Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].[C:32](Cl)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[C:17]([C:16]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[N:14][N:13]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:9][CH2:10][NH:11][C:12]=12)#[N:18]
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (730 mg, 2.21 mmol) in THF (30 mL) was added K2CO3 (610 mg, 4.42 mmol), CbzCl (564 mg, 3.32 mmol). After stirring at 65° C. for 16 hr, the mixture was concentrated in vacuum. The residue was partitioned between 150 mL of DCM and 150 mL of brine. Organic layers were separated from aqueous layers, dried over Na2SO4 and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 370 mg (62%) of benzyl 2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.33 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.44-7.28 (m, 7H), 7.17 (t, J=7.6 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.59 (d, J=7.6 Hz, 1H), 5.82-5.77 (m, 1H), 5.17 (s, 2H), 3.25-3.18 (m, 1H), 2.97-2.87 (m, 1H), 2.36-2.24 (m, 1H), 2.08-2.00 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[N:14]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:13])=[O:15]
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccc(O)c(N=O)c2c1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
110.2 g (0.633 mol) of 7-methoxy-β-naphthol were nitrosated in a mixture of 650 ml of glacial acetic acid and 65 ml of water at 0° C. in the course of two hours using a solution of 45.0 g (0.65 mol) of sodium nitrite in 340 ml of water. Stirring was continued for a further two hours and in this time the temperature of the reaction mixture was allowed to rise to 22° C. Then the volume was made up to 1.6 l with water and the precipitated product was filtered off by suction. After drying, 120.3 g (93.5%) of 1-nitroso-7-methoxy-β-naphthol were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:30]2[CH:42]=[N:43][N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:29]=2[C:28]1=[O:53]>>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[C:31]1[C:30]2[CH:42]=[N:43][N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[C:29]=2[C:28](=[O:53])[N:27]([CH3:26])[CH:32]=1
Reactant: COC(=O)CNc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cnn(COCC[Si](C)(C)C)c2c1=O
Product: COC(=O)CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using methyl {[4-bromo-3-(2,4-difluorophenoxy)-2-nitrophenyl]amino}acetate and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as the starting materials. LCMS calculated for C28H32F2N5O7Si (M+H)+: m/z=616.2. found: 616.2.
Reaction SMILES: C([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=2)=[N:9]1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(O)CCC>[OH:24][C:20]1[CH:19]=[C:18]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=3)[NH:8][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(Cl)c23)c1
Solvent: CCCCO
Product: Oc1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
A mixture of 70 mg (0.2 mmol) of 1-benzyl-4-chloro-3-(3-methoxy-phenyl)-pyrazolo[3,4-d]-pyrimidine, 115.6 μl (1.1 mmol) of 3-chloro-aniline and 7 ml of 1-butanol is heated under reflux for 20 hours and then concentrated by evaporation in vacuo. The residue is digested in hexane and filtered. Repeated digestion of the filter residue in diisopropyl ether and in ethanol yields the title compound; m.p. 118-119° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CN(C=O)C.O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2=[O:1])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (7.50 g, 26.8 mmol) was dissolved in DMF (30 ml) and treated with potassium carbonate (7.40 g, 53.5 mmol) and 4-methoxybenzyl chloride (5.45 ml, 40.1 mmol). The mixture was stirred at ambient temperature overnight. The reaction was diluted with water (150 ml) and the solid that crashed out was collected by suction filtration. The solid was washed with water and dried to give diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (9.00 g, 84.0% yield) as a light green solid. MS (M+H)+ 401.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]([F:25])([F:26])[C:12]1[CH:13]=[C:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3,5-bis(trifluoromethyl)phenylboronic acid (1.39 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and the residue partitioned between water and CH2Cl2. The organic layer concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide 1.36 g (79%) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:13]C)[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].O[CH2:16]C(NC(=O)OC(C)(C)C)(C)C>>[NH2:3][C:4]([CH3:13])([CH3:16])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: CC(C)(N)C(O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with tert-butyl 1-hydroxy-2-methylpropan-2-ylcarbamate in the second step (A2).
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCCl>[OH:2][C:3]1[CH:34]=[CH:33][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Oc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(OCCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Two g of the compound of Example 12 was added to a suspension of 4.2 g of aluminum chloride and 2.8 g of ethanethiol in 50 ml of 1,2-dichloroethane at 0° C. The mixture was stirred for 2.5 hours at 0° C., and then worked up by the procedure used in Example 13. Thereby there was obtained 2.0 g of crystalline product. The product was recrystallized from acetone to obtain 1.71 g of the desired product, m.p. 216°-217° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][OH:24].C(P(CCCC)CCCC)CCC.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1O.C([O-])(O)=O.[Na+]>C1COCC1>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[O:24][CH2:23][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[C:2]=1[CH3:1]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1c(CO)oc2cccc(OCCCNCc3cccnc3)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(F)cc2F)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a solution of the compound in Example 11 (65 mg), tributylphosphine (61 mg) and 2,4-difluorophenol (26 mg) in THF (1 ml) was added bispiperidine azodicarboxyl amide (76 mg) in THF (0.5 ml) at −45° C. under argon atmosphere, and the mixture was slowly warmed up to room temperature over 18 hoursi period. The mixture was poured into sat. NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (dichloromethane/methanol) to give a yellow oil (35 mg, 40%). ESIMS: m/z 439 (MH+); 1H-NMR (CDCl3): δ 2.07 (2H, tt, J=6.9 Hz, 5.9 Hz, CH2), 2.27 (3H, s, CH3), 2.89 (2H, t, J=6.9 Hz, NCH2), 3.83 (2H, s, NCH2), 4.13 (2H, t, J=5.9 Hz, OCH2), 5.10 (2H, s, OCH2), 6.59 (1H, d, J=7.9 Hz, Ar—H), 6.71-7.23 (6H, m, 6×Ar—H), 7.66 (1H, dd, J=1.7 Hz, 7.9 Hz, Ar—H), 8.49 (1H, d, J=4.9 Hz, Ar—H), 8.56 (1H, s, Ar—H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:11]2=O.[OH-].[NH4+]>>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[C:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(-c3cccnc3)[nH]c(=O)c2c1
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In a sealed tube, phosphorus oxychloride (11 mL, 120 mmol) was added to 6-methoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (2.70 g, 10.66 mmol). The mixture was refluxed at 120° C. for 12 h. After cooling, the remaining phosphorus oxychloride was removed in vacuo to leave a tan solid. This residue was added to an ice-water mixture (100 mL) with cooling and allowed to stir. The pH of the suspension was adjusted to about pH 9 via dropwise addition of 28% ammonium hydroxide, and stirring was continued for 30 mins. The resulting solid was filtered to give the desired product as a tan solid (2.55 g, 9.39 mmol, 88%). LC-MS m/z=272.0 (M+1) (retention time=2.05) 1H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 8.81-8.64 (m, 2H), 8.09 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.8 Hz, 1H), 7.61 (dd, J=7.9, 4.8 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])=[CH:25][CH:24]=3)[C@@H:14]([CH3:36])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:35])[C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])([CH3:37])[CH3:33])=[CH:27][CH:28]=3)[C@@H:14]([CH3:36])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(=O)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)O)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1-(4-(4-oxopentyl)benzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (40 mg, 0.079 mmol) in THF (2 mL), was added MeMgBr (68 uL, 0.095 mmol, 1.4 M solution in THF) at 0° C. The mixture was stirred at 0° C. for 2 h. After quenching with sat. NH4Cl solution, the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give 16 mg of desired product as a white solid (40% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OS(O)(=O)=O.[CH3:19]O>>[C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)=O)c1O
Yield: 20 %

Procedure:
To a solution of 3-acetyl-2-hydroxybenzoic acid 32 (3 g, 16.7 mmol) in MeOH (50 mL) was added conc. H2SO4 (3.0 mL. The reaction mixture was heated at reflux for 12 h. After concentration en vacuo, the crude residue was diluted with H2O, basified to pH=8 with aq NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give 38 as a white solid (550 mg, 20% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[CH:37][C:38]=1[C:39]#[N:40].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:31])[CH:8]=[CH:7][C:3]=1[C:4]([O:41][C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Cl)c(Cl)c3)cc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc(C#N)c(Cl)c4)c(Cl)c3)cc2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoyl chloride obtained was dissolved in 125 ml of benzene and then added dropwise to a solution of 4.0 g of 3-chloro-4-cyanophenol in 100 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-cold, dilute hydrochloric acid and extracted with diethyl ether. The extract was washed several times with 3N hydrochloric acid, then washed neutral with water, dried and evaporated. The crude 4'-hexyl-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-cyanophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/dichloromethane (1:1). The fractions (8.2 g) which were practically pure according to thin-layer chromatography were recrystallized once from ethyl acetate and once from ethyl acetate and a small amount of hexane; m.p. (C-N) 95° C., cl.p. (N-I) 235° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Br)c1C(F)(F)F
Temperature: 28 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
At 15° C., 9.5 g (0.03 mole) 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was slowly added to 100 mL of fuming nitric acid. The reaction warmed to 28° C. over a period of 20 minutes. The reaction mixture was stirred at 30° C. for 4 hours. The mixture was poured into 500 mL of ice. After stirring for 1 hour, the slurry was extracted 3 times with methylene chloride. The methylene chloride extracts were washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 10% ethyl acetate in hexane as the eluent to give 5.84 g (55%) of 4-bromo-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 45.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][CH2:8][N+:9]([O-:27])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2C=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.7 g (42 mmole) of 8-chloro-1-phenyl-3H-2-benzazepine, 10.7 g (53 mmole) of 85% metachloroperbenzoic acid and 100 ml of methylene chloride was stirred at room temperature or 16 hr. The mixture was washed with cold dilute aqueous sodium hydroxide and brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized with ether to give crude product, mp 130°-131° C. Recrystallization from ether gave tan prisms, mp 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](/[N:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]=O.[C:23]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[CH2:24]1>>[Cl:1][C:2]1[N:3]=[C:4](/[N:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]=[C:24]1[C:23](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:32]
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=O)s2)cc1
Reactant: O=C1CC(=O)c2ccccc21
Product: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.5 g (10.33 mmol) 4-chloro-2-((E)-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-diazenyl)-1,3-thiazole-5-carbaldehyde and 2.33 g (15.50 mmol) 1H-indene-1,3(2H)-dione were dissolved in 90 ml ethanole and stirred under reflux. After 6 hours the mixture was allowed to cool to room temperature. The formed precipitate was filtered, washed with ethanol and dried in vacuum at 40° C. to obtain a dark powder.
Reaction SMILES: [CH3:1][N:2]([N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.C(O)(C)C>[Pd].CO>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9])[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16]1
Reactant: CN(c1ccncc1[N+](=O)[O-])n1cccc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CO
Product: CN(c1ccncc1N)n1cccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a Parr shaker apparatus was placed a mixture prepared from 5.0 g of N-methyl-N-(1H-pyrrol-1-yl)-3-nitro-4-pyridinamine, 310 mg of 10% palladium on carbon, 175 ml of isopropanol and 30 ml of methanol. This was shaken for 18 hours at ambient temperature.
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH3:16])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[C@@H:1]1([NH:12][C:13]([N:15]([CH3:16])[N:17]=[O:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
1-(β-D-mannopyranosyl)-3-methyl-urea (200 mg) was dissolved in a mixture of 1.5 ml of glacial acetic acid and 3.5 ml of water, and the resulting solution was admixed with 99 mg of sodium nitrite. The mixture so obtained was agitated for 3 hours at ambient temperature to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove sodium cation therefrom. The reaction mixture so treated was then concentrated by distillation under reduced pressure at a temperature of less than 30° C to remove the solvent, so that a crystalline product was deposited. This crystalline product was collected by filtration and washed with n-propanol, affording 180 mg of the titled compound. Yield 78%. mp. 103° C (with decomposition). [α]D26 -12.6° (c 0.99, H2O).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:9]1[N:14]=[C:13]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1
Reactant: CC(C)NC(C)C
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(c1nc(Cl)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1)C(C)C
Reaction time: 24 h

Procedure:
26.1 g (258 mmol) of diisopropylamine are added with stirring to a solution of 29.9 g (86 mmol) of the product from Example 17 in 100 ml of toluene. The mixture is heated to reflux and kept at this temperature for 24 hours. After cooling, a solution of 4.1 g of NaOH in 21 ml of water is added. The solid product is filtered off and recrystallized from 25 ml of toluene. A yellowish powder which melts at 179°-184° is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>ClCCCl.CC(O)(C)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1
Reactant: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)O)ccc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
1-Methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylic acid (0.047 g, 0.14 mmol, Example #AN.1), methanesulfonamide (0.039 g, 0.41 mmol) and EDC (0.065 g, 0.34 mmol) were combined in a mixture of DCE (1.31 mL) and t-BuOH (1.31 mL). DMAP (0.050 g, 0.41 mmol) was added and the mixture was stirred at rt for about 16 h. The mixture was purified by flash chromatography (12 g silica gel column, (6:3:1 CHCl3/MeOH/saturated NH4OH)/EtOAc 50-85%) to give 1-methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-N-(methylsulfonyl)-1H-indole-5-carboxamide (0.024 g, 42%): LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z 423 (M+H)+. Syk IC50=A.