Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH:4]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:8][CH:7]=[C:6](N)[CH:5]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]=[O:27]>>[CH:12]1[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]=[C:2]=[O:3])=[CH:5][CH:4]=2)=[CH:16][CH:15]=[C:14]([N:17]=[C:26]=[O:27])[CH:13]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:2]=[O:3]
Reactant: [N-]=C=O
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: C=O
Solvent: Nc1ccccc1
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1

Procedure:
The instant emulsions are preferably used as binders for materials containing lignocellulose, as already mentioned. Emulsions which have proved to be particularly suitable for this purpose are those in which the isocyanate component (see German Offenlegungsschrift No. 2,711,958) is the phosgenation product of the undistilled bottom fractions. These may be obtained, for example, by the removal of 25 to 90% by weight, preferably 30 to 85% by weight of 2,2'-, 2,4'- and/or 4,4'-diaminodiphenylmethane from an aniline/formaldehyde condensate. The undistilled bottom fraction may also be obtained by the removal of 25 to 90% by weight, preferably 30 to 85% by weight of 2,2'-, 2,4'- and/or 4,4'diisocyanatodiphenylmethane from the crude phosgenation product of an aniline/formaldehyde condensate. In either case, the isocyanate component should contain 35 to 70% by weight, preferably 45 to 60% by weight of diisocyantodiphenylmethane. The 2,4'-diisocyanatodiphenylmethane content is from 1 to 8% by weight, preferably from 2 to 5% by weight and the content of 2,2'-diisocyanatodiphenylmethane is from 0 to 2% by weight. In either case, the isocyanate component has a viscosity at 25° C. of 50 to 600 mPas, preferably 200 to 500 mPas, and an isocyanate content from 28 to 32% by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1.Cl.[N:31](OCCC(C)C)=[O:32].C(N(CC)CC)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:31][OH:32])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C(=NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)propan-2-one are introduced into 4 ml of HCl 5% in dioxane, then 0.6 g of isopentyl nitrite is added dropwise thereto. After 1 hour's stirring at room temperature, 0.8 ml of triethylamine is added. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-oxime is obtained. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 2.51 (s, 3H), 4.16 (t, 2H), 4.30 (t, 2H), 4.58 (d, 2H), 6.11 (t, 1H), 6.84 (s, 2H), 6.98 (d, 2H), 7.34 (d, 2H), 8.30 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.C(Br)(=O)C([Br:23])=O>CN(C=O)C.ClCCCl>[Br:23][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) were placed in a vial (20 ml). To the resulting suspension was added carefully oxalyl bromide (0.53 ml, 1.24 g, 5.75 mmol). A foam was formed during the addition, and as the foam was settling down the stirring was started. DMF (3 drops) was added and the vial was sealed and the mixture was stirred overnight. Another portion of oxalyl bromide (0.2 ml, 0.46 g, 2.23 mmol) and DMF (3 drops) was added and the reaction was run for another 24 h. The mixture was partitioned between is DCM (20 ml) and water (20 ml) and the organic phase was dried. Filtration and evaporation gave a crude product, which was purified on silica, affording 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one (0.59 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:26]5[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=5)=[C:17]4[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(Cl)cc2)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (28 mg, 22%), MS (ISP) m/z=390.2 [(M+H)+], mp 154° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), methyl 2-hydroxy-3-naphthoate (271 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (7 mg, yield 4%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:18][C:19](=[O:30])[C:20](CO)([CH2:26]O)[C:21](OCC)=[O:22])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>C1C=CC=CC=1.C(O)C.CCCCCC>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]2[O:22][CH2:21][CH:20]([C:19]([OH:30])=[O:18])[CH2:26][O:13]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCOc1ccc(C2OCC(C(=O)O)CO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.6 g (0.1 mol) 4-n-hexoxybenzaldehyde and 24.2 g (0.11 mol) bis-hydroxymethyl-malonic acid-diethyl ester are heated in 150 ml benzene in a corresponding amount of 0.2 g p-toluenesulfonic acid, while stirring for 8 hours. After cooling, the benzene is carefully washed with 2% NaHCO3 solution, then with water, and then distilled under vacuum (rotating evaporator), with the residue being recrystallized from alcohol (2-(4-n-hexoxyphenyl)-1,3-dioxane-5,5-dicarboxylic acid-diethyl ester I). The yield at I is 31 g (76% of theoretical). I melts at 30° C. (from n-hexane). 31 g (0.074 mol) I and 18 g (0.32 mol) KOH in 150 ml 95% ethanol is heated for one hour at reflux in the continued preparation. Ethanol is then distilled from the reaction residue, water added to the residue, and the aqueous phase concentrated to 30-50 ml. After addition of 100 ml ether, it is cooled to 0° C. and concentrated HCl is added while stirring (up to pH 1). Subsequently, the ether fraction is immediately separated, washed with water, dried with Na2SO4, and the solvent removed in the rotating evaporator. The residue (16.5 g, 62% of theoretical) of 2(4-n-hexoxyphenyl)-1,3-dioxane-5,5-dicarboxylic acid (decomposition above 135° C.) is decarboxylized with a water jet vacuum pump at 120° to 170° C. Having completed the brisk CO2 development, the residue of benzene or cyclohexane is recrystallized. The yield of 5 n is 63% of theoretical. The melting point of 5 n is 176° to 178° C. Additional examples are listed in Table 5.
Reaction SMILES: [Mg].Br[C:3]([CH2:5][CH3:6])=[CH2:4].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[Na+].[Cl-]>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[NH:14][C:3]([CH2:5][CH3:6])=[CH:4]2
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=C(Br)CC
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2cccc(Br)c2[nH]1
Temperature: 60 °C
Yield: 207.8 %

Procedure:
2.4 g of magnesium are placed in a round-bottomed flask and the magnesium is covered with 10 ml of THF. 1 g of 2-bromo-1-butene, then 10 ml of THF and then again 12.5 g of 2-bromo-1-butene in 30 ml of THF are added. The reaction medium is observed to warm up and then it is heated at 60° C. for 30 minutes after the end of the addition reaction. The mixture is subsequently cooled to −20° C., 20 ml of THF are added and then 6.7 g of 2-bromonitrobenzene are added at −20° C. The mixture is allowed to return to AT. The reaction medium is poured onto 200 ml of a saturated NaCl solution. Extraction is carried out with ether, the extracts are then evaporated and the residue is taken up in DCM. The organic phase is washed with water and then with a saturated NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica while eluting with a cyclohexane/AcOEt (9.5/0.5, v/v) mixture. 3.45 g of the expected compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>ClCCl.O1CCOCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200.3 %

Procedure:
To a solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]piperidine-1-carboxylate (1 g) in dichloromethane (40 mL) was added 4M HCl in dioxane (6 mL) and methanol (5 mL). The mixture was stirred at room temperature for 2 hours and then evaporated to give the title compound as a white foam (0.87 g, 100%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:41]5[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(CCO)CC1
Yield: 32.1 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and 2-piperazin-1-yl-ethanol (135 mL, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (75 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.55 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.50 (s, 1H), 4.40 (s, 1H), 4.25 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 2.50-2.25 (m, 12H), 1.95 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 636 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.O.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 18.5 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide (10 kg) and 10% palladium oxide on charcoal (10 kg, 50% wet paste, added as two charges) in DMF (50L), water (20L) and 2N hydrochloric acid (15L) was hydrogenated at atmospheric pressure over 18.5 hr. The catalyst was removed by filtration. The filter cake was washed with water (20L). The filtrate was concentrated in vacuo to approximately 30L and cooled to 20°. Ethyl acetate (70L) was added over 1 hr and the resulting suspension cooled to 50 and aged for 30 min. The product was collected by filtration, washed with ethyl acetate (20L) and dried in vacuo at 40°-50° overnight (9.34 kg, 81.6% of theory). A portion (2.0 kg) of the solid was recrystallised from hot water (6.0L) and obtained as white crystals (1.40 kg, 70% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Br:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C(CC(=O)c2cccc(Br)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5,5-Dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol), 2-bromo-1-(3-bromophenyl)ethanone (2.78 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were combined in chloroform (40 mL). The mixture was stirred for 18 hr at room temperature whereupon a white precipitate formed. The solid was collected by filtration, suspended in water and acidified to pH 5 using 1M HCl (aq.). The resulting solid was filtered, washed with water and dried in vacuo to afford the title compound. The aqueous filtrate was evaporated and the crude residue purified on silica gel using a gradient elution of 0-100% ethyl acetate in 40-60 petroleum ether to yield the title product (2.77 g, 82%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:2]2[CH:8]=[C:7]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)[CH:6]=[C:5]([F:10])[C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1c(F)cc(Br)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c(F)cc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 159.5 %

Procedure:
2,4-dibromo-6-fluoroaniline (10 mmol), benzeneboronic acid (24 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-6-fluoroaniline (2.1 g) is yielded.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.Cl>CCO.O>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:2]=1[NH2:1]
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
5-amino-4,6-dichloropyrimidine (5.0 g, 30.49 mmol) and 4-chloroaniline (5.1 g, 40.0 mmol) were added to the solution of hydrochloric acid (1.3 mL, 15.24 mmol) in EtOH/H2O (8:1 v/v) (100 ml). The resulting reaction mixture was stirred for overnight at 80° C. The resulting mixture was filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (6.8 g, 88%) as white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].CO.C(O)(=O)C>[CH:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1=C(c2cscc2-c2cc(Nc3ccccc3)n[nH]2)CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(Nc2cc(-c3cscc3C3CCCCC3)[nH]n2)cc1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
Hydrogenation of [5-(4-cyclohex-1-enyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine (50 mg, 0.156 mmol) was carried out using 10% palladium on activated carbon (˜20 mg) in methanol (5 mL) and acetic acid (0.5 mL) under a balloon of hydrogen. After stirring for 16 h, the reaction was filtered through Celite. The filtrate was diluted with ether (50 mL), washed with saturated NaHCO3 solution (2×25 mL) and brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 29 mg (58%) of [5-(4-cyclohexyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH:13][CH3:14]>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: CNC
Reactant: Cc1c(O)cccc1C(=O)O
Product: Cc1c(O)cccc1C(=O)N(C)C
Yield: 42 %

Procedure:
The title compound was prepared from 3-hydroxy-2-methylbenzoic acid and dimethylamine, using the same method as that described for preparation 75, as a solid in 42% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 2.70 (s, 3H), 2.95 (s, 3H), 6.55 (d, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 9.50 (s, 1H); LRMS APCI m/z 180 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([O:22][CH3:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[F:33][C:34]1[CH:39]=[C:38]([C:12]2[N:11]=[C:10]([O:22][CH3:23])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:6]=4)[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COc1nc(Cl)cc2c1Oc1ccc(Br)cc1[C@@]21COC(N)=N1
Reactant: OB(O)c1cccnc1
Product: COc1nc(-c2ccnc(F)c2)cc2c1Oc1ccc(-c3cccnc3)cc1[C@@]21COC(N)=N1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-7-bromo-3-chloro-1-methoxy-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method CC16), pyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.CC([O-])=[O:19].[Na+].[O:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH2:3][N:2]([C:24](=[O:25])[C:23]([O:22][CH2:27][CH3:26])=[O:19])[OH:1]
Reactant: ONCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)[O-]
Reactant: C1COCCO1
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)N(O)Cc1ccc2c(c1)Cc1ccccc1-2
Temperature: -5 °C
Reaction time: 3 h

Procedure:
The crude hydroxylamine (4.2 g, 0.02 mol) from Example 1 is dissolved in dioxane (80 ml) and water (50 ml). The turbid solution is cooled to -5° C. and then treated with NaOAc (3.3 g, 0.04 mol) followed by ethyl oxalylchloride (3.0 g, 0.022 mol). The mixture is stirred at 24° C. for 3.0 hours, poured onto ice-1N HCl (40 mL) and extracted with CH2Cl2. The extract is washed with brine, water and dried over Na2SO4. The solvent is distilled off to give (9H-fluoren-2-ylmethyl)hydroxyamino-oxo-acetic acid, ethyl ester which is fractionally recrystallized from isopropyl ether and CH2Cl2 and then from isopropyl ether. Yield 1.6 g (26%); mp 130°-131° C.
Reaction SMILES: [N+:1]([C:4]([N+:23]([O-:25])=[O:24])([N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][C:7]([NH:9][NH:10][C:11](=[O:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCCl.C(Cl)Cl>[N+:1]([C:4]([N+:23]([O-:25])=[O:24])([N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][C:7]1[O:19][C:11]([C:12]([F:17])([F:18])[C:13]([F:15])([F:16])[F:14])=[N:10][N:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[N+]([O-])C(CCc1nnc(C(F)(F)C(F)(F)F)o1)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A solution containing 0.6 g (0.0016 mole) of N-(4,4,4-trinitrobutyryl)-N'-(perfluoropropionyl)hydrazine and 0.8 g (0.0038 mole) of phosphorus pentachloride in 7 mL of 1,2-dichloroethane was held at reflux temperature for 4 hours before the volatiles were removed to give an oil residue. The residue was dissolved in CH2Cl2, washed with water, and chromatographed on Silica gel 40 (CH2Cl2 as eluent) to give the product, 2-(3,3,3-trinitropropyl)-5-(perfluoroethyl)-1,3,4-oxadiazole, 0.4 g (70%), mp 36°-38° C. 1H NMR (acetone-d6): 3.80 (m, 2H), 4.20 (m, 2H).