Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:20][OH:21])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)(=[O:32])=[O:31]
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccccc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methanol (112 mg) obtained from Referential Example 75 was dissolved in methylene chloride (4 mL). To the solution, triethylamine (61 μL) and methanesulfonyl chloride (34 μL) were added at room temperature, followed by stirring for 15 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as an oily product (13.8 mg, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH3:18])=[O:16])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])(F)[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[C:5](F)[CH:4]=1)#[N:2].FC(F)C1C=C(N2C3C[CH2:50][C:51](=[O:52])C=3C(C3C=CC(C#N)=CC=3)NC2=O)C=CC=1.NCCCO>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH2:18][CH2:50][CH2:51][OH:52])=[O:16])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([F:27])[F:29])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1F
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: NCCCO
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)F)c3)C(=O)N2C(=O)NCCCO)cc1

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-fluorophenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 49), using 4-(1-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) as starting material and replacing methylamine with 3-aminopropanol. Yield: 70 mg; ESI mass spectrum [M+H]+=481; Retention time HPLC: 0.71 min (005_CA01).
Reaction SMILES: [CH3:1][C:2]1[CH:6]([N:7]=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=2)[N:3]=1.O=S(Cl)[Cl:28]>CN(C)C=O>[Cl:28][S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:4]2[C:5](=[O:15])[CH:6]([N:7]=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:2]([CH3:1])=[N:3]2)=[CH:17][CH:18]=1)(=[O:25])=[O:23]
Reactant: O=S(Cl)Cl
Reactant: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1N=Nc1ccccn1
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(S(=O)(=O)Cl)cc2)C(=O)C1N=Nc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
9.0 g (0.025 mole) of 3-methyl-4-(2-pyridylazo)-1-(p-sulfophenyl)-2-pyrazolin-5-one was added in portions with stirring to 70 ml of SOCl2. To this suspension was added dropwise 3 ml of dimethylformamide. The mixture was stirred overnight. The resulting solution was poured slowly with vigorous stirring into 500 ml of ice water. The solid product was filtered and pressed dry. This product was slurried in 50 percent tetrahydrofuran/ethyl ether, filtered, and dried to obtain 5.3 g (56 percent) of orange solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A solution of triphenylphosphine (290 mg, 1.1 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (195 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (192 mg, 0.55 mmol) in methylene chloride (3 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (166 mg, 1.66 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (40 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 to 2/3 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide (86 mg, 36%) as an amorphous solid: EI-HRMS m/e calcd for C20H21ClN6OS (M+) 428.1186, found 428.1189.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C[Mg]Cl.[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:16]=1C(Cl)=O>O1CCCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:16]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:15]=1[Cl:14])=[O:5])[CH3:9]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C[Mg]Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A 400 liter glass-lined reactor was charged with 129 liters of dry tetrahydrofuran and 21.7 kg (2.1 equivalents) of potassium ethyl malonate. With slight cooling, 42.4 liters of 3M methyl magnesium chloride was added at a rate to keep the temperature between 20° to 50° C. After a 30 minute stir, the solution was cooled to 0° to -5° C. and 12.8 kg of 2-chloro-4,5-difluorobenzoyl chloride was added at a rate to keep the temperature between 0° and 5° C. The solution was then quenched into 106 liters of 2N HCl. After the addition of 72 liters of toluene, the aqueous layer was removed. The product layer was washed with 53 liters of saturated bicarbonate and salt solution. After removal of the aqueous layer, the product layer was concentrated to an oil and 28 liters of isopropyl alcohol were added. The solution was cooled to -10° to -15° C., granulated and the solids filtered and vacuum dried to give 14.17 Kg (first crop) and 588 g (second crop) of the title compound, 92.8% yield. The high field NMR of the product was typical of that for a mixture of the keto (5%) and enol (95%) forms of the title compound 300 MHz 1H (CDCl3): 12.5 (s, 0.95H), 7.5 (d of d, J=11 Hz, J'=8 Hz, 1H) 7.3 (d of d, J=11 Hz, J'=8 Hz, 1H), 5.6 (s, 0.95H), 4.3 (q, J=6H, 1.9H), 4.2 (q, J=6 Hz, 0.1H), 4.0 (s, 0.1H), 1.4 (t, J=6 Hz,2.85H), 1.2 (t, J=6 Hz, 0.15H).
Reaction SMILES: [OH:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:18]O>S(=O)(=O)(O)O.COC(OC)(C)C>[CH3:18][O:16][C:15]([CH:11]1[CH2:12][C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][OH:1])=[CH:8][CH:7]=2)[CH2:10]1)=[O:17]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OO)cc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)OC
Product: COC(=O)C1CC(=O)N(c2ccc(OO)cc2)C1
Yield: 84 %

Procedure:
In a 10 1 4-necked flask equipped with a reflux condenser, a thermometer, and a mechanical stirrer, the crude (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is dissolved in a mixture of 5000 ml of methanol, 24 ml of concentrated sulfuric acid and 400 ml of 2,2-dimethoxypropane and stirred under reflux during 2 h. For the working-up, the reaction solution is reduced to half of its volume by distillation, then transferred into a 20 1 vessel. Under stirring at 40° C., a mixture of 2500 ml of water/ice (1:1) is added. Crystallisation started immediately, and, thereupon, the fine white crystals are collected on a filter funnel. They are washed with total 2000 ml of cold water until the filtrate, at the beginning brownish-rose, becomes colorless and neutral. The well pressed and pre-dried product from the filter funnel is dried under reduced pressure to yield 980 g (84% of theory, 2 steps) of the (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>>[F:30][C:31]([F:37])([F:36])[S:32]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)C(F)(F)F)C3)cnc21

Procedure:
1-(1-Trifluoromethanesulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and trifluoromethane sulfonyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:17]([CH2:20]C(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][CH2:18][C:17](=[O:19])[CH3:20])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Yield: 39.7 %

Procedure:
A mixture of 3-bromomethylbenzophenone (2.75 g.), acetylacetone (1 g.), potassium carbonate (1.4 g.) and ethanol (50 ml) was refluxed for 2 hours. The solvent was then evaporated and the residue extracted with ether. Distillation of the concentrated extracts gave 4-(m-benzoylphenyl)-2-butanone (1 g.), b.p. 220° C. (4 mm). [An alternative preparation of this compound appears in German Offenlegungsschrift 2243444].
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:21]>C(Cl)(Cl)Cl.O>[Br:21][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.1 g, 0.39 mmol) in chloroform (15 mL) was added PBr3 (0.316 g, 1.17 mmol) at 0-5° C. The solution was maintained at the same temperature for 1 h, was slowly warmed to rt and maintained at rt for another 2 h. The contents were diluted with water (75 mL) and chloroform (100 mL), the layers separated, the organic layer was washed with bicarbonate solution (2×30 mL), and the organic layer was dried over sodium sulphate and distilled off to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide (0.12 g, crude). LC-MS m/z calcd for [M+H]+ 321.03. found 321.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:12]([O:10][CH2:9][C:3]1([CH:2]=[O:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=CC1(CO)CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:3][CH2:2]1.O[C:13]1[CH:22]=[C:21]2[C:16]([C:17]([S:23][CH3:24])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>>[CH3:24][S:23][C:17]1[C:16]2[C:21](=[CH:22][C:13]([O:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:14][CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: CSc1ncnc2cc(O)ccc12
Reactant: OC/C=C/CN1CCOCC1
Product: CSc1ncnc2cc(OC/C=C/CN3CCOCC3)ccc12
Yield: 55.6 %

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [12] above, (E)-4-morpholinobut-2-en-1-ol (J. Med. Chem., 1972, 15, 110-112; 1.27 g), was reacted with 7-hydroxy-4-methylthioquinazoline (1.2 g) to give 4-methylthio-7-[(E)-4-morpholinobut-2-en-1-yloxy]quinazolin (1.15 g); NMR Spectrum: (CDCl3) 2.45 (br s, 4H), 2.7 (s, 3H), 3.05 (d, 2H), 3.7 (t, 4H), 4.7 (d, 2H), 5.9 (m, 2H), 7.15-7.25 (m, 2H), 7.95 (d, 1H), 8.9 (d, 1H); Mass Spectrum: M+H+ 332.
Reaction SMILES: OO.[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:23])=[CH:9][N:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reaction time: 1 h
Yield: 148.1 %

Procedure:
Add 30% aq. H2O2 (7.95 ml) to a suspension of 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g, 7.95 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (20 ml) stirring in an ice/water bath. After one hour, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (1.64 g) as a white solid. 1HNMR (DMSO-d6): 10.14 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H), 8.07 (s, 1H), 7.74 (t, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 7.27 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[C:17]([Br:19])=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Br:19][C:17]1[C:18]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:7]=3)[O:12][C:13]=2[CH:14]=[CH:15][C:16]=1[O:20][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(O)c(Br)c12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (S)-2-amino-1′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (163 mg, 0.384 mmol), cesium carbonate (375 mg, 1.152 mmol), and DMF (2.0 mL). The mixture was stirred for 10 min, then 1-iodo-2,2-dimethylpropane (102 μL, 0.768 mmol) was added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 2 h at 110° C. LCMS at this time shows no starting material and mainly desired product. The mixture was partitioned between water and EtOAc. Brine was added to break up the emulsioon that formed and this was partially successful. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 50-g SNAP column, eluting with 0-70% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid after evaporation from DCM/hexane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@H:16]1[C@@H:20]([O:21]C(=O)C2C=CC=CC=2)[C@H:19]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([CH2:54][NH:55][C:56]([NH:58][CH2:59][CH2:60][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[O:57])=[N:34][C:35]=3[NH:39][CH2:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:18][C@@H:17]1[C:67]([NH:69][CH2:70][CH3:71])=[O:68])(=O)C1C=CC=CC=1.CC(C)=O>CO>[C:42]1([CH:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:40][NH:39][C:35]2[N:34]=[C:33]([CH2:54][NH:55][C:56]([NH:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)=[O:57])[N:32]=[C:31]3[C:36]=2[N:37]=[CH:38][N:30]3[C@@H:19]2[O:18][C@H:17]([C:67]([NH:69][CH2:70][CH3:71])=[O:68])[C@@H:16]([OH:15])[C@H:20]2[OH:21])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
Potassium carbonate (20 mg, 0.14 mmol) was added to a solution of (2S,3S,4R,5R)-4-(benzoyloxy)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (100 mg, 0.13 mmol) (Preparation 14) in methanol (100 ml). The reaction mixture was stirred at room temperature for 2 hours. More potassium carbonate (20 mg, 0.14 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. The solvent was removed under reduced pressure to give a residue that was slurried with acetone and filtered. The filtrate was evaporated under reduced pressure and the residue was partially purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume). The residue after solvent evaporation under reduced pressure was repurified by more column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume). The solvent was removed by evaporation under reduced pressure to give the title compound as a foam (17 mg).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
To 10.4 g of ethyl acetoacetate were added 15 g of 1,2-dibromoethane, 23 g of potassium carbonate, and 150 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at room temperature for 2 days. Any insoluble matter was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting pale yellow oily substance was subjected to distillation under reduced pressure to obtain 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate having a boiling point of 70° to 71° C./2 to 3 mmHg.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1>>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: CC1(C)OB(c2ccc(OCc3ccccc3[N+](=O)[O-])cc2)OC1(C)C
Yield: 62 %

Procedure:
Alkylation of 1-Bromomethyl-2-nitro-benzene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 3.32 to give 4,4,5,5-Tetramethyl-2-[4-(2-nitro-benzyloxy)-phenyl]-[1,3,2]dioxaborolane in 62% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.5 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (dd, J=7.8, 1.0 Hz, 1 H) 8.2 (dd, J=8.1, 1.3 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5].C(N(CC)CC)C>CS(C)=O>[O:1]=[CH:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5]
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of (R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (5.0 g, 26.4 mmol) in DMSO (50 mL) was chilled to 15° C., followed by the addition of triethylamine (10.99 mL, 79 mmol) and a solution of sulfur trioxide-pyridine complex (12.62 g, 79 mmol) in DMSO (50 mL) in succession. The mixture was stirred at 15° C. for 30 minutes, then allowed to warm to ambient temperature overnight. The reaction was quenched with 200 mL 1.0 M citric acid, and extracted twice with 250 mL MTBE. The organic phase was washed with 200 mL water and 200 mL brine, separated, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-35% EtOAc in Hexanes (40 mL/min) to provide the title compound (4.561 g, 24.36 mmol, 92.2% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.42 (d, J=0.7, 1H), 7.27 (d, J=6.8, 1H), 3.73 (dd, J=13.3, 7.8, 1H), 1.78-1.58 (m, 1H), 1.54-1.28 (m, 10H), 0.87 (t, J=7.4, 3H).