Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1>C(#N)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:1](=[O:3])[CH3:2])=[N:21][CH:22]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)c1ccc(F)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Copper iodide (811 mg), 1-ethoxyvinyltri-n-butyltin (19.2 mL), and bis(triphenylphosphine)palladium (II) chloride (1 g) were added to a solution of 2-bromo-5-fluoropyridine (5 g) in acetonitrile (250 mL), and the reaction solution was heated and stirred in a nitrogen atmosphere at 100° C. for two hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with acetone (120 mL), and (1S)-(+)-10-camphorsulfonic acid (9.9 g) was added to the reaction solution. After confirming production of the target product by thin-layer chromatography, the solvent was evaporated under reduced pressure. The residue was diluted with an ether and neutralized with sodium carbonate. Water was added to the reaction solution, and the organic solution was separated. The organic layer was dried over magnesium sulfate, and the residue was purified by silica gel column chromatography (carrier: Chromatorex; elution solvent: hexane-ethyl acetate) to obtain 3.55 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=12
Reactant: OCc1ccn2ccnc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To imidazo[1,2-a]pyridin-7-yl-methanol (100 mg, 0.7 mmol) suspended in chloroform (5 ml) at room temperature was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 0.373 g, 0.9 mmol, 1.3 equiv). This mixture was stirred at room temperature overnight and then dilute sodium hydroxide solution was added and the mixture was stirred for 60 minutes. The mixture was then extracted with dichloromethane and the organic liquors were concentrated in vacuo to furnish imidazo[1,2-a]pyridine-7-carbaldehyde (90 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6): 10.00 (1H, s), 8.67 (1H, d), 8.33 (1H, s), 8.20 (1H, s), 7.86 (1H, d), 7.25 (1H, dd).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1.CO[C:21]1(OC)[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[C:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[C:10]2=[O:18])=[CH:7][CH:8]=1
Reactant: COC1(OC)CCCN1C
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1

Procedure:
1-(4-Methoxyphenyl)-2(1H,3H)-indolone (49 g, 0.205 mole), N-methyl-2-pyrrolidone dimethyl acetal (ca. 80%, 53 g, 0.245 mole, Ber, 97, pp. 3081-7, 1964) and 1000 ml chloroform were refluxed under nitrogen for 1.5 hours. The reaction mixture was cooled and evaporated in vacuo to solids. Two recrystallizations from ethyl acetate gave purified title product, 44.7 g, m.p. 90°-93° C. Thirty grams of this material were dried at 80° C./15 mm Hg for 20 hours to give 26.1 g of title product, m.p. 127°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH:26]([Mg]Br)([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH:26]([CH3:28])[CH3:27])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Product: CC(C)C(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and isopropylmagnesium bromide.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:47])([CH2:43][CH2:44][CH2:45][CH3:46])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:47])([CH3:38])[CH2:43][CH2:44][CH2:45][CH3:46])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCC(C)(C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 90.1 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.63 g (10.0 mmol) of 2,2-dimethylhexanoyl chloride, to provide 1.22 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=O)[C:8]=2[C:7]([OH:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[CH2:9][C:8]=2[C:7]([OH:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of ethyl {4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (2.50 g, 5.72 mmol) in THF (50 ml) under an argon atmosphere, was added sodium borohydride (0.217 g, 5.72 mmol) followed by borane THF complex solution (1.0M in THF, 5.72 ml, 5.72 mmol). This was stirred at room temperature for 2 hours. A further 5.72 mmol of sodium borohydride and borane THF complex was added to the reaction mixture and stirring continued for 2 hours. Finally, a further 2.86 mmol addition of sodium borohydride and borane THF complex was made and stirring continued for 1.5 hours until the reaction was complete. This was quenched with ethyl acetate (100 ml) and methanol (3 ml) then washed with 2N HCl (100 ml). The aqueous was re-extracted with ethyl acetate (200 ml). The combined organics were washed with brine (200 ml), dried over magnesium sulphate, filtered and evaporated to give the title compound as a pale yellow solid (2.45 g, 5.79 mmol).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)#[N:6].[CH3:17]O>>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.1 mL, 15.07 mmol) was added to cool MeOH (70 mL) at 0° C. After 5 min 2-(4-cyanophenyl)acetic acid (1 g, 6.21 mmol) was added. After 30 min, cooling was removed and the mixture stirred for 21 h at RT. The solvent was removed and toluene was added and evaporated 3 times to give a sticky yellow solid. The product was used crude for the next step.
Reaction SMILES: [N+:1]([CH2:4][C:5]1(O)[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6]1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[N+:1]([CH:4]=[C:5]1[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC1(O)COCCOC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])C=C1COCCOC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A stirred mixture of 6-nitromethyl-[1,4]dioxepan-6-ol (0.74 g, 4.18 mmol) and triethylamine (1.86 g, 2.56 mL, 18.4 mmol) in dichloromethane (20 mL), under nitrogen, was cooled to −78° C. and methanesulfonyl chloride (1.43 g, 970 μL, 12.5 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then quenched with saturated ammonium chloride solution. The mixture was removed from the cooling bath and allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:1 to give the title compound (512 mg, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.81-3.90 (m, 4H), 4.36 (d, J=0.5 Hz, 2H), 5.04 (d, J=2.5 Hz, 2H), 7.02 (t, J=2.5 Hz, 1H). LCMS (m/z) 182.1.0 [M+Na], Tr=1.04 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:18]([C:19]#[N:20])=[CH:17][CH2:16][C@@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([OH:22])[CH2:8]3)[CH2:3]2>CCOC(C)=O.[Pd]>[CH3:1][C@@:2]12[C@@H:18]([C:19]#[N:20])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([OH:22])[CH2:8]3)[CH2:3]2
Reactant: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(C#N)=CC[C@@H]3C[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H]3CC[C@@H]4C[C@@H](O)CC[C@@]4(C)[C@@H]3C[C@@H]1CC[C@@H]2C#N
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of the compound 27 (60 mg, 0.2 mmol) in EtOAc (40 mL) was added Pd/C (30 mg). Hydrogenation was carried out under 5 atm H2 at room temperature for 3 h. The reaction was filtered through Celite which was washed with EtOAc (100 mL). Solvents were removed and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 28 (54 mg, 90%): mp 145-147° C., [α]D25 +45.3 (c 0.23, CHCl3); 1H NMR (CDCl3) δ 4.05 (s, br, 1H), 2.27 (t, J=9.3 Hz, 1H), 0.89 (s, 3H), 0.78 (s, 3H); 13C NMR (CDCl3) δ 121.5, 66.5, 54.4, 48.6, 45.6, 44.3, 39.9, 39.2, 36.4, 35.7, 34.8, 32.1, 32.0, 28.8, 28.7, 26.6, 26.5, 24.1, 14.4, 11.2; IR νmax 3434, 2235, 1449 cm−1. Anal. Calcd for (C20H31NO): C, 79.68; H, 10.36; N, 4.65. Found: C, 79.47; H, 10.67; N, 4.77.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([CH3:33])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Reactant: CB(O)O
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: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(C)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.05 g, 0.1 mmol), methylboronic acid (0.01 g, 0.2 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol) and a solution of 2 N aqueous sodium carbonate (0.1 mL, 0.2 mmol) was added in a sealed tube with DMF (5 mL). The tube was capped and the resulting solution was degassed with argon for 5 minutes. The reaction was heated to 120° C. by microwave irradiation for 2.5 hours. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride (5 mL) and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with brine (10 mL) and dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 20-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[S:24][C:23]([C:25]5[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=5)=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl>>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[S:24][C:23]([C:25]5[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:27][CH:26]=5)=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: NCCCO
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: OCCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 3-aminopropanol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.54 (s, 1H), 8.44 (s, 1), 7.75 (dd, 4H), 7.42 (m, 4H), 7.23 (m, 1H), 6.41 (s, 1H), 3.67 (s, 2H), 3.43 (s, 2H), 3.30 (s, 2H), 1.54 (m, 2H); LC-MS: 430 (MH+); HPLC RT: 3.34 minutes.
Reaction SMILES: C(NC(=O)[O-])C.[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH:12]([CH3:20])[CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[C:18]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: Fc1ccc(CBr)cc1
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3ccc(F)cc3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 4-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)[C:5](=[O:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:18]=1
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CN4CCCC4)c3)c2n1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2c(n1)n(Cc1cccc(CN3CCCC3)c1)c(=O)n2Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (31 mg, 0.078 mmol) was dissolved in DMF (2 mL). Anhydrous potassium carbonate (50 mg) was added followed by p-methoxybenzyl chloride (13.7 μL, 0.101 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by preparative HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave 6-amino-7-(4-methoxy-benzyl)-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-7,9-dihydro-purin-8-one (Example P) (6 mg) as the HCl salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N-:23]=[N+:24]=[N-:25].[Na+].CCO.N[C@@H]1CCCC[C@H]1N>[Cu]I.O>[N:23]([C:12]1[CH:13]=[C:14]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1)=[N+:24]=[N-:25]
Reactant: NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Br)cnc1O2

Procedure:
A microwave vial was charged with (S)-3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (500 mg, 1.059 mmol, Intermediate 25), copper(I) iodide (20.17 mg, 0.106 mmol), (+)-sodium 1-ascorbate (10.49 mg, 0.053 mmol) and sodium azide (0.074 ml, 2.118 mmol). The vial was evacuated and backfilled with nitrogen. EtOH (2 ml), rac-trans-1,2-diaminocyclohexane (0.019 ml, 0.159 mmol) and water (0.9 ml) were added. The reaction mixture was heated overnight to 56° C. An additional portion of each reagent were added and the reaction was heated for additional 6 hours. The reaction mixture was partitioned between water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silical gel, 20-100% EtOAc/hexanes) to afford (S)-7-azido-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine as a yellow solid.
Reaction SMILES: CC(NC(C)C)C.[Li]CCCC.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][S:23][N:22]=2)=[CH:17][CH:16]=1)[CH3:14].[I:31]I>O1CCCC1>[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([I:31])[S:23][N:22]=2)=[CH:19][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)c1csnc1-c1ccc(CC)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (15 mL). This was followed by the addition of bis(propan-2-yl)amine (1.34 g, 13.24 mmol, 1.50 equiv). The mixture was cooled to −78° C. To this was added n-BuLi (2.5M) (5.28 mL). The mixture was stirred at −78° C. for 40 minutes. To the mixture was added a solution of ethyl 3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate (2.3 g, 8.80 mmol, 1.00 equiv) in tetrahydrofuran (5 mL). The mixture was stirred at −78° C. for 40 minutes. To the mixture was added a solution of I2 (3.35 g, 13.19 mmol, 1.50 equiv) in tetrahydrofuran (5 mL). The resulting solution was stirred for 40 min at −78° C. The reaction was then quenched by the addition of 80 mL of water. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum. This resulted in 2.1 g (62%) of ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate as red oil.
Reaction SMILES: NN.[N+:3]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-])=[O:4]>>[OH:4][NH:3][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: NN
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21

Procedure:
The hydrazine may be added gradually or all at once. If the hydrazine is gradually added, intermediate reduction steps of the nitroanthraquinone employed, e.g. hydroxylaminoanthraquinone, may be isolated. The nitroanthraquinone used is preferably reacted directly to the amino step. The resulting amino compound may be isolated from the reaction mixture by methods known per se.
Reaction SMILES: C(SCC1C=[N+]([O-])C2C(=CC=CC=2)[N+]=1[O-])CC.[CH2:18]([S:21]([CH2:23][C:24]1[CH:33]=[N+:32]([O-:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N+:25]=1[O-:35])=[O:22])[CH2:19]C>>[CH2:18]([S:21]([CH2:23][C:24]1[CH:33]=[N+:32]([O-:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N+:25]=1[O-:35])=[O:22])[CH3:19]
Reactant: CCCS(=O)Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Agent: CCCSCc1c[n+]([O-])c2ccccc2[n+]1[O-]
Product: CCS(=O)Cc1c[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
By means of this procedure, 2-n-propylthiomethylquinoxaline 1,4-dioxide is converted in 73 percent yield to 2-n-propylsulfinylmethylquinoxaline 1,4-dioxide, m.p. 137°-139°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH2:16][CH2:15]1.ClCCl.O>O1CCOCC1>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[C:22]([NH:23][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-(4-methylpiperazin-1-yl)aniline (127 mg, 0.663 mmol). The mixture was heated in microwave at 120° C. Dichloromethane and water were added, and the product extracted in dichloromethane. The organic layer was then dried over Na2SO4 and concentrated under reduced pressure to yield 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=337)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:18](C(C(OCC)=O)C(OCC)=O)[CH:19]=C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH2:12][CH:18]=[CH2:19])[C:9]([OH:11])=[O:10]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: C=CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-allyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl allyl-malonate.