Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:15]([NH:22][C:4]1[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)c1n[nH]c2c(Cl)nc(Cl)nc12
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Yield: 96 %

Procedure:
5,7-Dichloro-3-isopropylpyrazolo[4,3-d]pyrimidine (1.015 mmol; 234.6 mg), 1 mL benzylamine and n-butanol (2 mL) were stirred at 65° C. for 4 hours. The reaction mixture was evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with the following solvent system: CHCl3/MeOH (99/1), to give 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine. Yield 96%; MS (ES+): 302.3 (100%, M+H+), 304.3 (32%, M+H+). 1H NMR (CDCl3; 300 MHz): 1.37 d (6H, J=7.1 Hz); 3.39 sept (1H, J=7.1 Hz), 6.72 s (1H), 4.82 s (2H), 7.28 m (5H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.P(=O)(O)(O)O.[CH2:28]([C:32](=[CH2:35])[CH:33]=O)[CH2:29][CH2:30][CH3:31].O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:35][C:32]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:33]2
Reactant: Nc1cc(F)ccc1Br
Reactant: C=C(C=O)CCCC
Agent: N
Agent: O=P(O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: O
Product: CCCCc1cnc2c(Br)ccc(F)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.1 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (69.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2-butylacrolein (7.44 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.35 g of 8-bromo-3-butyl-5-fluoroquinoline as a brown solid (yield: 19.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:22])[CH3:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:22][S:30]([CH3:33])(=[O:32])=[O:31])[CH3:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(Oc1ccc(C(C)O)cc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Oc1ccc(C(C)OS(C)(=O)=O)cc1)c1ccccc1

Procedure:
0.5 g (1.7 mMol) of 1-[4-[(α-ethoxycarbonyl)benzyloxy]phenyl]ethanol and 0.22 g (2.2 mMol) of triethylamine are dissolved in 10 ml of methylene chloride. At 5° C., 0.23 g (2.0 mMol) of mesyl chloride are added dropwise with stirring. After one hour at ambient temperature the reaction mixture is poured onto ice water, extracted with methylene chloride and dried over sodium sulphate. The crude product obtained is reacted directly without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cnc(C)c(C)c3)c(=O)c3ccccc32)n1

Procedure:
Compound 4h was prepared following the procedure described in Step 3 of Example 1. Briefly described here, 65 mg (0.23 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one 3c, 11 mg (0.28 mmol) of 60% sodium hydride and 52 mg (0.28 mmol) of 2-bromomethyl-6-methyl-pyridine (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) in 0.7 mL N,N-dimethylformamide were stirred at rt for 2 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. HPLC fractions containing pure product 4h were lyophilized to give 41 mg of a white solid as trifluoroacetate salt: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.5, HPLC retention time: 0.4 min; 1H NMR (400 MHz, CDCl3): δ 2.5 (s, 3H), 2.8 (s, 3H), 2.85 (s, 3H), 6.05 (s, 2H), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.6-7.7 (m, 1H), 8.0-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.4 (s, 1H), 8.7 (s, 1H), 8.9 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([OH:16])[C@H:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[ClH:18].[CH2:19](O)[CH2:20]CC>>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([OH:16])[C@H:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH2:2][CH2:19][CH3:20].[ClH:18]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Temperature: 70 °C

Procedure:
(2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (100 mg, 0.4 mmol) was combined with 1-butanol (5 mL) and concentrated HCl (1 mL) and heated at 70° C. for 24 hours. Excess solvent was removed to yield the title compound as an HCl salt.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=O)[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.CO.[BH4-].[Na+].Cl.[NH3:31]>>[NH2:31][CH:12]([C:11]1[C:2]([OH:1])=[C:3]2[CH:23]=[CH:22][C:21]([CH3:25])([CH3:24])[O:20][C:4]2=[C:5]2[C:10]=1[O:9][C:8](=[O:16])[CH:7]=[C:6]2[CH2:17][CH2:18][CH3:19])[CH2:13][CH3:14]
Reactant: N
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(=O)oc2c(C(N)CC)c(O)c3c(c12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
5-Hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (1.0 g, 2.9 mmol, 1.0 eq) was dissolved in 7 N ammonia in methanol (100 mL, 0.7 mol, 241 eq). The mixture was stirred overnight at ambient temperature. Solvent and excess of ammonia were removed under vacuum and the residue re-dissolved in methanol (100 mL). The solution was cooled to 0° C. and sodium borohydride (550 mg, 14.6 mmol, 5.0 eq) added portionwise. The mixture was allowed to warm up room temperature and stirred for 3 h. The mixture was then poured into ice-water and pH adjusted to 8.5 with concentrated hydrochloric acid. The product was extracted into ethyl acetate (3×50 mL). The extracts were combined and washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel column eluted with 5-10% methanol in dichloromethane to yield 612 mg of 24a (61% yield). 1H NMR (CDCl3): 0.97 (t, J=7.5 Hz, 3H), 1.03 (t, J=7.5 Hz, 3H), 1.47 (s, 3H), 1.49 (s, 3H), 1.67 (m, 2H), 1.78 (m, 2H), 2.89 (m, 2H), 4.85 (t, J=7.0 Hz, 1H), 5.52 (d, J=10.0 Hz, 1H), 5.88 (s, 1H), 6.67 (d, J=10.0 Hz, 1H); 13C NMR (DMSO-d6): 10.17, 13.99, 23.54, 26.24, 27.23, 27.31, 37.99, 49.84, 76.35, 96.60, 102.88, 103.95, 107.80, 118.29, 123.55, 150.87, 153.82, 158.66, 160.26, 167.83; IR: 1683 cm−1; MS (ACPI+): 344 (M+1), 327 (M-NH3+1); Anal. Calcd. for C20H25NO4: C 69.95, H 7.34, N 4.08; Found C 69.97, H 7.30, N 4.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:23])[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[CH:30](O)[CH2:31][CH2:32][C:25]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:23][CH:30]2[C:26]3[C:25](=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:32][CH2:31]2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: OC1CCc2ncccc21
Reactant: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3O)n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3OC3CCc4ncccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
1-(4-(5-(5-Bromo-3-hydroxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.083 g, 0.21 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol (0.028 g, 0.21 mmol) and triphenylphosphine (0.057 g, 0.22 mmol) were combined in THF (1 mL) under nitrogen. Diisopropyl azodicarboxylate (0.043 ml, 0.22 mmol) was added in one portion. The reaction stirred at ambient temperature overnight. The solution was diluted with water, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 1-(4-(5-(5-bromo-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.022 g, 21%); Mass spectrum (apci) m/z=515.0, 517.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:4]1)[CH3:2].[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([I:13])[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:4]1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCn1ccc(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(I)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of 1-ethyl-3-(2-thienyl)-1H-pyrazole (13.5 mmol) in 45 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (14.1 mmol) in small portions. The reaction mixture was stirred overnight at room temperature. N-Iodosuccinimide (4.4 mmol) was added and stirring was continued for 24 h. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 2.10 g 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (51% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)CC(C)COc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(C)COc1cc(N)ccc1OC

Procedure:
At ambient temperature a rapidly stirred solution of methyl 3-methyl-4-(2-methoxy-5-nitrophenoxy)butyrate(400 mg) in methanol (20 mL) containing 10% palladium on carbon (40 mg) was exposed to an atmosphere of hydrogen. When uptake of hydrogen had ceased the solution was filtered and the filter cake washed with methanol. The combined filtrates were evaporated to dryness under reduced pressure, to give methyl 3-methyl-4-(2-methoxy-5-aminophenoxy)butyrate as an oil. (317 mg) m/Z 254(M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A solution of ethyl 3-[4-benzyloxyphenyl)-2-hydroxypropanoate (5.0 g, 16.6 mmol) (prepared in a similar manner as described in Ref: WO95/18125) in dry dimethyl formamide (5 mL) was added to a suspension of sodium hydride (0.1 g, 41.6 mmol) (60% dispersion in oil) in dry dimethyl formamide (3 mL) at 0° C. and stirring was continued for further 1 h. To the above reaction mixture n-butyl bromide (3.4 g, 24.0 mmol) was added at 0° C. and stirring was continued for 10 h at ca. 25° C. Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with water (50 mL), brine (25 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and and pet. ether (1:9) as an eluent to afford the title compound (0.7 g, 20%) as an oil.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[C:9]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([N:15]2[C:14]([C:9]3[C:10](=[O:13])[CH:11]=[CH:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[CH:18][CH:17]=[N:16]2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 1-phenyl-3-[2-(3-trimethylsilanylethynyl-phenyl)-2H-pyrazol-3-yl]-1H-pyridazin-4-one (example 31, 50 mg, 0.12 mmol) is dissolved in THF (2 ml). Tetrabutylammoniumfluoride trihydrate (77 mg, 0.24 mmol) is added at 0° C. and the reaction mixture is allowed to warm up to ambient temperature within 15 minutes. Stirring is continued for another 2 hours. The reaction mixture is quenched with water and extracted with ethyl acetate. The solvent is removed and the obtained crude product is triturated with diethyl ether. The solid material is filtrated and dried to obtain 39 mg (94% yield) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=CC1CCOCC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)cc1

Procedure:
4-Aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and acetic acid (15 mL) were stirred at room temperature for 24 hours. The reaction was concentrated and taken up in ethyl acetate. The resulting solution was washed with water and brine, concentrated, and chromatographed on silica gel with 50% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Temperature: 120 °C

Procedure:
2,6-dichloro-9-isopropylpurine (0.019 g, 0.081 mmol) was dissolved in butanol (0.5 ml) and aniline (0.044 ml, 0.244 mmol) was added. The reaction mixture was heated to 120° C. for 10 hr, cooled, diluted with EtOAc and washed 3 times with water. The mixture was dried over MgSO4 and concentrated to an off white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]1([S:40]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.1 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0403 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.043 mL, 0.0316 g, 0.245 mmol, 2.00 equiv.) and benzenesulfonyl chloride (0.023 mL, 0.0324 g, 0.183 mmol, 1.50 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc, and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.0649 g) was chromatographed (SiO2 25 g, eluted with 2:1 hexane:EtOAc) to give tert-butyl 6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0430 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.46, 1.52, 2.95-3.02, 3.22-3.30, 3.63-3.75, 4.24-4.31, 4.63, 4.79, 7.09-7.26, 7.45-7.51, 7.48, 7.58, 7.79; MS (ESI+) for C25H31N3O4S m/z 470.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Na+].[I-].C[Si](C)(C)[C:22]([F:25])(F)[F:23].C1COCC1>C(Cl)Cl>[F:23][C:22]1([F:25])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), NaI (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL), The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.2 mL of a 0.46 M solution in toluene, 0.552 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.307 g, 1.1 mmol) were combined in toluene under nitrogen and heated to 110° C. After 4 h the toluene was replaced by xylenes (1 mL) and heating was continued under reflux overnight. After cooling to room temperature the crude reaction mixture was dissolved in CH2Cl2 and washed with saturated aqueous ammonium chloride solution then with brine. The organic layer was dired (MgSO4), filtered and evaporated to dryness. Chromotagraphy on silica gel eluting with 5% CH3OH in CH2Cl2 followed by a second chromatography step eluting with ethyl acetate provided 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 22%) as a yellow solid. MS (APCI); M++1: Calc'd, 580.32. Found 580.2. 1H NMR: 68 (400 MHz, DMSO) 8.50 (s, 1H), 8.26 (d, J=9 Hz, 1H), 7.94 (d, J=3 Hz, 1H), 7.39 (dd, J=3, 9 Hz, 1H), 6.78 (s, 1H), 5.89-5.98 (m, 1H), 4.15 (t, J=5 Hz, 2H), 3.86 (t, J=5 Hz, 2H), 3.56-3.62 (m, 6H), 3.09 (br t, J=5 Hz, 4H), 2.29-2.33 (m, 2H), 2.07-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.63-1.69 (m, 2H), 1.47 (s, 9H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][C:9]2[C:17]3[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=3[C:12]([CH3:21])=[C:11]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]=2[CH3:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C1COCC1.CCCCCC>[OH:20][CH:14]1[C:13]2[C:12]([CH3:21])=[C:11]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([CH3:30])=[C:9]([CH2:8][C:7]3[CH:31]=[CH:32][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:17]=2[O:16][C:15]1([CH3:19])[CH3:18]
Reactant: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Yield: 81 %

Procedure:
Using N-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Reference Example 330, the title compound was synthesized in the same manner as in Example 234. Yield: 81%. Melting point: 244-245° C. (THF-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]=[N+:15]=[N-:16])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 15.0 g (0.069 mole) of o-nitrobenzenesulfonyl chloride dissolved in 150 ml ethanol was added 5.89 g (0.090 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred for 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was filtered, dried and recrystallized from ethanol. The purified product had a melting point 73°-74° C. (lit. 73°-74° C.) and was isolated in 92% yield (14.47 g).