Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9](CCCCCCCBr)[C:8]2=[O:32])C=CC=CC=1.[P:33]([O:40][CH2:41][CH3:42])([O:37]CC)[O:34][CH2:35][CH3:36]>C1(C)C(C)=CC=CC=1>[C:12]1([N:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:7]=[C:8]2[O:32][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:10][CH2:11][P:33]([O:34][CH2:35][CH3:36])(=[O:37])[O:40][CH2:41][CH3:42])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1)OCC

Procedure:
A mixture of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.0 g) and triethyl phosphite (1.66 g) was heated at reflux temperature in xylene (5 ml) for 40 hours. The solution was evaporated to an oil and re-evaporated from ethanol. The oil was partitioned between ether and water, the ether solution was separated, dried over magnesium sulphate and evaporated to an oil which was chromatographed on silica gel (ethyl acetate) to give diethyl 7-(1,4,5-triphenylimidazol-2-yl-oxy)heptanephosphonate as an oil which solidified on standing to a white solid (0.83 g; 75%), m.p. 76°-7° C. Found: C, 70.49; H, 7.40; N, 4.94%; C32H39N204P; Requires: C, 70.31; H, 7.19; N, 5.12%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH:22][C:23]([NH:25][C@@H:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([O:36][C:37]4[CH:38]=[CH:39][C:40]5[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=5)[CH:42]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:20][C:19]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.N.CO>CCO.[Pd]>[C:49]([C:19]1[CH:20]=[C:21]([NH:22][C:23]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:29]([O:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=4)[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCN(C(=O)OCc5ccccc5)CC4)c4ccccc43)cn12
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: CO
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCNCC4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A suspension of Intermediate 16d (165 mg, 0.234 mmol), Pd/C (10%, 16 mg), and 2M NH3 in MeOH (0.117 mL, 0.234 mmol) in EtOH (5 mL) under N2 was evacuated and purged with H2 twice, then stirred at rt for 8 h. The suspension was filtered through Celite, then the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to ˜0.5 mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH (5 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left a pale yellow solid that was triturated with diethyl ether (10 mL) to leave a buff solid (121 mg). Half of this material was purified by HPLC (XBridge C18, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound as a white solid after freeze-drying (20.0 mg, 15%). LCMS (Method 5): Rt 3.16 min, m/z 571 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.16 (9H, s), 1.33 (3H, d, J 6.8), 1.35 (3H, d, J 6.8), 1.68 (2H, m), 1.79 (2H, m), 1.91 (2H, m), 2.09 (2H, m), 2.47 (2H, m), 2.98 (2H, d, J 12.3), 3.50 (1H, sept, J 6.8), 3.92 (1H, m), 4.82 (1H, m), 5.51 (1H, t, J 4.5), 5.97 (1H, s), 6.88 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.26 (1H, m), 7.31-7.38 (3H, m), 7.65 (1H, dd, J 9.8, 0.8), 8.07 (1H, br s), 8.18 (1H, d, J 2.0).
Reaction SMILES: [CH3:1]N(N=O)C(N[N+]([O-])=O)=N.C(OCC)C.[OH-].[Na+].[S:18]1[C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1>C1COCC1>[CH3:1][O:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][S:18][C:22]=2[CH:23]=1)=[O:29]
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2ncsc2c1
Yield: 102 %

Procedure:
Add 1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 33.9 mmol) to a mixture of diethyl ether (20 mL) and 1N aqueous NaOH (20 mL) at ambient temperature. Separate the organic layer and add it slowly to a solution of benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at 0° C. Evaporate the solvent to obtain the desired intermediate as a yellow solid (1.1 g, 100%). MS (ES+) m/z: 194 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 96.7 %

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate (22.5 mg, 0.0627 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (24 mg, 0.085 mmol, from Example 108, Step 1) and DIPEA (33 μL, 0.19 mmol) in ethanol (1.0 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl 3-[3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate (34 mg). LCMS calculated for C27H35ClFN6O4 (M+H)+: m/z=561.2. found: 561.2. The coupling product made above was treated with 4.0 M HCl in dioxane (0.5 mL, 2 mmol) in methylene chloride (0.2 mL) at room temperature for 1 hour. The reaction mixture was then evaporated to dryness to give N-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9H-purin-6-amine dihydrochloride. The resultant HCl salt was dissolved in methanol (0.2 mL)/acetonitrile (0.2 mL)/THF (0.2 mL) and treated with DIPEA (0.1 mL, 0.6 mmol) until the solid dissolved. Acetone (0.05 mL, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (0.066 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 4 h and then purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C23H25ClFN6O (M+11)+: m/z=419.2. found: 419.1. 1H NMR (300 MHz, DMSO-d6) δ 9.96 (1H, m), 8.41 (1H, m), 8.23 (1H, s), 8.20 (1H, s), 7.53 (1H, s), 5.69 (1H, m), 4.52 (2H, m), 4.26 (1H, m), 4.12 (2H, m), 3.77 (3H, s), 2.08 (3H, m), 1.46 (3H, d, J=6.9 Hz), 1.11 (6H, m) ppm.
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16])([O-])=O.[H][H]>[Pd]>[NH2:7][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: N#CCCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCOc1ccccc1N
Reaction time: 4 h
Yield: 98 %

Procedure:
To palladium (0.00748 g, 0.0702 mmol) in a 50 mL flask with stirbar was added ethyl acetate (11.7 g, 133 mmol) under nitrogen, and then nitrile 83 (0.675 g, 3.51 mmol) was added (FIG. 18). The flask was fitted with a balloon containing hydrogen, and the nitrogen inlet was removed. The reaction was stirred vigorously for 4 hours, and then was filtered through celite, washing with ethyl acetate. The product 84 required no further purification, 98% yield. 1H NMR (500 MHz, CDCl3) δ 6.85-6.77 (m, 1H), 6.74-6.62 (m, 3H), 4.08 (t, J=6.1 Hz, 2H), 3.94-3.74 (m, 2H), 2.72 (t, J=6.1 Hz, 2H). LRMS m/z Calcd. for C9H10N2O: 162.07931. found: 163.1 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([Br:23])C(=O)C1>ClCCCl>[Br:23][C:6]1[N:5]([CH3:14])[C:4](=[O:15])[C:3]([O:2][CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Solvent: ClCCCl
Product: CCOC(=O)c1cc(Br)n(C)c(=O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of Intermediate 1 (109 mg, 0.516 mmol) in DCE (2.0 mL) was added NBS (110 mg, 0.619 mmol). The reaction mixture was stirred at rt overnight and then was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in a small amount of DCM and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 18 (138 mg, 0.476 mmol, 69% yield) as a white solid. HPLC/MS (Method D) RT=1.4 min, [M+1]+ 291.9; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (1H, s), 4.42 (2H, q, J=7.28 Hz), 3.99 (3H, s), 3.55 (3H, s), 1.39 (3H, t, J=7.15 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([C:22]([O:24]CCCC)=[O:23])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1>C(Cl)Cl>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: CCCCOC(=O)C1(c2ccc(-n3cccn3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(c2ccc(-n3cccn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1.0 mL) was added to butyl 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylate (60 mg) in methylene chloride (1.0 mL). The mixture was stirred at room temperature overnight, and then concentrated to give a crude product which was directly used in the reaction of next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: COc1c(C)cccc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C)cccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
DMF (1 ml) was added to 3-methyl-2-(methyloxy)benzoic acid (134 mg, 0.81 mmol) (Apin Chemicals), HATU (306 mg, 0.81 mmol) and DIPEA (0.422 ml, 2.417 mmol). The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.403 mmol). The reaction was stirred under nitrogen at RT overnight, then it was loaded onto a PS-aminopropyl cartridge and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (2 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen to give title compound (6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9](O)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:7]=1)=[O:5])[CH3:2].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NN(c2ccc(OC)nc2)C(O)(c2ccccn2)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nc2)n1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
The above-obtained 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazole-3-carboxylic acid ethyl ester (0.546 g) was dissolved in ethanol (11 mL). Acetic acid (0.456 mL) was added to the resultant mixture, followed by stirring at 105° C. for 4 hours. The mixture was cooled in air. Subsequently, the reaction mixture was partitioned by use of saturated aqueous solution of sodium hydrogencarbonate, water, and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (0.516 g, 100%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].Br[C:18]1C=NN(C2CC2)C=1>>[CH3:16][C:10]1([CH3:15])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:6]2[CH:5]=[N:4][N:3]([CH:1]3[CH2:18][CH2:2]3)[CH:7]=2)[O:9]1
Reactant: Brc1cnn(C2CC2)c1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-cyclopropyl-1H-pyrazole.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)=[O:5].[CH3:19][Mg+].[Br-].O>C1COCC1>[N:13]1([C:8]2[N:7]=[C:6]([C:4](=[O:5])[CH3:19])[CH:11]=[C:10]([CH3:12])[N:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CON(C)C(=O)c1cc(C)nc(-n2ccnc2)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
To a solution of 2-imidazol-1-yl-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (162 mg, 0.800 mmol) in THF (10 mL) at 0° C. was added MeMgBr (0.8 mL, 3M in Et2O, 2.40 mmol). The solution was warmed to rt and stirred for 20 min. Water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 143 mg (88%) of 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone as a yellow solid. [M+H]+ 203.17.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[N:30](COCC[Si](C)(C)C)[C:29](=[O:39])[O:28][CH2:27][C:26]=3[CH:40]=2)[CH2:18][CH2:17]1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:39])[O:28][CH2:27][C:26]=3[CH:40]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCN(c3ccc4c(c3)COC(=O)N4COCC[Si](C)(C)C)CC2)nc(-c2ccncn2)cc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(OC2CCN(c3ccc4c(c3)COC(=O)N4)CC2)nc(-c2ccncn2)cc1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
To a solution of 1-methyl-2-{[1-(2-oxo-1{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-2H-3,1-benzoxazin-6-yl)piperidin-4-yl]oxy}-1H-[4,4′]bipyrimidinyl-6-one (78 mg, 0.14 mmol) in tetrahydrofuran (1.4 ml) was added 6N aqueous hydrochloric acid (1.4 ml, 8.4 mmol). The mixture was stirred at 70° C. for 3 hours. The mixture was poured into water. The aqueous solution was neutralized with sodium hydrogen carbonate. Extraction with dichloromethane was performed three times. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=98/2) to afford 1-methyl-2-{[1-(2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)piperidin-4-yl]oxy}-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (22 mg, 0.051 mmol, 38%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)[C:6](N)=[N:5]1)([CH3:3])[CH3:2].C(ON=O)CC(C)C.C(I)[I:27]>>[I:27][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)=[CH:8][N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: ICI
Reactant: CSc1nccc(-c2cn(C(C)C)nc2N)n1
Agent: CC(C)CCON=O
Product: CSc1nccc(-c2cn(C(C)C)nc2I)n1
Temperature: 100 °C

Procedure:
A mixture of Intermediate 1-isopropyl-4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine (4.0 g, 16.0 mmol), isopentylnitrite (13.2 g, 112 mmol), and methylene iodide (30 mL) was heated at 100° C. for 3 h. Removal of the volatiles under vacuum provided a dark residue, which was purified by silica gel chromatography (2:1 hexane/ethyl acetate eluant) to afford the title compound as a solid; MS m/z: 361.1 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cnn(C2CCCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnn1C1CCCCO1
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.10 g, 13.8 mmol) in anhydrous THF (30.0 mL) was added n-BuLi (2.5 M in hexane, 14.0 mL) at −78° C. The mixture was kept at this temperature for 30 min. Triisopropyl borate (2.85 g, 15.2 mmol) was added over 10 min at −78° C. and held for 1 hr. The resulting mixture was allowed to reach room temperature over 4 hr. After being quenched by aq. HCl (2.00 M, 55.0 mL) with intensive stirring, the aqueous phase was added NaCl (s) and extracted with THF/EtOAc. The combined organic layer was washed with brine, sat NaHCO3, dried over MgSO4, filtered and evaporated to afford 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (3.6 g, 52% yield) as yellow oil. LCMS (ESI) m/z: 197.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:6][N:5]=1
Reactant: COCc1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
A solution of tert-butyl 4-[1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (872 mg; compound B8) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (1.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([OH:26])=[CH:21][CH:22]=2)[CH:17]=1>ClC(Cl)C>[CH3:9][O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([C:1](=[O:3])[CH3:2])[C:20]([OH:26])=[CH:21][CH:22]=2)[CH:17]=1
Reactant: COC(=O)CCCOc1ccc2ccc(O)cc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)CCCOc1ccc2ccc(O)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Under argon, 2.8 ml of acetyl chloride was added to a suspension of 5.15 g of aluminum chloride in 120 ml of dichloroethane. Then 8 g of 4-[(7-hydroxy-2-naphthalenyl)oxy]butanoic acid methyl ester was added and the resulting mixture was stirred at room temperature for 30 minutes and at reflux for 16 hours. The solution was filtered and the dark residue was broken up with 3N hydrochloric acid and extracted with methylene chloride. The filtrate was combined with the methylene chloride extract, washed and dried to give a black oil which was purified by HPLC (eluting with 2% ethylacetate/toluene) to yield 2.72 g (29%) of 4-[(8-Acetyl-7-hydroxy-2-naphthalenyl)oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O>C(O)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
A solution of pyruvic acid (13.6 mL, 195.3 mmol) in ethanol (20.0 mL) was added to a 0.5 M sodium hydroxide solution (533.0 mL). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 2-chlorobenzaldehyde (20.0 mL, 177.6 mmol) in ethanol (155.0 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid was washed with ethyl acetate, diluted with a 6N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 34.5 g of the titled compound as a yellow liquid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([O:36][C:37](=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:46])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOC(=O)CCCCCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82-84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86-7.65 (m, 3H), 5.18-5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97-2.83 (m, 1H), 2.64-2.48 (m, 2H), 2.30-2.15 (m, 4H), 2.08-2.04 (m, 1H), 1.56-1.47 (m, 4H), 1.32-1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.