-60% ethyl acetate/hexane) to give N-(2-chlorophenyl)-N-methyl-(3-nitrophenyl)sulfonamide which solidifies on standing. 1H NMR (300 MHz) 3.29 (s, 3H), 7.25-7.45 (m, 4H), 7.71 (t, J=7.82 Hz, 1H), 8.06 (d, J=7.82 Hz, 1H), 8.40-8.50 (m, 1H), 8.60-8.65 (m, 1H). MS (ESI): m/e 327.13, 329.13 (M+1).
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[C:6]=1C#N.C[CH2:16][O:17][CH2:18][CH3:19]>C1C=CC=CC=1>[CH3:10][C:9]([C:6]1[C:5]([F:4])=[CH:12][CH:11]=[CH:19][C:18]=1[O:17][CH3:16])=[O:13]
Reactant: COc1cccc(F)c1C#N
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: c1ccccc1
Product: COc1cccc(F)c1C(C)=O
Temperature: 25 °C

Procedure:
To a flask containing methyl magnesium bromide (1.18 g, 9.93 mmol) in ether is added dropwise 2-fluoro-6-methoxybenzonitrile (0.5 g, 3.31 mmol, Lancaster Synthesis Inc.) in benzene (9 ml). The reaction mixture is refluxed overnight. The reaction is cooled to room temperature and quenched slowly with saturated ammonium chloride (15 ml) and concentrated hydrochloric acid (1 ml). The mixture is extracted with diethyl ether (2×50 ml). The combined organic layers are dried over Na2SO4, filtered, and rotary evaporated to give 0.55 g of a crude yellow material. Purification is accomplished by vacuum column (eluting with 16% ethyl acetate in hexane). The compoundcontaining fractions are combined, yielding 5.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:59]5[CH2:58][CH2:57][CH:56]([N:53]6[CH2:52][CH2:51][N:50]([CH3:49])[CH2:55][CH2:54]6)[CH2:61][CH2:60]5)=[O:12])[CH:24]=4)=[CH:27][CH:28]=3)=[O:34])[CH2:36][CH2:37]2)=[O:47])=[CH:45][CH:44]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (56.7 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (37.7 mg, 79%).
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3](=[O:15])[C:2]1=[O:16].[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[N+:17]([C:7]1[C:8]2[CH2:14][CH2:13][NH:12][CH2:11][C:9]=2[C:10]2[NH:1][C:2](=[O:16])[C:3](=[O:15])[NH:4][C:5]=2[CH:6]=1)([O-:19])=[O:18]
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Reaction time: 19 h
Yield: 58 %

Procedure:
A solution of the quinoxalinedione from Example 30 (50 mg, 0.23 mmol) in 2 mL of trifluoroacetic acid was treated with fuming nitric acid (0.1 mL, 2.3 mmol) and stirred under a nitrogen atmosphere for 19 h. After evaporating to dryness, the residue was triturated with acetone and the precipitant collected by filtration. The solid was suspended in water, heated on a hot plate and basified to pH 8 with an ammonium hydroxide solution. The solid was collected by filtration while hot, and dried in vacuo to give a yellow solid (35 mg, 65% yield). mp=245-240° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=O)[O:14][C:10]=2[CH:9]=1.[ClH:18]>ClC1C=CC=CC=1Cl>[Cl:18][C:13]1[O:14][C:10]2[CH:9]=[C:8]([Cl:7])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Clc1ccc2nc(Cl)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
1 litre of o-dichlorobenzene and 625 g (3 moles) of phosphorus pentachloride are heated to 160° C., then 169.5 g (1 mole) of solid 6-chlorobenzoxazolin-2-one are introduced in small portions over the course of 60 minutes, vigorous evolution of hydrogen chloride occuring for a short time after each portion. The mixture is then stirred for a further 15 minutes at 150°-160° C., and then cooled to 0° C., whereupon the major part of the excess pCl5 crystallises out. The phosphorus pentachloride precipitate is filtered off with suction, Washed with a little cold o-dichlorobenzene, and the filtrate is fractionated under reduced pressure. phosphorus oxychloride distils over first, then o-dichlorobenzene together with the remainder of the excess phosphorus pentachloride, and last, at about 110° C. and 17.3 mbar, 2,6-dichlorobenzoxazole. About 136 g of 2,6-dichlorobenzoxazole of melting point 48-49° C. are obtained. GC purity 99.7%. yield: 72% of theory.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[N+:1]([C:4](=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)[C:11](=[O:13])[CH3:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
4.0 g of 2b was added in portions to 50 ml of acetic anhydride at 25°. The solution was heated at 95°-105° for 2 hours. Excess acetic anhydride was removed under reduced pressure to leave 5.0 g of a slightly gummy brown solid which was crystallized from ethyl acetate (after treatment with charcoal) to give 2 as a yellow-brown solid, m.p.: 110°-113°.
Reaction SMILES: C([O:8][C:9]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:12]([CH:13]=[CH:14][N+:15]([O-:17])=[O:16])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:20][C:19]1[CH:18]=[C:12]2[C:11](=[CH:10][C:9]=1[OH:8])[NH:28][CH:14]=[CH:13]2.[OH:8][C:9]1[C:19]([OH:20])=[CH:18][C:12]([CH:13]=[CH:14][N+:15]([O-:17])=[O:16])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1
Reactant: O=[N+]([O-])C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
or by debenzylation of 4,5-dibenzyloxy-2,β-dinitrostyrene; in this case the debenzylation is performed by means of trifluoroacetic acid. In a second stage 5,6-dihydroxyindole is obtained from 4,5-dihydroxy-2,β-dinitrostyrene as indicated above (U.S. Pat. No. 4,595,765).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[NH:12]([C:19]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=[C:21](SC)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:39]1([C:45]2[CH:49]=[C:48]([CH2:50][N:51]3[CH2:56][CH2:55][CH:54]([CH2:57][NH2:58])[CH2:53][CH2:52]3)[O:47][N:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(OCC)(=O)C>[NH:12]([C:19]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=[C:21]([NH:58][CH2:57][CH:54]2[CH2:53][CH2:52][N:51]([CH2:50][C:48]3[O:47][N:46]=[C:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:49]=3)[CH2:56][CH2:55]2)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CSc1ncc(C(N)=O)c(Nc2ccccc2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
3-Chloroperoxybenzoic acid (195 mg) was added to a 0° C. suspension of the compound prepared in Example 93 (100 mg) in dichloromethane (4 mL). The reaction was stirred one hour at room temperature. Diisopropylethylamine (0.669 mL) and the compound prepared in Example 9 (198 mg) were added and the mixture was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (concentrated aqueous ammonia:methanol:ethyl acetate=0.1:0.9:25) to obtain the title compound (51 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:25])[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([CH3:18])[C:16]=1[CH3:17])=[O:11].CC([O-])(C)C.[K+].CN(C=O)C.Cl[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([C:44]([NH2:46])=[O:45])[CH:39]=1>CCOC(C)=O.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([NH2:46])=[O:45])[CH:39]=3)=[CH:7][C:2]=2[F:1])=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a mixture of N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.879 mmol) and t-BuOK (118 mg, 1.05 mmol) was added DMF (2.5 mL). The resulted mixture was stirred at rt for 30 minutes, then 4-chloropicolinamide (165 mg, 1.05 mmol) was added. The mixture was heated at 120° C. for 5 hours, then cooled to rt, and H2O (50 mL) and EtOAc (2 mL) was added. The resulted mixture was stirred at rt overnight. Filtered and the precipitation was washed with water (5 mL) to give the title compound as a dark brown solid (370 mg, 91.2%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]([F:31])([F:30])[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([CH2:28][NH2:29])=[CH:23][CH:22]=2.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:29][CH2:28][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:18]([F:31])([F:17])[F:30])=[CH:27]3)=[O:10])=[CH:6][N:7]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cnc(Cl)nc1
Reaction time: 2 h
Yield: 56.5 %

Procedure:
2-Chloro-pyrimidine-5-Carboxylic acid (209 mg, 1.317 mmol) was stirred in dichloromethane (20 ml). Oxalyl chloride (0.210 ml, 2.394 mmol) then DMF (4.63 μl, 0.060 mmol) was added. The reaction mixture was then left to stir for 2 h under Argon gas. The reaction mixture was then evaporated to dryness and the resulting residues were then dissolved in dichloromethane (20 ml). A solution of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 300 mg, 1.197 mmol) in DCM (10 mL) was added then triethylamine (0.500 ml, 3.59 mmol) was added. The reaction mixture was then left to stir at room temperature for 24 h. The reaction mixture was evaporated to dryness. The resulting residues where then partitioned between 2M HCl (50 ml) and ethyl acetate (50 ml). The organic layer was collected, dried (MgSO4), filtered and the solvent was removed. The resulting residues where then purified on the MDAP to give the title compound (240 mg);