Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:27]2[NH:28][C:29](=[O:34])[C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:14]\[CH2:15][N:16]2[C:24](=O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:27]2[NH:28][C:29](=[O:34])[C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:14]\[CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(/C(=C\CN2C(=O)c3ccccc3C2=O)c2ccc(Cl)c(=O)[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(/C(=C\CN2Cc3ccccc3C2=O)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
Sodium borohydride (52 mg) was added to a suspension of 2-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-oxo-1,6-dihydropyridin-2-yl)prop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (50 mg) in methanol (2 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. A solution of the resulting residue in trifluoroacetic acid (2 mL) was stirred under ice-cooling, during which sodium borohydride (50 mg) was added thereto. The mixture was stirred at room temperature for one hour. The reaction solution was ice-cooled, adjusted to a pH of 12 or more with a 1 M sodium hydroxide solution and then extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) and then powdered with ethyl acetate. The precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (11 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)ccc2C)cc1
Temperature: 100 °C

Procedure:
A mixture of N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide (0.069 g) and morpholine (3 ml) was stirred and heated to 100° C. for 6 days. The mixture was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed in turn with water and diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.033 g); NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 2.2 (s, 3H), 2.46-2.49 (m, 4H), 3.20-3.24 (m, 4H), 3.58 (s, 2H), 3.72-3.75 (m, 4H), 6.95 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.3 (s, 1H), 7.45 (s, 2H), 7.58 (d, 1H), 7.78 (s, 1H), 7.91 (d, 2H), 9.82 (s, 1H), 10.15 (s, 1H); Mass Spectrum: M+H+519.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCOc1ccc(CO)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-hydroxymethylphenoxy)propionic acid (4.00 g, 20.40 mmol) in THF (20 mL) is added a solution of LiAlH4 (10 mL, 1 M in THF). The mixture becomes warm and is diluted with THF (20 mL) before it is refluxed. After 1 and 2 h two further portions of LiAlH4 (2×10 mL, 1 M in THF) are added. The mixture is refluxed overnight, cooled to rt and carefully quenched by the addition of water (1.2 g), 15% aq. NaOH (1.2 g) and water (3.2 g). The white precipitate is filtered off, and the filtrate is evaporated and dried to give 3-(4-hydroxymethyl-phenoxy)-propan-1-ol. 1H NMR (D6-DMSO): δ 7.21-7.15 (m, 2H), 6.86-6.81 (m, 2H), 5.00 (t, J=5.9 Hz, 1H), 4.51 (t, J=5.3 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 3.57-3.50 (m, 2H), 1.83 (p, J 06.4 Hz, 2H).
Reaction SMILES: P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([O:14][CH2:15][CH:15]([O:14][C:11](=[O:13])[CH3:12])[CH3:16])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClP(Cl)Cl
Product: CC(=O)OCC(C)OC(C)=O

Procedure:
2 g phosphorus trichloride and 2 g phosphorus pentachloride were dissolved with 2 g cupric chloride in 500 ml glacial acetic acid and 50 ml acetic anhydride and then further treated a described in Example 4. 5.2 g propylene glycol diacetate were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([OH:22])(=O)=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24].O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([Cl:24])(=[O:22])=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)O)cc2cc1OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Temperature: 80 °C
Yield: 15.6 %

Procedure:
To a suspension of the crude 2,3-diacetoxy-6-naphthalenesulphonic acid (973 mg) in CCl4 (3 ml) was added phosphorus pentachloride (750 mg). The mixture was heated at 80° C. for 20 minutes, cooled, and water added cautiously. The CCl4 was separated from the aqueous layer and the latter was extracted with CH2Cl2. The organic extracts were combined, washed with water and dried over magnesium sulphate. Evaporation of the solvent yielded 2,3-diacetoxy-6-naphthalenesulphonyl chloride (160 mg, yield: 15%). NMR in CDCl3 : 2.37(s,6H); 7.82(s,1H); 7.87(s,1H); 7.99(s,1H); 8.01(s,1H); 8.54(br.s,1H).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][S:27][CH3:28])[CH:20]([NH:29][C:30](=[O:60])[C:31](=[N:57][O:58][CH3:59])[C:32]1[N:33]=[C:34]([NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:35][CH:36]=1)[C:19]2=[O:61])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.O>C(O)=O>[NH2:37][C:34]1[S:35][CH:36]=[C:32]([C:31](=[N:57][O:58][CH3:59])[C:30]([NH:29][CH:20]2[C:19](=[O:61])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][S:27][CH3:28])=[C:17]3[C:15]([OH:16])=[O:14])=[O:60])[N:33]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSC)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSC)CSC12)c1csc(N)n1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
2-Benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-3-(2-methylthiovinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, mixture of E- and Z-forms) (1.26 g) is dissolved in formic acid (35 cc), water (13 cc) is added and the mixture is heated at 50° C. for 15 minutes. It is then allowed to cool, filtered and concentrated to dryness under reduced pressure (20 mm Hg at 20° C.). The residue is triturated in diethyl ether (20 cc), filtered off, washed with ether (20 cc) and dried. 7-[2-(2-Aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-3-(2-methylthio-vinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, mixture of E- and Z-forms) (0.63 g) is obtained as a solvate with formic acid, in the form of a cream-coloured powder.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC#N.C(=O)=O.N1C=CC=CC=1.[CH3:24][NH:25][C:26](=[O:28])[CH3:27]>C(Cl)Cl>[C:1]([N:25]([CH3:24])[C:26](=[O:28])[CH3:27])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC(C)=O
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N(C)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dry, 3-necked, round-bottomed flask equipped with a mechanical stirrer under an inert atmosphere is charged with 41.6 g (0.25 mol, ) of cinnamoyl chloride (available from Aldrich Chemical Company, Inc. of Milwaukee, Wis.) and 150 mL of CH2Cl2 (available from Aldrich Chemical Company). The stirred, homogeneous solution is cooled to −40° C. (CH3CN/CO2 bath), and 22.0 mL (0.275 mol) of pyridine (available from Aldrich Chemical Company) is added slowly (keeping solution temperature below −30° C.) in one portion. The reaction mixture is stirred for 20 min at which point a precipitate is observed. To the stirred heterogeneous solution is added 19.0 mL (0.25 mol) of N-methyl acetamide (available from Aldrich Chemical Company) in one portion. The resulting reaction mixture is allowed to warm gradually to room temperature and is stirred overnight. The reaction is diluted with 150 mL of CH2Cl2 and extracted twice with 150 mL of 1 N HCl, twice with 0.1 N aqueous NaOH, and twice with water. The organic layer is dried over Na2SO4, and concentrated by rotory evaporation to give the desired N-cinnamoyl-N-methyl acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][Si](C)(C)C)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(C#C[Si](C)(C)C)c2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc2oc(C(=O)OCC)c(C)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
To the product of Example 33, Step 1, 3-methyl-4-trimethylsilanylethynyl-benzofuran-2-carboxylic acid ethyl ester (1.5 g, 4.99 mmol, 1 eq), in THF (10 mL) under argon, was added tetrabutylammonium fluoride (1.0 M in THF, 6 mL, 5.99 mmol, 1.2 eq.) and the reaction was stirred at ambient temperature for 45 minutes. After work-up and flash column chromatography, 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 35% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.8 (s, 3 H) 4.4 (m, J=7.1, 7.1, 7.1 Hz, 2 H) 4.6 (s, 1 H) 7.5 (m, 2 H) 7.7 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[CH3:14]>C(O)(=O)C>[CH3:14][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[NH2:11]
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(N)c1C
Temperature: 25 °C

Procedure:
1,2-Dimethyl-3,5-dinitrobenzene (2.5 g, prepared as described in the above scheme) was dissolved in glacial acetic acid (25 mL, from Mallinckrodt) under N2 and heated to reflux. The heat source was removed and iron (2.13 g) was added all at once. After the initial vigorous reaction, the mixture was heated at reflux for 10 min and then cooled to room temperature. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and refiltered through a celite pad and then washed with saturated sodium bicarbonate solution and half-saturated sodium chloride solution. After drying over magnesium sulfate and evaporation of the solvent, 2,3-dimethyl-5-nitro-phenylamine (1.41 g) was obtained.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:10]=1.O>C1COCC1>[Cl:15][C:13]1[N:14]=[C:9]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])[N:10]=[C:11]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: CC(C)CS
Reactant: CC(C)CCOc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCOc1cc(Cl)nc(SCC(C)C)n1
Temperature: 20 °C
Yield: 108.3 %

Procedure:
A solution of 6.7 ml (55.3 mmol) of isobutyl mercaptan in 40 ml of THF is added dropwise to a suspension of 2.2 g of NaH in 90 ml of THF. During this addition, the temperature is prevented from rising above 50° C. by cooling. The solution is cooled to 20° C. and added to a solution of 13.0 g of 2,4-dichloro-6-(3-methylbut-1-oxy)pyrimidine in 80 ml of THF at -10° C. When the temperature has slowly risen to 25° C., the reaction mixture is poured into 200 ml of water. Extraction three times with toluene, drying of the combined organic phases using MgSO4 and evaporation of the solvent give 17.3 g of a mixture. Separation on SiO2 (petroleum ether 80°-110° C.) gives 11.5 g (71.9% of theory) of the title product.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:38][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:22]1[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3cccc(F)c3)cc12

Procedure:
6-[3-(3-Fluoro-phenoxy)-propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 46% overall yield using the method described in example 161, starting from 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 101A) and 3-fluorophenol.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[OH:22][C:23]1C=CC(C#N)=C(OC)C=1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: COc1cc(O)ccc1C#N
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (2.46 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methoxy-benzonitrile and L-α,β-isopropyliden glycerol; LC-MS: tR=0.62 min, [M+H]+=296.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: CC(C)(CO)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(CO)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 96.9 %

Procedure:
5-Chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzaldehyde (2.4 g, 10 mmol) and 6-chloro-1,3-dihydro-indol-2-one (1.7 g, 10 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (0.8 g, 11.2 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. Then the precipitate was collected by filtration to give title compound as yellow solid (Yield: 3.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Then, ethyl 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (17.7 g) and sodium hydroxide (3.5 g) were added to a mixed solvent of ethanol (80 ml)-water (80 ml), and the mixture was stirred at a refluxing temperature for 2 h. After the reaction, ethanol was evaporated and dilute hydrochloric acid was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (12.3 g), melting point: 165–166° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)[CH:2]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cccnc2)n[nH]1

Procedure:
The title compound was prepared using the method of Example 54 but starting from 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (181 mg; 0.96 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (250 mg; 0.96 mmol). The product precipitated out from DCM during workup and after filtration and drying 110 mg (27%) of pure title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (s, 3H), 4.20-4.60 (m, 3H), 7.05-7.36 (m, 1H), 7.40-7.65 (m, 1H), 7.80-8.60 (m, 7H), 8.85-9.07 (m, 1H), 13.76 (s, 1H).
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:30])[C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:30][N:18]([CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1)[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]
Reactant: CN(C(=O)c1ccc2[nH]ncc2c1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C(=O)c1ccc2[nH]ncc2c1)C1CCNCC1
Yield: 76.5 %

Procedure:
Ammonium formate (400 mg) and 10%-Pd/C (80 mg) were added to a solution of the N-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide (435.1 mg, 1.25 mmol) obtained in Example 318 in ethanol (10 ml) at room temperature, and the resulting mixture was refluxed for 2 hours. The reaction mixture was filtered by the use of Celite, and the filtrate was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol (1%-aqueous ammonia)) to obtain N-methyl-N-piperidin-4-yl-1H-indazole-5-carboxamide (247 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](I)=[N:21][N:22](C3CCCCO3)[C:16]=2[CH2:15]1)=[O:13].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[NH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)nn(C3CCCCO3)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(n[nH]c2-c2cncc(F)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (90 mg, 0.167 mmol) in 1,4-dioxane (1 mL) was added 5-fluoropyridine-3-boronic acid (70 mg, 0.50 mmol), potassium phosphate (106 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18 mg, 0.025 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (6 mg, 0.010 mmol). The reaction was stirred at 100° C. overnight under an atmosphere of N2. The reaction was filtered through Celite© and the Celite© was washed with EtOAc. The solvent was concentrated and the residue was purified by HPLC (Agilent prep system, Waters XBridge, C18, 5 μm, 30×100 mm column, 5-99% MeOH/20 mM NH4OH over 18 min at 30 mL/min) followed by THP deprotection as described in Example 94 to provide the desired product (30 mg, 42%). MS (ESI) mass calcd. C19H13ClF4N4O, 424.1. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.73-8.64 (d, J=6.1 Hz, 1H), 8.48-8.39 (m, 1H), 7.83-7.74 (m, 1H), 7.72-7.60 (m, 1H), 7.56-7.44 (m, 2H), 5.15 (d, J=16.6 Hz, 0.7H), 4.88 (d, J=16.6 Hz, 0.7H), 4.50 (d, J=15.9 Hz, 0.3H), 4.39 (d, J=15.9 Hz, 0.3H), 4.25 (dt, J=12.8, 5.5 Hz, 0.3H), 4.04-3.95 (m, 0.3H), 3.54 (t, J=5.7 Hz, 1.4H), 2.99 (t, J=5.7 Hz, 0.7H), 2.92-2.73 (m, 1.3H).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].C[Si](C)(C)[N:7]([Si](C)(C)C)[C:8](=[O:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>>[S:1](=[N:7][C:8](=[O:31])[C:9]([F:29])([F:30])[C:10]([F:27])([F:28])[C:11]([F:25])([F:26])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)N(C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[Si](C)(C)C
Product: O=S=NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Next, thionyl chloride (SOCl2) 2.4 g was added gradually to N,N-bis(trimethylsilyl)perfluorooctaneamide 12 g in the dry nitrogen atmosphere, which was allowed to react for two hours while being stirred. Then this was distilled and thereby sulfinylperfluorooctaneamide was obtained.
Reaction SMILES: C([NH:8][CH2:9][CH:10]([CH3:25])[C:11]([C:13]1[C:14]([CH:22]([CH3:24])[CH3:23])=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12])C1C=CC=CC=1>CO>[NH2:8][CH2:9][CH:10]([CH3:25])[C:11]([C:13]1[C:14]([CH:22]([CH3:24])[CH3:23])=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12]
Reactant: CC(CNCc1ccccc1)C(=O)c1c(C(C)C)nn2ccccc12
Solvent: CO
Product: CC(CN)C(=O)c1c(C(C)C)nn2ccccc12
Reaction time: 2 h
Yield: 16.6 %

Procedure:
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one (0.312 g, 0.93 mmol) was dissolved in MeOH (25 mL). The flask was evacuated and flushed with argon (3 cycles). Pd on C (0.312 g, 10 wt %) was added in small portions. The flask was then evacuated and flushed with hydrogen (4 cycles). The heterogeneous mixture was then vigorously stirred for 2 hours before evacuating and flushing with argon (3 cycles). The mixture was then filtered through Celite, washing with MeOH (50 mL), and concentrated. The dark yellow oil was then subjected to flash column chromatography (100% MeOH) while monitoring the fractions with HPLC and 1H NMR. The first major fractions contained 0.164 g (53% recovered starting material); which was followed by 0.0379 g (16% yield) of 3-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one as a yellow oil.