Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Yield: 90.7 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (172 mg, 0.596 mmol) in dry DMF (3 mL) under an atmosphere of dry nitrogen was added 2-(bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) and potassium carbonate (165 mg, 1.19 mmol) with stirring. The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified using preparative chromatography on silica, eluting with hexane/ethyl acetate (3:1) to give 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (213 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([O:43][CH2:44][O:45][CH3:46])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[N:33][C:32]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[N:40][C:31]1=2)(C(C)(C)C)(C)C>O1CCCC1.ClCCl>[OH:26][CH2:27][CH:28]([O:43][CH2:44][O:45][CH3:46])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[N:33][C:32]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[N:40][C:31]1=2
Reactant: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOC(CO)Cn1c(=O)cnc2ccc(OC)nc21
Reaction time: 15 h
Yield: 87 %

Procedure:
A solution of tetrabutyl ammonium fluoride in 1M tetrahydrofuran (3.22 ml, 3.22 mmol) was added to a solution of 4-[3-{[tert-Butyl(dimethyl)silyl]oxy}-2-(methoxymethoxy)propyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.02 g, 2.48 mmol) in tetrahydrofuran (15 ml) under cooling on ice and the mixture was stirred for 15 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium bicarbonate water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 637 mg (87%) of the title compound in the form of an orange oily product.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[C:35]([F:43])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[C:39]([F:42])([F:41])[F:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Compound 26 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.20 (s, 1H), 9.01 (dd, J=4.7, 1.7 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.45-8.34 (m, 1H), 8.25-8.10 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.61 (d, J=12.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 5.53 (t, J=6.5 Hz, 1H), 3.21-3.08 (m, 1H), 3.05-2.88 (m, 1H), 2.30 (s, 3H), 2.01 (s, 1H).
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[NH:3][CH2:2]1.[P:10](=[O:21])([N:18]=[C:19]=[O:20])([S:14][CH2:15][CH2:16][CH3:17])[O:11][CH2:12][CH3:13]>CCOCC>[CH2:12]([O:11][P:10]([NH:18][C:19]([N:3]1[CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])([S:14][CH2:15][CH2:16][CH3:17])=[O:21])[CH3:13]
Reactant: COC(=O)C1CSCN1
Reactant: CCCSP(=O)(N=C=O)OCC
Solvent: CCOCC
Product: CCCSP(=O)(NC(=O)N1CSCC1C(=O)OC)OCC

Procedure:
To a solution of 2.2 g of methyl thiazolidine-4-carboxylate in 50 ml of ether was added dropwise with stirring at ambient temperature 3.14 g of O-ethyl S-propyl phosphoroisocyanatidothioate. The mixture was allowed to react overnight at ambient temperature and was then concentrated by evaporation under reduced pressure to obtain 5.2 (97 percent of theory) of the title compound as a colorless oil having a refractive index at 25° C. of 1.5312.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([CH3:16])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[O:7][N:6]=[C:5]([CH3:16])[C:4]=4[CH2:1][CH:2]=[CH2:3])=[CH:10][CH:11]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CCc1c(C)noc1-c1ccc(Br)cc1
Product: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 4-allyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([O:6]C)=[O:5].[BH4-].[Na+].Cl>CO>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCC(=O)CC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCC(O)CC(=O)O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of methyl 3-oxododecanoate in methanol was added sodium borohydride (83 mg). After stirring for 20 minutes, 1N-hydrochloric acid (2.2 ml) was added. After concentration, the residue was dissolved in ethyl acetate (30 ml) and 0.1 N-hydrochloric acid (20 ml). The organic phase was washed with water (20 ml), saturated aqueous sodium bicarbonate (20 ml), and brine (20 ml), dried, and concentrated. The residue was dissolved in methanol (3 ml), and to this solution was added 1N-sodium hydroxide (2.4 ml). The mixture was refluxed for an hour, and diluted with water (30 ml). This aqueous solution was washed with dichloromethane (20 ml), acidified with 1N-hydrochloric acid (2.6 ml), and extracted with ethyl acetate (30 ml). This organic phase was washed with brine (20 ml), dried, and concentrated. The residue was recrystallized from a mixture of ethyl acetate (1 ml) and n-hexane (3 ml) to give 3-hydroxydodecanoic acid (0.27 g).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:19]O>>[C:1]([O:18][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CO
Product: CCCCCCCCCCCCCCCC(=O)OC

Procedure:
The ZrO2 materials functionalized with sulfonic acid and phenolsulfonic acid groups were used as the solid acid catalysts in the liquid phase esterifications of palmitic acid (PA) with MeOH. The reactions were carried out at the reflux temperature of MeOH. Methyl palmitate was obtained as the only product in the present reaction condition based on the GC and GC-MS analyses. The esterification of palmitic acid (PA) with MeOH was carried out at 60° C. in order to totally dissolve PA in the reaction mixture.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49]([OH:55])(=O)[CH2:50][CH:51]([CH3:53])[CH3:52]>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:49](=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)CC(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.3 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using isovaleric acid as the acylating agent. LCMS: m/e 726.8 (M+H)+, 3.71 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 3.77-3.55 (m, 4H), 3.09-3.02 (m, 1H), 2.91 (br. s., 1H), 2.86-2.72 (m, 2H), 2.71-2.60 (m, 3H), 2.59-2.52 (m, 1H), 2.52-2.43 (m, 1H), 2.31 (d, J=7.3 Hz, 2H), 2.21-1.80 (m, 7H), 1.76 (s, 3H), 1.73-1.08 (m, 16H), 1.22 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.99 (d, J=6.4 Hz, 6H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: O.NN.[CH:4]1([C:7]2[CH:8]=[CH:9][C:10](/[C:15](/[C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)=[CH:16]/[CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[N:11][C:12]=2[O:13][CH3:14])[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)C>[CH:4]1([C:7]2[CH:8]=[CH:9][C:10](/[C:15](/[C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)=[CH:16]/[CH2:17][CH2:18][NH2:19])=[N:11][C:12]=2[O:13][CH3:14])[CH2:6][CH2:5]1
Reactant: COc1nc(/C(=C/CCN2C(=O)c3ccccc3C2=O)c2ccc(SC)cc2)ccc1C1CC1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1nc(/C(=C/CCN)c2ccc(SC)cc2)ccc1C1CC1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (1 mL) was added to a solution of 2-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}-1H-isoindole-1,3(2H)-dione (320 mg) in ethanol (4 mL), and the mixture was stirred at 95° C. for one hour. The reaction solution was poured into a 3 M sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give (3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-amine as a colorless amorphous (225 mg, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].I[CH2:24][CH3:25]>>[CH2:24]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21])[CH3:25]
Reactant: CCI
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2c1ccccc1
Product: CCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 61, 992 mg, 3.08 nmol) and 1-iodoethane (1.67 mL, 15.4 mmol) were reacted to produce the title compound as a white solid
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl:13][C:11]1[N:12]=[C:8]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(Oc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
42 g (0.036 mol) of anhydrous potassium carbonate are added to a solution of 72.0 g (0.36 mol) of 2,4-dichloro-5-nitrothiazole in 300 ml of acetonitrile. A solution of 28.2 g (0.3 mol) of phenol in 300 ml of acetonitrile is then added dropwise at 15° C. to 20° C. in the course of about 1.5 hours and the mixture is subsequently stirred at the same temperature for a further 0.5 hour. It is then heated at the reflux temperature for 15 minutes, cooled to room temperature and then stirred into 3 liters of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 500 ml of petroleum ether at about 20° C., filtered off, washed with petroleum ether and dried. 75.4 g (98.0% of theory) of 4-chloro-5-nitro-2-phenoxythiazole are thus obtained. Melting point 96° C. (from petroleum ether).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([CH:43]=[O:44])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:42]=[N:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
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: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.1 g, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (0.064 g, 0.274 mmol) and Pd(PPh3)4 (0.013 g, 0.011 mmol) in 1,4-dioxane (2 mL) was purged with argon for 10 min. A solution of 2M Na2CO3 (0.087 g, 0.820 mmol) was then added to it and argon again purged for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1H-indazole-4-carboxamide (0.1 g, 94.3%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 88 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.070 g, 0.160 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.030 g, 0.240 mmol), the title compound (0.074 g, 87%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:22]
Reactant: Nc1cccc2ncccc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2ncccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
To a solution of 5-aminoquinoline (1.0 g, 6.9 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (40 mL) was added trichloroacetyl chloride (1.4 g, 7.7 mmol) at 0° C., and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated, and to the residue was added ethyl acetate, and the resulting mixture was extracted three times with 1 N hydrochloric acid. The aqueous layers were combined and neutralized with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (1.9 g, yield 94%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Pd]>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)C1CCCC(=O)C1
Reaction time: 21 h
Yield: 75.2 %

Procedure:
300 g (2 mol) of 3-tert.butylphenol are hydrogenated in the presence of 3 g of palladium-on-active charcoal 5% and 3 g of anhydrous sodium carbonate at 0.15-0.3 bar hydrogen over-pressure and 115° C. In an autoclave for 21 hours. The mixture is then filtered over Celite. The Celite is washed with ether and the solution is evaporated. In this manner there are obtained 310.8 g of crude product, namely 1.5% trans-tert.butylcyclohexanol, 3.5% cis-tert.butylcyclohexanol, 86% 3-tert.butylcyclohexanone and 7.6% 3-tert.butylphenol. This product can be purified by distillation. There are obtained 232 g (75%) of 3-tert.butylcyclohexanone, b.p. 75°-76° C., 2 mbar (olfactorily acceptable, purity 94%) in addition to 11.3 g (3.6%) of impure material (purity 92%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:18])[CH2:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:4][CH:5]([CH3:18])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC(C)CCC(=O)O

Procedure:
87.5 g (0.35 mol) of benzyl 4-acetoxypentanoate are dissolved in 900 ml of abs. ethanol and the solution is hydrogenated at room temperature under normal pressure with the addition of 5 g of 10% Pd/C as catalyst. Upon cessation of hydrogenation, the catalyst is removed by filtration and the filtrate is concentrated by evaporation. Distillation of the residue gives 4-acetoxypentanoic acid as a colourless oil of b.p. 110°-112° C./2.10-2 torr.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:19](=[C:20]([F:23])[C:21]=1[F:22])[N:18]1[CH2:24][C@@H:25]([CH3:29])[O:26][C@@H:27]([CH3:28])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2)(=O)[CH3:2].Cl.[NH2:31][OH:32]>CO>[F:22][C:21]1[C:20]([F:23])=[C:19]2[C:6]([CH2:7][C:8]3([C@H:17]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:18]42)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]3=[O:14])=[CH:5][C:4]=1/[C:1](=[N:31]/[OH:32])/[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Agent: Cl
Solvent: CO
Product: C/C(=N\O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Temperature: 85 °C

Procedure:
To a solution of (2R,4S,4aS)-rel-8-acetyl-9,10-difluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 12, 250 mg, 0.63 mmol) in MeOH, was added hydroxylamine hydrochloride (88 mg, 1.3 mmol) and the mixture heated to 85° C. for 12 hours. After cooling to room temperature, solvent was removed, and the residue was purified via normal phase HPLC (95:5: Hexane:IPA) to give the title compound as a racemic mixture in the form of a pale yellow solid. Yield: 50 mg (20%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[C:25]12[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:30]C(=O)O[C:26]2=[O:27]>>[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=1[C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([O:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: Nc1ccccc1C(=O)NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 66 %

Procedure:
Using the method similar to that in Reference Example 1 and using 1-(3-aminopropyl)-4-diphenylmethoxypiperidine instead of 4-methoxybenzylamine and starting from isatoic anhydride (2.87 g), the title compound (6.19 g, 66%) was synthesized. This product was used in the next reaction without further purification.