Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[CH:14]=[CH:13][O:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[OH-].[NH4+].[Cu]I>[O:12]1[CH:13]=[CH:14][C:10]([N:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]2=[O:1])=[CH:11]1
Reactant: Cc1ccnc(O)c1
Reactant: Brc1ccoc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccoc2)c(=O)c1
Temperature: 180 °C
Yield: 61.8 %

Procedure:
A mixture of 2-hydroxy-4-methylpyridine (0.66 g, 6.0 mmol), 3-bromofuran (1.7 g, 12 mmol), copper (I) iodide (0.11 g, 0.60 mmol), and potassium carbonate (0.84 g, 6.0 mmol) in N,N-dimethylformamide (12 mL) were heated at 180° C. for 2 hours in a 300 W microwave reactor. The completed reaction mixture is diluted with 10% aqueous ammonium hydroxide solution and extracted 3× with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-furan-3-yl-4-methyl-1H-pyridin-2-one (0.65 g, 62%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:9])[CH:7]=[CH2:8])=[CH:2]1.[Cl:10]CCl>C(OCC)C.Cl>[Cl:10][CH2:8][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:9]
Reactant: ClCCl
Reactant: C=CC(=O)c1ccsc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CCCl)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
The product from step (b) (1.288 g, 9.3 mmol) was dissolved in a mixture of diethyl ether (30 ml) and dichloromethane (20 ml) and 1M hydrochloric acid in diethyl ether (25 ml) added. The reaction was stirred for 18 h at room temperature. The solvent was removed in vacuo to give the title compound (1.482 g, 91%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:21]([N:18]([CH2:19][CH3:20])[CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:4][OH:3])=[CH:14]2)[CH3:22]
Reactant: CCOC(=O)c1cc2cc(CCCN(CC)CC)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCCc1ccc2[nH]c(CO)cc2c1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
5-(3-Diethylamino-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.2 g, 3.97 mmol) in tetrahydrofuran (48 mL) was added dropwise to the lithium aluminum hydride (602 mg, 15.87 mmol) stirred in tetrahydrofuran (30 mL) under nitrogen. After stirring for 2 hours, the reaction was quenched in water (0.6 mL), 15% sodium hydroxide (0.6 mL) and then water (1.8 mL). The mixture was stirred overnight. The precipitate was filtered off and the filtrate was concentrated to give 680 mg (66%) of [5-(3-diethylamino-propyl)-1H-indol-2-yl]-methanol.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])=O)C.O.[NH3:20]>C(O)C>[C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])(=[O:3])[NH2:20]
Reactant: N
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)ccc21
Solvent: CCO
Solvent: O
Product: NC(=O)CN1C(=O)COc2cc(F)ccc21
Yield: 40 %

Procedure:
A mixture of 4-ethoxycarbonylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.27 g), ethanol (20 ml) and 28% ammonia water (10 g) was mixed at room temperature for 2 hours, and refluxed for 3 hours. After the solvent was concentrated, it was mixed with water, and filtered. Resulting product was washed with water and ethanol in that order, and recrystallized from methylisobutyl ketone to give the desired 4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.45 g). mp. 216.5°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:23][C:20]1[CH:19]=[N:18][C:17]([N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[CH2:7]2)=[N:22][CH:21]=1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: Clc1ncc(Br)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Yield: 87.4 %

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (313 mg, 1.28 mmol), 2-chloro-5-bromopyrimidine (248 mg, 1.28 mmol) and diisopropylethylamine (335 μL, 1.91 mmol) in acetonitrile (2 mL) at 80° C. overnight. Concentrate and chromatograph on SCX-2 column to give the title compound (450 mg, 87%). Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 8.41 (2H, s), 7.62-7.67 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 4.46 (2H, d, J=5.62 Hz), 4.16 (1H, m), 3.99-4.05 (1H, m), 3.79-3.86 (2H, m), 3.65 (1H, m), 2.60 (1H, m), 2.28-2.37 (1H, m), MS (ES): m/z=402 [M+].
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])C=C>C1(C)C=CC=CC=1>[C:11]1([CH3:14])[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH:1]=[CH:17][CH2:16][CH2:15]2)(=[O:6])=[O:7])=[CH:13][CH:12]=1
Reactant: C=CCN(CC=C)S(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C=CCC2)cc1
Reaction time: 4 h
Yield: 8 %

Procedure:
A solution of 257 mg (1.02 mmol) N,N-diallyl 4-methylbenzenesulfonamide (prepared according to S. Varray, R. Lazaro., J. Matinez, F. Lamaty, Organometallics 2003, 22, 2426-2435) and 19 mg (0.03 mmol) [RuCl2(ImH2Mes)((4-chloro-2-trifluoromethyl-8-quinolinyl)methylene)] in 5 ml toluene was stirred at 110° C. To monitor the conversion and selectivity, 0.2-ml samples were taken were after 1 h and 4 h. Each sample was filtered over a silica gel pad, the filtrate was evaporated to dryness and analyzed by GC (column: DB-1701; injector: 260° C.; detector: 260°; oven: 70 to 250° C./5° C. per min; carrier gas: H2 (60 kPa); retention times: 15.5 min N,N-diallyl 4-methylbenzenesulfonamide, 24.5 min 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole, 25.5 min 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole). After 1 h (98% conversion), 96% of the title compound and 2% of 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole and after 4 h (100% conversion) 92% of the title compound and 8% of 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole were formed. 1H-NMR of 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole (300 MHz, C6D6): 2.43 (s, 3H); 4.12 (s, 4H); 5.65 (s, 2H); 7.32 (d, J=8.3 Hz, 2H); 7.73 (d, J=8.3 Hz, 2H). 1H-NMR of 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole (300 MHz, C6D6): 2.40-2.55 (m, 2H); 2.43 (s, 3H); 3.48 (t, J=8.9 Hz, 2H); 5.10-5.15 (m, 1H); 8.35-8.40 (m, 1H); 7.32 (d, J=8.3 Hz, 2H); 7.67 (d, J=8.3 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+].C([O:28][C:29]1[CH:34]=[N:33][CH:32]=[C:31]([CH:35]=[CH2:36])[N:30]=1)(C)(C)C.O>CN(C)C=O.C(OCC)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][C:31]2[NH:30][C:29](=[O:28])[CH:34]=[N:33][CH:32]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1F)C1CCN(CCc2cncc(=O)[nH]2)CC1
Reaction time: 64 h
Yield: 2 %

Procedure:
After dissolving 1.00 g of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride in 8 ml of N,N-dimethylformamide, 643 mg of potassium carbonate and 899 mg of 2-tert-butoxy-6-vinylpyrazine were added while stirring, and the stirring was continued for 64 hours at 100° C. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Three milliliters of 4N hydrogen chloride/ethyl acetate was added to the obtained product and the mixture was stirred for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol/ammonia water) to obtain the title compound (27 mg, 2% yield).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:22])(=[O:23])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Sc3ccc(Cl)cc3)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 g (2 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one was dissolved in 10 ml of tetrahydrofuran and 0.29 g (2 mmol) of 4-chlorothiophenol and 0.22 g (2.2 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 2 hours, stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid and dried, and the solvent was removed. This gave 0.9 g of beige crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([CH3:28])[CH:19]=[C:20]([O:26][CH3:27])[C:21]=4[CH3:25])[CH:16]=3)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]([C:44]3[CH:53]=[CH:52][C:51]4[C:46](=[C:47]([CH3:57])[CH:48]=[C:49]([O:55][CH3:56])[C:50]=4[CH3:54])[CH:45]=3)=O)[CH:38]=2)[C:33]=1[CH2:58][CH3:59])(=[O:31])=[O:30])[CH3:2].Cl>[Zn].C(O)(=O)C>[CH2:58]([C:33]1[C:34]2[CH:35]=[CH:36][C:37](=[CH:42][C:44]3[CH:53]=[CH:52][C:51]4[C:46](=[C:47]([CH3:57])[CH:48]=[C:49]([O:55][CH3:56])[C:50]=4[CH3:54])[CH:45]=3)[CH2:38][C:39]=2[CH:40]=[CH:41][C:32]=1[S:29]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C:9](=[CH:13][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([CH3:28])[CH:19]=[C:20]([O:26][CH3:27])[C:21]=4[CH3:25])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[C:3]=1[CH2:1][CH3:2])(=[O:30])=[O:31])[CH3:59]
Reactant: CCc1c(S(=O)(=O)c2ccc3cc(C(=O)c4ccc5c(C)c(OC)cc(C)c5c4)ccc3c2CC)ccc2cc(C(=O)c3ccc4c(C)c(OC)cc(C)c4c3)ccc12
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1c(S(=O)(=O)c2ccc3c(c2CC)C=CC(=Cc2ccc4c(C)c(OC)cc(C)c4c2)C3)ccc2c1C=CC(=Cc1ccc3c(C)c(OC)cc(C)c3c1)C2
Yield: 20.8 %

Procedure:
A suspension of 0.43 g (1 mmole) of ethyl 6-[(5,8-dimethyl-6-methoxy-2-naphthyl) carbonyl]-2-naphthylsulfone, described in Example XIX, 10 cm3 of glacial acetic acid and 0.65 g of zinc powder (10 mmoles), is heated at reflux with stirring. There is then slowly added 0.85 cm3 (10 mmoles) of 12N HCl and reflux is maintained for 1 hour. There is again added 0.85 cm3 of 12N HCl and the mixture is stirred for 1 hour, while letting the reaction mixture cool. After the addition of 20 cm3 of 12N HCl, it is extracted with ether (3×30 cm3), washed with water, dried on sodium sulfate and evaporated to dryness. The crude yellow solid is rapidly purified by silica 60 gel chromatography (eluant: dichloromethane), followed by recrystallization in a hexane/acetone mixture. After drying, 160 mg of white needles of ethyl 6-[(5,8-dimethyl-6-methoxy- 2-naphthyl) methylene]-2-naphthylsulfone whose melting point is 166° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[OH:11])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:17][CH2:18][OH:19].[I-].[Na+]>O>[OH:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[OH:11])=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: CC(C)(O)CCc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)CCc1ccc(OCCO)cc1
Yield: 114.1 %

Procedure:
To a suspension of 4-hydroxy-α,α-dimethylbenzenepropanol (15 g, 0.083 m) in water, was added a solution of sodium hydroxide (5 g, 0.125 m) in water (50 ml). 2-Bromoethanol (11.4 g, 0.091 m) and sodium iodide (6.3 g) were successively added and the solution stirred and heated under reflux for 3 hours. The reaction mixture was then diluted with more water and extracted with ethyl acetate. Evaporation of the ethyl acetate gave a cream solid (21.3 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12>[Pd].CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[C:5]=12
Reactant: Oc1ccc(-c2cccn3ccnc23)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2CCCn3ccnc32)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 62.4 %

Procedure:
A mixture of 4-(imidazo[1,2-a]pyridin-8-yl)phenol (0.22 g), 10% palladium on carbon (containing water (50%), 0.10 g) and methanol (15 ml) was stirred under a hydrogen atmosphere at room temperature for 5 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (0.14 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH2:67]([O:74][NH2:75])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:24])[NH:75][O:74][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[CH:25][CH:26]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
The acid compound 4 (0.6 g, 1.22 mmol) was dissolved in dry DMF (15 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.18 g, 1.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.22 mmol), and triethylamine (0.6 mL, 3.66 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.22 g, 1.34 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), water (1×25 mL) and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography using hexanes-ethyl acetate (1:1) yielded the desired benzyl hydroxamate 7 (0.4 g, 56%). 1H NMR (DMSO-d6): 11.73 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.29-7.47 (m, 13H), 6.99 (d, J=8.8 Hz, 2H), 6.99 (5.12 (s, 2H), 4.92 (s, 2H), 4.23-4.28 (m, 1H), 3.03 (dd, J=13.6 and 5.2 Hz, 1H), 2.90 (dd, J=13.6 and 10.0 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=O)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (4.0 g, 20.4 mmol) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (800 mg, 21.1 mmol) by small portions at 0° C., and the mixture was allowed to warm to room temperature and stirred for 1 hr. Sodium sulfate decahydrate (7.6 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. The filtrate was concentrated and the residue was dissolved in tetrahydrofuran (100 mL). Manganese dioxide (10.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (2.13 g, yield 69%) as colorless crystals. 1H NMR (CDCl3) δ: 1.37 (9H, s), 6.65 (1H, s), 9.95 (1H, s).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-:22])=[O:21])=[C:10]([NH:12]C(=O)OC(C)(C)C)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-:22])=[O:21])=[C:10]([CH:11]=2)[NH2:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 14.13 mmol, 1.0 equiv.) in dichloromethane (50 mL) was added TFA (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was then evaporated under reduced pressure. The crude residue was quenched with a saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate, washed with water and brine, dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 60% EtOAc/hexanes) to give 5-(cyclopent-1-en-1-yl)-2-nitroaniline (2.5 g, 87% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:3][CH:4]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 75 %

Procedure:
A mixture of 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 0.064 g, 0.235 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.030 g, 0.214 mmol), and DIEA (0.045 ml, 0.257 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.060 g, 75%). 1H NMR (400 MHz) 12.51 and 12.09 (s, 1H), 9.70 and 9.64 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.02 and 7.93 (b, 1H), 7.63 (m, 1H), 7.40 (m, 1H), 5.93 and 5.80 (s, 1H), 5.06 (m, 1H), 1.83 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.94 (m, 1H), 0.84 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 373. Found: [M+H]+374.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14]1([CH3:13])[CH:2]2[O:3][CH:1]2[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: COC(OC)C(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)Oc2ccc(C#N)cc2C2OC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
In 100 ml of toluene were dissolved 8.06 g (50 mmole) of 3-acetyl-4-hydroxybenzonitrile and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, then 1.67 ml (20 mmole) of pyrrolidine was added thereto at room temperature. 30 minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus; the solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added thereto. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml×2), washed with 50 ml of water and with 50 ml of saturated sodium chloride aqueous solution, and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 11.19 g (yield 86%) of the title compound in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]2[CH2:19][CH2:18]2)=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.S([O-])(O[O-])(=O)=[O:21].[K+].[K+]>CC(C)=O.O.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:21])[CH:5]=[N:4][C:3]=1[CH:17]1[CH2:19][CH2:18]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC1(C)OB(c2cnc(C3CC3)c(Cl)c2)OC1(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: Oc1cnc(C2CC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
3-Chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 41, 3.092 mmol assuming 100% in previous step) was dissolved in acetone (10.0 mL) and cooled to 0° C. with an ice bath. Then potassium peroxymonosulfate (2.55 g, 4.15 mmol) in water (10.0 mL) was added dropwise to the mixture and stirred at this temperature for 1 hour. The reaction was then diluted in TBME (25.0 mL) and washed with brine (3×25.0 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a pale yellow solid (0.220 g, 1.28 mmol, 42% over 2 steps).