Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:8]([OH:17])([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:9]\1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)([OH:17])[C:9]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: CN(C)/C=C1\CCCC(O)(c2cccnc2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O)(c2cccnc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 6-[1-dimethylamino-meth-(E)-ylidene]-2-hydroxy-2-pyridin-3-yl-cyclohexanone (59 mg, 0.24 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (74 mg, 0.20 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (54 mg, 63%). MS ISP (m/e): 429.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.63 (s, 1H), 8.51 (s, 1H), 8.42 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.62 (s, 1H), 7.33 (dd, 1H), 7.04 (s, 2H), 6.97 (s, 1H), 5.95 (s, 1H), 5.76 (s, 1H), 3.39 (s, 3H), 2.75 (m, 3H), 2.12 (s, 3H), 2.02 (m, 3H), 1.75 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (470 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[N:16][N:15]4[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>CN(C=O)C.O>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:37][C:36]([O:35][CH3:34])=[O:39])=[N:16][N:15]4[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CBr
Reactant: NC1(c2ccc(-c3nc4ccc(O)nn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol that was prepared in a manner analgous to that described for Example 79 (0.093 g, 0.26 mmol) in DMF (2.5 mL) was added cesium carbonate (0.26 g, 0.79 mmol, 3.0 equiv) and bromoacetic acid methyl ester (0.03 mL, 0.31 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 1 h, then was warmed to 60° C. for 3 h. The resulting mixture was diluted with water (10 mL). The aqueous mixture was extracted with EtOAC (3×10 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2× Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mm column; gradient from 100% water with 0.1% HCO2H to 70% water with 0.1% HCO2H/30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO2H/70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl ({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate (0.056 g, 49%):
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:11][NH2:12])[CH2:7][C:8](Cl)=[O:9].[CH3:13][OH:14]>N1C=CC=CC=1>[CH3:13][O:14][C:8](=[O:9])[CH2:7][CH:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:11][NH2:12]
Reactant: NCC(CC(=O)Cl)c1ncc[nH]1
Reactant: CO
Solvent: c1ccncc1
Product: COC(=O)CC(CN)c1ncc[nH]1

Procedure:
0.01 mol of the compound obtained in stage A of Example 16 is dissolved in 30 cm3 of pyridine. 1 cm3 of methanol is added. The whole is heated under reflux for five hours, the reaction medium is evaporated in vacuo on a water bath. The residue is dried and purified by chromatography.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]C)[C:10]([CH3:16])=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:16])([CH3:3])[CH3:2]
Reactant: COc1cc2c(C)cccc2cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc2cc(C(C)C)c(O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
6-Isopropyl-7-methoxy-1-methyl-naphthalene (2.1 g, 9.79 mmol) was dissolved in 30 mL methylene chloride and the resulting solution was cooled in an ice bath. Boron tribromide (3.3 mL, 2.2 mmol in methylene chloride) was added dropwise, and the solution was stirred for one hour at 0° C. under nitrogen atmosphere, then for 18 hours at room temperature. The reaction mixture was poured into ice water and extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (8:1 hexanes/dichloromethane) on silica to yield 1.79 g of 3-isopropyl-8-methyl-naphthalen-2-ol as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:10]([NH2:12])[CH3:11].C(N(CC)CC)C.C(O)CCC>CCCCCC.CCOC(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:12][CH2:10][CH3:11])[N:7]=1
Reactant: CCN
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1nccc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dichloropyrimidine 21-1 (7.0 g, 47 mmol), ethylamine hydrochloride (5.75 g, 70.5 mmol), triethylamine (19.6 mL, 141 mmol) and n-butanol (150 mL) was heated at 90° C. for 6 hours. The solution was cooled, poured into water and extracted with EtOAc (2×). After washing with water then brine, the organic layer was dried (MgSO4) and concentrated to give an oil. Column chromatography (hexane:EtOAc 2:1 then 1:1) afforded the title compound 21-2 as the minor compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([S:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:12]([S:14][C:15]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1)=[O:18])[CH3:13]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 1.62 g of 2-amino-5-trifluoromethylpyridine, 2.5 g of 2-ethylsulfanyl-4-trifluoromethylbenzoic acid, 2.3 g of EDCI hydrochloride, 0.13 g of HOBt and 5 mL of pyridine was stirred at room temperature for 2 hours and at 60° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 2.56 g of 2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](/[CH:13]=[C:14]3/[C:15](=[O:23])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:12][C:11](/[CH:13]=[C:14]3/[C:15](=[O:23])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][CH:9]=2)[CH:3]=1)=[O:28]
Reactant: Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Product: O=C(CCCl)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Reaction time: 0.33 h

Procedure:
To a solution of (E)-3-((5-(3-aminophenyl)furan-2-yl)methylene)indolin-2-one (80 mg, 0.26 mmol) and TEA (0.11 mL, 0.79 mol) in DCM (5.0 mL) was added 3-chloropropanoyl chloride (0.04 mL, 0.42 mmol). The reaction was stirred for 20 min and the precipitate was collected by filtration to yield desired (E)-3-chloro-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)propanamide. LCMS (ES): m/z 357 [M+1-Cl]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: ClCCCN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-bromo-3-chloropropane (65.6 g, 0.417 mol) and piperidine (62 ml, 0.625 mol) in anhydrous THF (200 ml) was heated to reflux for 24 h. The mixture was cooled to RT and filtered to remove solids. The organics were concentrated under in vacuo. The resultant residue was taken up in 2N HCl and washed twice with ethyl acetate. The aqueous layer was basicified with 2N NaOH to pH 14. The compound was extracted three times with ethyl acetate and the combined organics dried over anhydrous magnesium sulfate. The solution was then concentrated under reduced pressure to give the desired compound as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: NC1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (4.21 g, 20 mmol) in DCM (20 mL) was added dropwise to a stirred suspension of 4-aminotetrahydropyran (2.03 g, 20 mmol) and N-ethyldiisopropylamine (4.19 mL, 24 mmol) in DCM (20 mL) at 0° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2,6-dichloro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (5.03 g, 92%) as a white solid.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[CH3:13][NH:14][NH2:15]>CCO>[CH3:13][N:14]1[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:8])([F:7])[F:6])=[N:15]1
Reactant: CNN
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1N
Yield: 82.1 %

Procedure:
Using the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.34 g, 12.78 mmol) and methylhydrazine (0.645 g, 14 mmol) were reacted in EtOH (10 mL) at 95° C. for 8 hours, and purified by silica gel chromatography with 30-40% EtOAc/hexane as eluants to afford 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (1.733 g, 68.3%). MP: 100-101° C.; 1H NMR (300 MHz, CDCl3) δ 5.80 (s, 1H), 3.71 (s, 3H), 3.62 (br, 2H); LC-MS (ESI) m/z 166 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:23])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: c1ccncc1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Solvent: ClCCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21

Procedure:
In a manner similar to that described in Example 1 above, 5.2 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine at ambient temperature overnight to obtain 4.5 g of 3-methoxy-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green-colored solid which melted over the range of 141° to 149° C. An infrared maximum appeared at 1770 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Analysis by mass spectrum showed m/e peaks at 326 (M+) and 295 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a green-colored image.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1N=CN(C2C=[C:21]3C(=CC=2)NC=[C:22]3[CH2:28][CH2:29][OH:30])C=1>CO>[N:1]1([CH2:6][C:7]2[CH:13]=[C:12]3[C:10](=[CH:9][CH:8]=2)[NH:11][CH:21]=[C:22]3[CH2:28][CH2:29][OH:30])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: Nc1ccc(Cn2cncn2)cc1
Solvent: CO
Product: OCCc1c[nH]c2ccc(Cn3cncn3)cc12

Procedure:
Prepared from 4-(1,2,4-triazol-1-ylmethyl)aniline (EP497512) as described for Intermediate 3, δ (250 MHz, D4 -MeOH) 2.96 (2H, t, J=7.2 Hz, CH2), 3.80 (2H, t, J=7.2 Hz, CH2), 5.46 (2H, s, CH2), 7.08 (1H, dd, J=1.7 and 8.6 Hz, Ar--H), 7.11 (1H, s, Ar--H), 7.33 (1H, d, J=8.6 Hz, Ar--H), 7.58-7.59 (1H, d, J=1.7 Hz, Ar--H), 7.97 (1H, s, Ar--H), 8.44 (1H, s, Ar--H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:15][CH2:16][CH2:17]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid (Frontier Scientific, Inc., Logan, Utah, USA) for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.07 (d, J=8.48 Hz, 1H) 7.97 (d, J=2.03 Hz, 1H) 7.59 (dd, J=8.48, 2.03 Hz, 1H) 4.08 (s, 3H) 3.93-4.06 (m, 1H) 3.18-3.34 (m, 5 H) 2.49-2.61 (m, 1H) 2.34-2.47 (m, 3H) 2.03-2.19 (m, 2H). MS: (M+H)+=353.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:18]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCOc1ccccc1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
2-Phenoxyethanol (50 g, 0.362 mol) was dissolved in dichloromethane (500 ml) and the solution was cooled to 0-5° C. Triethylamine (101 ml, 0.724 mol) was added to the cooled solution followed by pivaloyl chloride (53.5 ml, 0.434 mol) maintaining the temperature, below 5° C. After additions the mixture was stirred at 5° C. for 30 min and at room temperature for 12 h. The reaction was quenched by addition of 1M HCl-solution (300 ml) and stirred vigorously. The phases were separated and organic phase was washed with saturated NaHCO3-solution (2×150 ml), water (1×100 ml) and brine (1×100 ml). After drying (Na2SO4) and filtration the solvent was evaporated yielding the title compound (76.78 g, 0.345 mol, 95%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.31-7.27 (2H, m, ArH), 6.96-6.93 (3H, m, ArH), 4.34 (2H, m, CH2CH2OPiv), 4.19 (2H, m, ArOCH2CH2), 1.13 (9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 177.7, 158.7, 130.1, 121.1, 114.9, 66.1, 62.9, 38.5, 27.6.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Br:10][C:11]1[CH:17]=[C:16]([F:18])[C:14]([NH2:15])=[C:13]([F:19])[CH:12]=1>C(O)(=O)C>[Br:10][C:11]1[CH:17]=[C:16]([F:18])[C:14]([N+:15]([O-:6])=[O:5])=[C:13]([F:19])[CH:12]=1
Reactant: O
Reactant: Nc1c(F)cc(Br)cc1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 55 °C

Procedure:
To a suspension of sodium perborate tetrahydrate (1.04 g, 5 mmol) in acetic acid (20 mL), stirred at 55° C., was added a solution of 4-bromo-2,6-difluoroaniline in acetic acid (10 mL) over 1 hour in a dropwise fashion. After stirring at 55° C. for an additional 3 hours, the solution was allowed to cool to room temperature and filtered. The filtrate was poured into ice, and extracted twice with ethyl acetate. The combined organic extracts were washed successively with 5×100-mL portions of water, brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:20) to afford 780 mg of the title compound as a tan solid. 1H NMR (CDCl3) δ 7.32 (dt, 2H).
Reaction SMILES: C([NH:8][C@@H:9]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:28]>CO>[ClH:28].[ClH:28].[NH2:8][C@@H:9]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:17][CH2:16]1)=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(C2CCN(C)CC2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Temperature: 0 °C
Yield: 96 %

Procedure:
1-(Boc-D-Valinyl)-4-(1-methylpiperidin-4-yl)piperidine (23.3 g, 61.1 mmol) is dissolved in anhydrous methanol (700 mL), cooled to 0° C. and treated with HCl (gas) until HPLC indicates consumption of starting material is complete. The solvent is removed in vacuo to give 20.8 g (96%) of the title compound as an off-white foam.
Reaction SMILES: [Cl:1][CH:2]1[CH:13]([CH3:14])[CH:12]2[CH:4]([C@@:5]3([CH:42]=[O:43])[CH2:26][C@H:9]4[C@@:10]([CH2:15]OCC5C=CC(OC)=CC=5)([CH2:11]2)[C@:6]3([C:30]([O:32]CC2C=CC(OC)=CC=2)=[O:31])[C:7]([CH:27]([CH3:29])[CH3:28])=[CH:8]4)[CH2:3]1.[CH3:44][OH:45]>[OH-].[OH-].[Pd+2]>[OH:45][CH2:44][CH2:15][C@@:10]12[C@@H:9]3[CH2:26][C@@:5]([CH:42]=[O:43])([C@:6]1([C:30]([OH:32])=[O:31])[C:7]([CH:27]([CH3:29])[CH3:28])=[CH:8]3)[CH:4]1[CH:12]([CH:13]([CH3:14])[CH:2]([Cl:1])[CH2:3]1)[CH2:11]2
Reactant: COc1ccc(COC[C@@]23CC4C(C)C(Cl)CC4[C@@]4(C=O)C[C@@H]2C=C(C(C)C)[C@@]34C(=O)OCc2ccc(OC)cc2)cc1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CCO)[C@@]13C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of 40 (40 mg, 0.066 mmol) in CH3OH (5 mL) was added Pearlman's catalyst (10 mg). The mixture was stirred under hydrogen (balloon pressure) for about 15 minutes. After filtration and concentration in vacuo, about 23.7 mg of 41 was obtained and used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.N[C@@H]1CC[CH2:16][CH2:15][C@H:14]1[OH:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC1COC1>CC(O)C.[Ni](I)I>[F:1][C:2]1[CH:3]=[C:4]([CH:15]2[CH2:14][O:19][CH2:16]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: IC1COC1
Solvent: CC(C)O
Product: Fc1cc(F)cc(C2COC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
3,5-difluorophenylboronic acid (2.0 equiv.), (1R,2R)-2-aminocyclohexanol (0.06 equiv.), NaHMDS (2.0 equiv.), and nickel(II) iodide (0.06 equiv.) were dissolved in 2-propanol (0.35 M). The mixture was degassed with N2, stirred at rt for 10 min and then a solution of 3-iodooxetane (1.0 equiv.) in 2-Propanol (0.70 M) was added. The mixture was sealed and heated at 80° C. in the microwave for 20 min. The mixture was filtered through celite, eluting with EtOH and concentrated. The crude residue was purified by ISCO SiO2 chromatography eluting with 0-100% EtOAc in Heptanes to afford 3-(3,5-difluorophenyl)oxetane in 63% yield. 1H NMR (400 MHz, <cdcl3>) δ 6.88-6.96 (m, 2H), 6.72 (tt, J=2.20, 8.95 Hz, 1H), 5.08 (dd, J=6.26, 8.22 Hz, 2H), 4.71 (t, J=6.26 Hz, 2H), 4.14-4.24 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[N:6]=[C:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]3[CH2:27][CH3:28])[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:10]=2[N:11]=1.[CH3:29][O:30][P:31]([O:34]C)[O:32][CH3:33]>>[CH3:29][O:30][P:31]([CH2:2][C:3]1[S:4][C:5]2[N:6]=[C:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]3[CH2:27][CH3:28])[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:10]=2[N:11]=1)(=[O:34])[O:32][CH3:33]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)sc2n1
Reactant: COP(OC)OC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CP(=O)(OC)OC)sc2n1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 2-bromomethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (670 mg, 1.46 mmol) in trimethylphosphite (10 mL) was heated to reflux (120° C.) for 1 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) then (Si—PCC, MeOH:EtOAc, 0-5%) affording the title compound as a yellow solid (620 mg, 87%)._LCMS (method H): RT 2.46 min, [M+H]+ 489.3
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=1)(=[O:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:4]2[C:5]3=[N:11][N:10]([CH2:12][C:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:29])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccc(CCl)cc1
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)cc1

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(chloromethyl)phenyl acetate using potassium carbonate as a base in DMF at 80° C.