Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.O>[C:2]1([C:1]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:10](=[O:11])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccccc1)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c2ccccc2[nH]1

Procedure:
Benzoylacetanilide (150 g) (prepared according to the method of Brown et al., J. Am. Chem. Soc., 79, 2919, (1957)) in concentrated sulphuric acid (76%) (130 cc) is heated for 4 hours at 100° C. The reaction mixture is slowly poured with stirring in distilled water (3150 cc). The precipitate obtained is filtered, washed with water and then with acetone, and dried at 40° C. under reduced pressure. The residue obtained is recrystallised in ethanol. (white solid; m.p.=268°-269° C.)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C#N)c1
Yield: 24.9 %

Procedure:
If the procedure described in Preparation LXXVIII is followed starting from 0.5 g (1.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10-3 mol) of 3-hydroxybenzonitrile and 170 mg (2.1.10-3 mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 ml of acetonitrile, 138 mg (yield: 25%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:19]([CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: CC(=O)S[C@@H]1CO[C@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Yield: 87.8 %

Procedure:
The title compound is prepared by the procedure of Example 43 using 0.560 g of product from Example 60 in 2 ml of methylene chloride, 0.569 g of tetrabutylammonium azide in 2 ml of methylene chloride to give 0.321 g of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[O:14]1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)[CH:7]=1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: C1CC2(CCN1)OCCO2
Product: COc1cc(N2CCC3(CC2)OCCO3)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and 1,4-dioxa-8-azaspiro[4.5]decane. m/z 309.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11]([C:37](=[O:39])[NH2:38])=[CH:10][CH:9]=2)[CH2:3]1.CCN(CC)CC.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[C:47]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[C:11]([C:37](=[O:39])[NH2:38])=[CH:10][CH:9]=2)[CH2:3]1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a mixture of (R)-benzyl 4-(4-(6-(3-aminopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate (1.1 g, 2.077 mmol) and Et3N (0.579 mL, 4.15 mmol) in THF (10 mL) was added benzoyl chloride (0.350 g, 2.492 mmol). The reaction mixture was stirred at rt for 30 min., quenched with satd NaHCO3, and extracted twice with CH2Cl2. The combined organic layers were concentrated and the residue was triturated with CH2Cl2 to obtain 1.15 g of (R)-benzyl 4-(4-(6-(3-benzamidopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate as an off-white solid. LCMS: (M+H)+=634.40. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (1H, s), 8.30 (1H, d, J=8.06 Hz), 7.67-7.96 (3H, m), 7.30-7.37 (3H, m), 7.19-7.30 (7H, m), 6.59 (2H, d, J=9.15 Hz), 6.06 (1H, d, J=9.15 Hz), 4.98 (2H, s), 4.34-4.58 (1H, m), 3.93-4.10 (1H, m), 3.75-3.91 (1H, m), 3.08-3.36 (8H, m), 2.52-2.90 (1H, m), 1.86 (1H, s), 1.59-1.75 (1H, m), 1.47-1.58 (1H, m), 1.40 (1H, d, J=2.93 Hz).
Reaction SMILES: C1(C=[N:8][CH:9]2[C:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)C=CC=CC=1.O.NN>C(O)C>[NH2:8][CH:9]1[C:17]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C1Nc2ccccc2C12Cc1ccccc1C2N=Cc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1c2ccccc2CC12C(=O)Nc1ccccc12
Temperature: 25 °C

Procedure:
To a slurry consisting of 1,3-dihydro-1-[(phenylmethylene)amino]spiro[2H-indene-2,3'-[3H]indole]-2'(1'H)one (13.8 g), and absolute ethanol (300 ml) was added hydrazine hydrate (13.9 ml). The resulting mixture was heated at reflux for 3 hours, cooled to room temperature and the resulting precipitate removed by filtration. The mother liquor was concentrated and the resulting oil solidified upon addition of ethyl acetate-hexane. The resulting solid was recovered by filtration. Additional product was obtained from the mother liquor as above. Recrystallization from ethyl acetate afforded 1-amino- 1,3-dihydrospiro[2H-indene-2,3'-[3H]indol]-2'(1'H)one, m.p. 195°-197° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[C:19]([NH:23][S:24]([C:27]1[S:28][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:31]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:19]([NH:23][S:24]([C:27]1[S:28][C:29]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][N:10]=3)[C:5]([Cl:18])=[CH:4][N:3]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CC(C)(C)c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C(C)(C)C)[nH]n3)n2)s1
Temperature: 95 °C
Yield: 23.3 %

Procedure:
A mixture of 2-bromo-N-(5-tert-butyl-1H-pyrazol-3-yl)-5-chloropyrimidin-4-amine (250 mg, 0.87 mmol), PdCl2(dppf)CH2Cl2 (106 mg, 0.13 mmol, 0.15 eq), N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (336 mg, 1.13 mmol, 1.3 eq), Na2CO3 (323 mg, 3.18 mmol, 3.5 equiv.) in dioxane was heated at 95° C. for 2 h under N. The reaction mixture was cooled to room temperature, and extracted with THF. The combined layers were concentrated and purified by silica gel chromatography (EA/PE 1:2) to afford N-tert-butyl-5-(4-(5-tert-butyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophene-2-sulfonamide (95 mg, 21%). LC-MS (m/z)=427 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N=Nc2ccc(OCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
1.95 g (0.006 mol) of ethyl 2-[4(4-cyanophenylazo)phenoxy]-ethanoate was dissolved in a mixture of 100 mL of dimethylformamide and 20 mL of water in a 250 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 1.3 g (0.033 mol) of NaOH was added. Stirring and heating were continued for ½ h. After cooling on an ice-water bath 6 mL of 6 N HCl was added. The precipitated crude product was recovered by filtration. The precipitate was suspended in a mixture of 10 mL of ethanol and 3 mL of water for 15 min. and filtered. The filtercake was washed with 10 mL of cold ethanol. After drying under vacuum overnight 1.17 g (yield 69%) of 2-[4-(4-cyanophenylazo)phenoxy]-ethanoic acid was obtained
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.[H-].[Na+].[P:29](Cl)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH:26][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Nc1c(-c2cc(Cl)cc(C(F)(F)F)c2)c(C(F)(F)F)nn1-c1ncccn1)OCC
Reaction time: 12 h
Yield: 23 %

Procedure:
To a mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.766 g, 2.00 mmol) and NaH (0.054 g, 2.20 mmol) in tetrahydrofuran at 0° C. is added diethyl chlorophosphate (0.414 g, 2.40 mmol). The mixture is allowed to reach room temperature (20-25° C.) and further stirred for 12 hours. The reaction was diluted with water and extracted with ethyl acetate; the organic layer separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (125 mg; 12%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Product: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1

Procedure:
The product from Example 10D and pyrrolidine were processed as described in Example 10E to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]([O:10][CH3:11])([O:8][CH3:9])[C:5]=1[O:6]C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C:2]1[C:5](=[O:6])[C:4]([O:10][CH3:11])([O:8][CH3:9])[C:3]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: COC1=C(C)C(=O)C1(OC)OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cccc(C2=C(C)C(=O)C2(OC)OC)c1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
A THF solution (12 mL) of known 2-methyl-3,4,4-tris(methyloxy)-2-cyclobuten-1-one (0.500 g, 2.91 mmol, 1 equiv) was cooled to ca. −78° C. 3-Methoxyphenyl magnesium bromide (4.36 mL, 1.0 M, 1.5 equiv) was added. After 5 min, TFAA (0.657 mL, 4.66 mmol, 1.6 equiv) was added. The reaction was quenched with saturated NaHCO3 (5 mL) after an additional 5 min. Extraction with EtOAc was followed by drying (Na2SO4), filtration, and concentration to a bright yellow oil. Radial chromatography (SiO2, 4 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (245) as a bright yellow oil (0.540 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.44-7.33 (m, 3H), 7.15-7.09 (m, 1H), 3.89 (s, 3H), 3.54 (s, 6H), 2.13 (s, 3H). TLC (60:40; hexanes/EtOAc): Rf=0.45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br.O>CO>[Br:13][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrBr
Solvent: CO
Solvent: O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 500 g of 3,4-dimethoxybenzaldehyde in 2.5 L of methanol was added dropwise 529 g of bromine at room temperature (under cooling, if necessary) over 1 hour, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added dropwise 2.5 L of water, and the crystals were precipitated. To the crystal suspension was added 20% aqueous sodium hydroxide solution at room temperature to adjust it to pH about 9 to 10, and then cooled. The precipitated crystals were collected by filtration and washed with water, and then dried at 50° C. for 12 hours to give 718.78 g of 6-bromo-3,4-dimethoxybenzaldehyde (yield: 98%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[C:9]=1[NH:20][C:21](=O)[CH3:22].O>C(O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:17](=[O:18])[C:16]3[C:11]([C:10](=[O:19])[C:9]=2[N:20]=[C:21]1[CH3:22])=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: COCCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCn1c(C)nc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.7 %

Procedure:
2 M Sodium hydroxide aqueous solution (0.9 ml) was added to a solution of N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.5 g) in ethanol (10 ml) and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was collected by filtration and washed with ethanol to give 1-(2-methoxyethyl)-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazole (0.58 g) as a light orange powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(C=C(C)C)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(C)c(CC(C)C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.7 %

Procedure:
To a solution of 4-methyl-5-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (1.33 g, 6.06 mmol) in THF (10 mL) and ethanol (10 mL), Pd/C (300 mg, 10% Pd) is carefully added. The slurry is stirred at rt for 15 h under 2 bar of H2. The catalyst is filtered off and the filtrate is concentrated and dried to give 5-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (1.27 g) as a colourless oil; LC-MS: tR=0.86 min, [M+1]+=222.10.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C:28]4[CH2:29][C:30]([CH3:37])([CH3:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH:33]=4)[CH:13]=[C:14]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:28]4[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]4)[CH:13]=[C:14]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.119 mmol) in EtOH (10 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-5 hr. On completion of reaction, reaction mass filter it through celite bed, then filtrate was concentrated under reduce pressure. The residue was washed with acetonitrile followed by ether to provide the desired product (75% yield). LCMS:505.30 (M+1)+; HPLC: 99.69% (@ 254 nm) (Rt;5.517); 1H NMR (CD3OD-d6, 400 MHz) δ 11.54 (bs, 1H), 8.76 (t, 1H, J=4.8 Hz), 8.26 (s, 1H), 7.51 (s, 1H), 5.89 (s, 1H), 5.38-5.36 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 2.21 (s, 3H), 2.12 (s, 3H), 2.12 (m, 3H), 2.01-1.98 (m, 2H), 1.96-1.89 (m, 2H), 1.75-1.71 (m, 4H), 1.52 (m, 2H), 1.27 (s, 6H), 1.12 (s, 6H).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccccc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: Cc1ccccc1C
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2)s1
Yield: 67.3 %

Procedure:
A 1-liter stainless steel stirred autoclave was charged with 33 g. (0.0946 mole) of 1,2-diphenyl-4-o-chlorophenylbutane-1,4-dione, 100 ml. of xylene, 20 g of phosphorus pentasulfide and 125 g of hydrogen sulfide. The autoclave was then heated at 160°-187° C. for three hours. The autoclave was cooled and vented. The residue was washed with ethanol and filtered off to give 17 g (51.8%) of crude product, m.p. 103°-107° C. Recrystallization from 20 ml of dioxane and 40 ml of ethanol gave 10.5 g (32%) of pure product, m.p. 117°-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]#[C:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([CH3:27])[N:19]=1>>[CH3:27][C:20]1[N:19]=[C:18]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1cccc(CC#CC2CCNCC2)n1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Product: Cc1cccc(C#CCC2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1

Procedure:
The title compound was prepared following the procedure described for the Compound of Example 31, using 2-chloro-3-nitro-6-picoline instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether/EtOAc 7:3, affording the title product as a yellow oil.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:16]>>[NH2:16][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CC(c2ccc(F)nc2)CC1=O
Reactant: [NH4+]
Agent: [OH-]
Product: CN1CC(c2ccc(N)nc2)CC1=O
Temperature: 140 °C

Procedure:
To 4-(6-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one(100 mg, 0.515 mmol) was added ammonium hydroxide (2 mL, 15.41 mmol). The reaction mixture was heated in heating block at 140° C. for 48h. LC-MS shows 80% product. Reaction mixture was evaporated. Azeotrope with Toluene (x=3) and proceed for next step. LCMS (m/z): 192.2 (MH+), 0.256 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][NH2:16].Cl>CC(O)C>[OH:9][C:8]1[C:7]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[C:11]([OH:10])=[N:16][N:15]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NN
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2c(O)nnc(O)c2c1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
A mixture of 4-nitrophthalic anhydride (10.0 g, 51.78 mmol) and IPA (180 mL) was stirred by a mechanical stirrer. Anhydrous hydrazine (2.77 mL, 56.96 mmol) was added dropwise and the reaction heated to 85° C. for 5 h. The reaction was cooled then acidified to pH 3 with conc. HCl. The solids were filtered and washed with IPA to afford the desired compound (7.76 g, 72%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.00 g of 3-hydroxymyristic acid in 50 ml of DMF were added at room temperature 2.85 ml of triethylamine and 2.43 ml of benzyl bromide. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, ethyl acetate and water were added to the residue, and the organic layer was separated, washed twice with water and dried over anhydrous sodium sulfate. After the solvent was removed in vacuo, the crude product was purified by a silica gel column chromatography to afford 3.69 g of benzyl 3-hydroxymyristate (Intermediate 2).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1.CO>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(CCc3ccccc3)ccc12
Yield: 60 %

Procedure:
A solution of 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one O-tert-butyl oxime (60 mg, 0.13 mmol) (prepared using the procedure described in example 20 starting from example 2B) and Lindlar's catalyst (22.5 mg) in tetrahydrofuran (9.2 ml) and methanol (1.8 ml) was stirred at room temperature under 1 atmosphere of hydrogen for 18 h. The catalyst was removed by filtration and the solvent evaporated under reduce pressure to yield the title compound in 60% yield.