Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.[Br:23]Br>C(O)(=O)C>[Br:23][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]([CH:11]([C:8]1[N:6]3[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)[CH3:12])=[CH:22][CH:21]=2
Reactant: BrBr
Reactant: Cc1ccc2nnc(C(C)c3ccc4ncccc4c3)n2n1
Solvent: CC(=O)O
Product: Cc1ccc2nnc(C(C)c3ccc4ncc(Br)cc4c3)n2n1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
2-Quinolin-6-yl-propionic acid hydrazide (intermediate 63) (500 mg, 2.32 mmol) was added to a stirred solution of 3-chloro-6-methylpyridazine (299 mg, 2.32 mmol) in n-butanol. The reaction mixture was heated at 120° C., overnight. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to obtain 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 53% yield). To 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 1.23 mmol) was added a dropwise solution of bromine (1.73 uL, 3.69 mmol) in acetic acid (3 mL). The reaction was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. A solution of 10% aq. NaSH (10 mL) was added and the product extracted with 10% methanol in dichloromethane. The organic phase was washed with 5% aqueous sodium sulfite. The filtrate was then concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (168 mg, 37% yield). Analytical data presented in Table 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1.[CH3:22][C:23]([OH:40])([CH3:39])[CH2:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[OH:40][C:23]([CH3:39])([CH3:22])[CH2:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:21]=2)[CH:27]=[N:26]1
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(NC(C)(C)CO)nc2-3)cn1
Yield: 18 %

Procedure:
2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol from Example 356, was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 428. Yield 18%. MS (ESI+): 429.2. 1H NMR (400 MHz, DMSO) δ 8.14-8.04 (m, 2H), 7.87 (s, 1H), 7.29 (dd, J=8.2, 1.8, 1H), 7.17 (d, J=1.8, 1H), 7.07 (s, 1H), 4.97 (t, J=5.6, 1H), 4.70 (s, 1H), 4.26 (t, J=5.0, 2H), 4.02 (s, 2H), 3.58 (d, J=5.6, 2H), 3.05 (t, J=5.0, 2H), 1.34 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.[C:19]1([CH2:25][C:26]2[N:30]=[C:29]([CH2:31][CH2:32][CH2:33]O)[O:28][N:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:33][CH2:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:30]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: OCCCc1nc(Cc2ccccc2)no1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (195 mg, 0.89 mmol) and PPh3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated and further purified by a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh3)4 (86 mg, 0.074 mmol) and morpholine (644 μl, 7.4 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (74 mg, 23%).
Reaction SMILES: CC(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22]
Reactant: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OCC
Reaction time: 4 h

Procedure:
diethyl [({[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}amino)methyl]phosphonate (360 mg, 0.628 mmol) was taken up in DCM (6 mL)/TFA (2 mL). After 4 hours at room temperature, the solvent was removed in vacuo, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give diethyl [({[4-({[2-amino-5-(2-thienyl)phenyl]amino) carbonyl}phenyl]methyl}amino)methyl]phosphonate as a beige solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.67 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.43 (m, 3H), 7.32 (dd, J=4.8 and 0.6 Hz, 1H), 7.26 (dd, J=8.4 and 1.8 Hz, 1H), 7.21 (m, 1H), 7.01 (dd, J=5.4 and 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.12 (s, 2H), 3.99 (m, 4H), 3.81 (s, 2H), 2.81 (d, J=12.0 Hz, 2H), 2.40 (br s, 1H), 1.20 (t, J=7.2 Hz, 6H). MS: cal'd 474 (MH+), exp 474.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([S:30]CC[Si](C)(C)C)[CH:29]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH2:37]([O:39][C:40](=[O:45])[C:41](Br)([F:43])[F:42])[CH3:38].CCOC(C)=O>CCOCC>[CH2:37]([O:39][C:40](=[O:45])[C:41]([F:43])([F:42])[S:30][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:7])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH:29]=1)[CH3:38]
Reactant: CC(C)(c1cc(-c2cccc(-c3cncc(SCC[Si](C)(C)C)c3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Sc1cncc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 24 (Step 5) but using 6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinoline from EXAMPLE 24 (Step 2) and bromo-difluoro-acetic acid ethyl ester as starting materials. Flash chromatography (Hex:EtOAc; 1:4) and stirring in Hex:Et2O afforded the title compound as a white solid after filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)(Cl)=O.[CH2:32](OCC)C>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:32])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C(=O)O)nc3)[nH]n2)c1
Reactant: CCOCC
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Temperature: 50 °C
Yield: 47 %

Procedure:
To a stirred suspension of 5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic acid (55 mg, 0.15 mmol, 1 eq) in methanol (0.5 mL) was added thionyl chloride (23 uL, 0.32 mmol, 2.1 eq) dropwise. The resulting solution was heated at 50° C. for 3 h. The mixture was concentrated in vacuo to yield an orange solid. This was dissolved in DCM and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers were dried over magnesium sulphate, filtered and concentrated to give the crude product as a yellow solid. Trituration with diethyl ether gave the title compound as a white solid 27 mg (47%); 1H NMR (400.13 MHz, DMSO) δ□ 2.92 (4H, s), 3.74 (3H, s), 3.92 (3H, s), 6.49 (1H, s), 6.25 (1H, m), 6.82 (2H, m), 7.19 (1H, t), 8.14 (1H, d), 8.46 (1H, m), 9.20 (1H, d), 11.11 (1H, s), 12.25 (1H, s) MS m/z 381 (MH+)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:50][CH2:49][N:46]1[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:41])=[O:42])[CH2:44][CH2:45]1)[CH:5]=2
Reactant: CS(=O)(=O)N1CCN(CCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 2 h
Yield: 73 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(4-(methylsulfonyl)piperazin-1-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h, and being purified by silica gel column chromatography (acetone/hexanes=2:1) to obtain the title compound (73%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]=[C:14]1[C:27](=[O:28])[N:17]2[C@@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH2:20][C@@H:16]2[CH2:15]1>C1COCC1>[C:21]1([C@@H:18]2[N:17]3[C:27](=[O:28])[C:14]4([CH2:7][CH2:13]4)[CH2:15][C@H:16]3[CH2:20][O:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=C1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N2[C@H](CO[C@@H]2c2ccccc2)CC12CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Trimethylsulfoxonium iodide [Me3S(O)I] (1.5 eq) and anhydrous THF (12 vol) were charged to a reactor. Cooled to 10˜20° C. and then added t-BuOK (1.5 eq). The resulting mixture was warmed to 60±5° C. and stirred for 1 h. Cooled down back to 10˜20° C. and then dropwise added a solution of (3R,7aS)-6-methylene-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(1H)-one (1.0 eq) in THF (3 vol) while maintaining the temperature at 60±5° C. The completion of reaction was monitored by HPLC every hour until the conversion >99% (system purity was 55%˜60%). The reaction mixture was then cooled to 15˜20° C., filtered and washed the cake with EtOAc (2 vol). The combined filtrate was washed with brine (3 vol) and the aqueous phase was back-extracted with EtOAc (3 vols). The combined organic phase was concentrated to about 3 vol under vacuum below 45° C. Add silica gel (1 wt/wt) and continued to concentrate to almost dryness. The solid residue was purified by silica gel (2 wt/wt) chromatography eluting with petroleum ether (PE) followed by EtOAc/PE=1:10 (v/v). The yield was about 40% (97.1% HPLC purity). ESI MS m/z (M+H)+ 230.16.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(=[O:3])[NH2:2].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: NC(=O)CCn1ccc2cc(C(=O)NCC3CCCC3)ccc21
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2cn(CCC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
Silver(I) oxide (0.17 g) was added to a solution of 1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indole (0.70 g) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.19 g) in 1,4-dioxane (10 ml). The mixture was protected from light and stirred at 80° C. under an atmosphere of nitrogen for 12 hours. The mixture was then diluted with 1:1 v/v ethyl acetate:ether (50 ml) and filtered. The filtrate was washed sequentially with water and brine, dried (MgSO4), and evaporated. The residual yellow gum was purified by flash chromatography on silica gel (500 ml), eluting with 5:95 v/v methanol:chloroform to give the title compound (0.14 g, 39%) as a white solid; mp 189°-191° C. (d); NMR (250 MHz, DMSO-d6):
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]([CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:4].O>CCCCCC>[C:3]([CH2:5][CH2:6][N:7]([CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]1)([OH:4])=[O:2]
Reactant: COC(=O)CCN(CCCCCCN(CCC(=O)OC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Solvent: CCCCCC
Solvent: O
Product: CC1(C)CC(N(CCCCCCN(CCC(=O)O)C2CC(C)(C)NC(C)(C)C2)CCC(=O)O)CC(C)(C)N1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a four-necked flask equipped with a stirrer and a reflux condenser were added 26.3 g (46 mmoles) of N,N'-bis(2-methoxycarbonylethyl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine (Compound A) obtained in Example 1 and 100 g of water. The resulting mixture was stirred at room temperature. After dissolution of Compound A was confirmed, 100 ml of hexane was added to separate the reaction mixture into two layers. The aqueous layer of the two layers was isolated and concentrated to obtain 23 g (43 mmoles) of Compound C in a yield of 92%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#N)=[C:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:11]([CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C[OH:30]>>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:30])=[C:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:11]([CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(OCc2ccccc2)n1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
To a 0° C. solution of 2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridine-3-carbonitrile (Cpd I, 1.0 g, 2.8 mmol) in MeOH (5 mL) was added NaBH4 (81 mg, 2.1 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated under vacuum to give [2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridin-3-yl]methanol (Cpd J, 147 mg, 14%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)=[O:28]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:31]3[CH2:32][CH2:33][CH2:34][C@@H:29]([C:27]([NH:26][CH3:25])=[O:28])[CH2:30]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CNC(=O)[C@@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)C1
Temperature: 25 °C
Yield: 12.6 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 76 mg, 0.220 mmol) and (R)—N-methylpiperidine-3-carboxamide (62.7 mg, 0.441 mmol) in NMP (1.1 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12.5 mg, 13%); ESI-MS: m/z 451.3 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 1-amino-1,4-dihydro-2,3-quinoxalinedione (53 mg, 0.30 mMol) and pyridine (1 mL, fresh distilled from KOH before use) and acetic anhydride (1 mL, Aldrich) was stirred under nitrogen at 60° C. for 4 hrs. The reaction mixture became a clear solution. All of solvent and reagent were then evaporated under reduced pressure and washed with benzene:cyclohexane=1:1(2×2 mL); ether (2×2 mL), dried at 60° C. with rotavapor for 2 h, affording 57 mg (86%) of pure 1-acetamido-1,4-dihydro-2,3-quinoxalinedione as a white powder; mp:211°-213° C. IR (KBr, cm-1): 3430; 3127; 1741; 1717; 1668. NMR (1H, DMSO-d6) δ:2.326 (s, 3H); 7.121-7.287 (m, 4H); 12.345 (s, 1H). Mass:calcd for C10H9N3O3 (M+) m/z:219.0641; found: 219.0651.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH2:14][CH2:13][C:12]2=[N:19][C:20]#[N:21].[CH3:22][OH:23]>>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:20]([NH2:21])=[N:19]3)[CH2:13][CH2:14][O:23][C:22]2=[CH:17][CH:18]=1
Reactant: CNO
Reactant: N#CN=C1CCOc2ccc(Br)cc21
Reactant: CO
Agent: CO[Na]
Agent: Cl
Product: CN1OC2(CCOc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (101 mg, 1.2 mmol) in MeOH (4 mL) was added MeONa (0.24 mL, 25% (Wt.) in MeOH), followed by N-(6-bromochroman-4-ylidene)cyanamide (300 mg, 1.2 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The resulting residue was purified by preparative TLC to give 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (315 mg, 88%).
Reaction SMILES: C[N:2]1[C:10]2[N:9]=[C:8](OC3C=CC=C(OC(F)(F)F)C=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:4]1[C:5](=[O:31])[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[NH:2][C:3]1=[O:32]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Agent: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Temperature: 50 °C
Yield: 279.1 %

Procedure:
To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.12 mmol, intermediate 12, step 2) in DMF (10 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.57 g, 2.54 mmol, intermediate 3) and potassium carbonate (0.88 g, 6.36 mmol). The reaction was heated at 50° C. for 3 h. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (1:3) to give 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-7-(2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.9 g, 70.0% yield) as a white solid. LCMS retention time 2.270 min, LCMS MH+-THP 531.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCC[N:25]([CH3:27])C.Cl.C1C=CC2N(O)N=NC=2C=1.CN([CH:42]=[O:43])C>C(N(CC)CC)C>[CH3:42][O:43][N:25]([CH3:27])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C=O
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A except using 2(S)-t-butoxycarbonylaminohexanoic acid (10.6 g, 0.045 mol), N, O-dimethylhydroxylamine hydrochloride (4.69 g, 0.048 mol), EDC.HCl (9.45 g, 0.049 mol), HOBT (6.18 g, 0.045 mol), DMF (200 mL) and triethylamine at pH 7. The crude product was chromatographed on silica gel with 15-20% ethyl acetate in hexane. The title compound was obtained as an oil. NMR (DMSO-d6, 300 MHz) δ 7.01 (1H, d, J=8 Hz), 4.34 (1H, q, J=5 Hz), 7.72 (3H, s), 3.09 (3H, s), 1.50 (2H, m), 1.36 (9H, s), 1.17 (3H, m), 0.85 (3H, t, J=6 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[F:14])[CH:2]=C.[O:15]=[O+][O-].CSC>CO>[F:14][C:5]1[C:6]2[CH2:10][O:9][C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[O:15]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1F)COC2=O
Solvent: CO
Solvent: CSC
Product: O=CCc1ccc2c(c1F)COC2=O
Temperature: 25 °C

Procedure:
To a solution of 5-allyl-4-fluoro-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in MeOH at −78° C. was bubbled ozone through until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.1 mL, 1.1 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to deliver (4-fluoro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 195 [M+1]+.