Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]([CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]([CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH2:20][CH2:21][N:22]1[C:23](=[O:32])[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]1=[O:31])=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1CCNCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution chloroacetyl chloride (1.2 mL, 15.2 mmol) in DCM (65 mL) at 0° C. was added dropwise a solution of 2,2′-(iminodi-2,1-ethanediyl)bis(1H-isoindole-1,3(2H)-dione) (5 g, 13.7 mmol) [prepared according to Anelli, P. L.; et. al. J. Org. Chem. 1984 49, 4197.] and Et3N (2.5 mL, 17.9 mmol) in DCM (65 mL). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 5% MeOH in DCM (NH4OH)) yielding the title compound (5.9 g, 98%) as a yellow foam: LCMS (ES) m/e 440 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(F)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (11 g, 31.16 mmol) in dry CH2Cl2 (140 mL) was added Et3N (12.60 g, 16.68 mL, 124.65 mmol, 4 eq) at −5-0° C. Then a solution of MsCl (7.1 g, 4.72 mL, 62.32 mmol, 2 eq) in dry CH2Cl2 (40 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Water (100 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×80 mL), the combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (13.8 g), which was used in the next step without purification.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)(O)[O-].[Na+].O>CCOCC>[CH:2]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1ccsc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)CSc1ccsc1C=O
Reaction time: 1 h
Yield: 87 %

Procedure:
Methyl-3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) (117.63 g, 0.515 mole) was dissolved in actone (500 mL), and p-tolunesulfonic acid hydrate (1.30 g., 6.83 mmole) was added and stirred over 1 hour. A saturated solution of sodium bicarbonate (20 mL) was added followed by water (250 mL). The acetone was evaporated leaving a tacky solid in water. This tacky solid was dissolved in ether and washed with water four times, dried (MgSO4), filtered and the solvent evaporated in vacuo to leave 96.91 g of crude methyl 3-(2-formylthiophen-3-yl)-3-thiapropionate (5) which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17](=[O:22])(=[O:21])[N:18]([CH3:20])[CH3:19])[N:6]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]3)[C:5]=2[CH:4]=1.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17](=[O:21])(=[O:22])[N:18]([CH3:19])[CH3:20])[N:6]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([CH2:32][CH2:33][O:34][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31]3)[C:5]=2[CH:4]=1
Reactant: CCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(=O)(=O)N(C)C)c1S2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)OCCC1CCN(CCCN2c3cc(OC)ccc3Sc3c2cccc3S(=O)(=O)N(C)C)CC1
Reaction time: 6 h
Yield: 103.4 %

Procedure:
Working in the absence of moisture, a mixture of 2-methoxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]phenothiazine (11.4 g.) and heptanoyl chloride (3.8 g.) in toluene (150 cc.) is heated under reflux, with stirring, for 6 hours. After cooling, ethyl acetate (75 cc.) is added and the mixture is then rendered alkaline, without exceeding a temperature of 5°C., by adding a solution of anhydrous sodium carbonate (2.3 g.) in distilled water (75 cc.). After decanting, the aqueous layer is extracted with ethyl acetate (100 cc.). The organic extracts are combined and then washed three times with distilled water (total 240 cc.). The organic extract is dried over sodium sulphate and the solvent evaporated. 2-Methoxy-6-dimethylsulphamoyl-10-[3-(4-heptanoyloxyethylpiperidino)propyl]phenothiazine (14.4 g.), in the crude state, is thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:54][O:55][CH2:56][C@H:57](O)[CH3:58]>ClC>[CH3:54][O:55][CH2:56][C@@H:57]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:58]
Reactant: COC[C@@H](C)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2C)cc(C(=O)OC)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A stirred suspension of methyl 3-hydroxy-5-{[(2-methylphenyl)methyl]oxy}benzoate (15.3 g, 56.25 mmol) and triphenyl phosphine (14.4 g, 55 mmol) in dry chloromethane (900 ml) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 ml, 55 mmol) was added dropwise. The reaction mixture was stirred at 0-5° C. for 30 minutes and (R)-methoxy-propan-2-ol was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, and filtered through diatomaceous earth. The filtrate was evaporated and purified by column chromatograph on silica gel eluting with 10% ethyl acetate in iso-hexane to give the desired compound (10.7 g, 55%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]1[CH2:21][OH:22])([CH3:4])[CH3:3].O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:4][C:2]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]1[CH2:21][O:22][N:25]1[C:29](=[O:30])[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]1=[O:35])([CH3:1])[CH3:3]
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a mixture of cis-2-hydroxymethyl-1-(4-methoxyphenyl)-4-oxo-3-azetidinyl-carbamic acid 1,1-dimethylethyl ester (5.8 g, 18 mmol), N-hydroxyphthalimide (3.0 g, 18 mmole) and triphenylphosphine (5.7 g, 22 mmol) was added diethyl azodicarboxylate (3.7 g, 21 mmol). The reaction was allowed to stir at room temperature for 0.5 hours whereby the solvent was removed in vacuo. The reaction mixture was dissolved in methylene chloride and again the solvent evaporated to remove any residual THF. A solid precipitates and is washed with a solution of methylene chloride-diethyl ether (1:1). The filtrate is concentrated and the solid precipitate is again washed with a solution of methylene chloride-diethyl ether (1:1) and combined with the previously recovered material to afford 5.0 g of [cis-2-[[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]methyl]-1-(4-methoxyphenyl)-4-oxo-3-azetidinyl]carbamic acid 1,1-dimethylethyl ester (59%). Another 1.9 g (22.3%) of product could be recovered after concentration of the filtrate followed by flash chromatography (ethyl acetate-hexane, 1:9): mp 188°-189° C.; IR (KBr) 3435, 2980, 1795, 1735, 1710, 1500, 1390, 1370, 1160, and 1130 cm-1 ; NMR(CDCl3) δ 1.48 (9H, s), 3.74 (3H, s), 4.40 (1H, br d, J=12 Hz), 4.52 (1H, m), 4.98 (1H, br d, J=12 Hz), 5.44 (1H, m), 6.22 (1H, d, J-9 Hz, exchangeable), 6.82 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 7.78 (4H, m).
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:23][C:21]([F:22])([F:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29021.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidine-1-carboxylate (0.75 g, 2.2 mmol) in pyridine (15 mL) cooled in an ice bath was slowly added thionyl chloride (0.79 mL, 11 mmol) and the mixture was warmed to room temperature and stirred overnight (17 h). The reaction was quenched with ice water. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel (0-40% B over 25 min. Bottle A=hexanes, Bottle B=EtOAc) gave 209 g of the desired product as a solid. MS calculated for C17H20F3NO2: (M+H) 328; found 228.0 (M-Boc+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[NH4+:13].[OH-]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5,6-dichloropyridine-3-sulfonyl chloride (32.16 g) in isopropyl alcohol (300 mL) at 0° C. was added a 30% aqueous solution of NH4OH (50.8 mL). After stirring overnight, the solvent was reduced to ⅓ of the original volume. It was then partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel. The material was then slurried in 1:9 ethyl acetate/hexanes, filtered and dried under vacuum to give the title compound.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si](C(C)(C)C)(C)C)[CH2:15][C@H:14]([OH:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CC(O)C>[OH:17][C@@H:16]1[CH2:15][C@H:14]([OH:25])[C@H:13]([CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([OH:8])[CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Yield: 111 %

Procedure:
A solution of compound (11b) (60 g) prepared in EXAMPLE 20 and aqueous HF (2N, 135 mL) in IPA (240 mL) was stirred. Saturated aqueous NaHCO3 (120 mL) was added and the mixture was extracted with EtOAc (600 mL). The separated aqueous layer was extracted with EtOAc (300 mL) and the combined organic layer was washed with saturated aqueous NaCl (300 mL), dried with Na2SO4, filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was concentrated to furnish 43.5 g of crude compound (11c) (84.3% HPLC purity, 84% yield) which was directly used without purification in EXAMPLE 22.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.O>CS(C)=O.[OH-].[Na+]>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:16][CH:17]=2)=[CH:22]1
Reactant: ClCCOc1cccc2ncccc12
Reactant: C1=C(c2c[nH]c3ncccc23)CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C1=C(c2c[nH]c3ncccc23)CCN(CCOc2cccc3ncccc23)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 5-(2-chloroethoxy)quinoline (0.5 g, 24 mmol), ), 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.58 g, 29 mmol) and triethylamine (0.67 ml, 48 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 4 hours at 80° C. The mixture was poured into water dilute with sodium hydroxide solution and extracted with ethyl acetate (3×100 ml). The organic layer was washed with water (3×100 ml), sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum to give a pale yellow solid, which was triturated with ethanol-ethyl ether to afford a pale yellow solid: mp 202-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>O1CCCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromoaniline (10.0 g, 58.1 mmol) in tetrahydrofuran (230 mL) was treated with sodium bicarbonate (9.77 g, 116.2 mmol) and water (100 mL) followed by isobutyl chloroformate (8.3 mL, 63.9 mmol), and the mixture was stirred at ambient temperature for 2 hrs. The mixture was then diluted with water (100 mL) and EtOAc (100 mL), the layers were separated, and the organic phase was washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization of the resulting solid from EtOAc/hexanes provided the title compound, mp 95-96° C.; MS (ESI−) for C11H14NO2Br m/z 270 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[NH:7][C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: BrBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 966.3 %

Procedure:
To a solution of 3-methyl-1H-purine-2,6(3H,7H)-dione (11.3 g, 6.8 mmol) in acetic acid (300 mL) was added sodium acetate (8.37 g, 13.6 mmol) followed by drop-wise addition of bromine (13.04 g, 8.2 mmol) at 50° C. After addition, the mixture was stirred at 65° C. for 3 h. The mixture was cooled and poured into ice-water (500 g), and the product precipitated. The slurry was filtered and the filter cake was washed with water twice and dried under vacuum to give 8-bromo-3-methyl-1H-purine-2,6(3H,7H)— dione (16.1 g, 96.6% yield) as light yellow solid. LCMS retention time 0.541 min; LCMS MH+ 245.
Reaction SMILES: COC1C=NNC=1C1C=C(C=CC=1C)C(O)=O.[C:18]([C:20]1[CH:21]=[N:22][NH:23][C:24]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:28]([O:30]C)=[O:29])#[N:19].COC1C=NNC=1C1C=C(C=CC=1C)C(OC)=O>>[C:18]([C:20]1[CH:21]=[N:22][NH:23][C:24]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:28]([OH:30])=[O:29])#[N:19]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]ncc2C#N)c1
Agent: COC(=O)c1ccc(C)c(-c2[nH]ncc2OC)c1
Agent: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Product: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1C#N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 244.7, except methyl 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoate (compound 256.4) was used in place of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[O:24]C(C)(C)[N:22]([C:27](OC(C)(C)C)=[O:28])[C@@H:21]3[CH2:34][F:35])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.[Cl:52][CH:53]([Cl:58])C(OC)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:52][CH:53]([Cl:58])[C:27]([NH:22][C@H:21]([CH2:34][F:35])[C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[N:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:16]=1)[OH:24])=[O:28]
Reactant: COC(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(CNS(C)(=O)=O)c(F)c3)cc2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl 5-(4-(5-fluoro-6-(methylsulfonamidomethyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (890 mg, 1.74 mmol) is dissolved in CH2Cl2 (20 mL), cooled to 5° C., and treated with trifluoroacetic acid (4 mL), stirred for 1 h at room temperature, diluted with toluene, concentrated to an oil. The oil is basified with aqueous sodium bicarbonate, extracted with ethyl acetate, dried, filtered, concentrated to an oil. The oil is dissolved in methanol (8 mL) and treated with diisopropylethyl amine (0.455 mL, 2.6 mmol) and methyl dichloroacetate (305 mg, 2.1 mmol), stirred at 60° C. for 18 hours, then cooled, and chromatographed on silica eluting with ethyl acetate in heptane to give the title compound. 1H NMR (400 MHz, DMSO-d6) 2.94 (s, 3H), 4.15-4.45 (m, 4H), 4.55-4.75 (m, 1H), 4.92 (t, 1H, J=3.54 Hz), 6.01 (d, 1H, J=4.29 Hz), 6.52 (s, 1H), 7.49 (d, 2H, J=8.08 Hz), 7.59 (t, 1H, J=5.94 Hz), 7.77 (d, 2H, J=8.34 Hz), 8.07 (m, 1H), 8.63 (d, 2H, J=8.84 Hz), 8.77 (s, 1H). m/z (CI) M+H 465.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[F:14][C:11]([F:12])([F:13])[O:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:16])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: O=[Se]=O
Product: O=CC(=O)c1cccc(OC(F)(F)F)c1

Procedure:
3-(Trifluoromethoxy)acetophenone (2 g, 9.80 mmol) was reacted with selenium dioxide (1.63 g, 14.7 mmol) using the method described in Example 1 to give crude (3-trifluoromethoxyphenyl)oxoacetaldehyde as a yellow oil: m/z (ES+) 219.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C1COCC1.C(O)C(O)C.O>[C:1]1([C:7]2([C:14]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(O)CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Temperature: 110 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
To a solution of 2b (67.0 mg, 0.14 mmol) in THF (3 mL) and 1,2-propanediol (3 mL) was added aqueous potassium hydroxide (0.40 mL of a 8 M solution in water, 3.20 mmol). The mixture was stirred at 110° C. for 18 h and then cooled to room temperature. The reaction mixture was diluted with water, acidified with 1 N hydrochloric acid and extracted three times with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; dichloromethane/methanol/concentrated aqueous ammonium hydroxide (85:15:1) gave a solid (48.0 mg) that was triturated with ether/hexane to provide 2c as a solid (38 mg), m.p. 205-210° C. (dec.).
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][CH:5]([F:28])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22](N(OC)C)=[O:23])=[N:14]1>C1COCC1>[C:22]([C:15]1[C:16](=[O:21])[C:17]([O:19][CH3:20])=[CH:18][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]([F:4])[F:28])[N:14]=1)(=[O:23])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
MeMgBr (1 M solution in THF, 40.4 ml, 40.4 mmol) was added dropwise at −78° C. to a solution of 1-[2-(difluoromethoxy)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.79 g, 13.48 mmol) in THF (500 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and warm to room temperature. The reaction mixture was concentrated under reduced pressure and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1-0/1) and recrystallized from diisopropyl ether/AcOEt to give the title compound (3.33 g, 80% yield) as colorless crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.68 (3H, s), 3.89 (3H, s), 6.55 (1H, t, J=72.7 Hz), 7.36-7.45 (2H, m), 7.50-7.57 (1H, m), 7.61 (1H, dd, J=7.8, 1.7 Hz), 7.72 (1H, s).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6 g, 17.89 mmol) was dissolved in methanol (50 ml). Trifluoroacetic acid (20.67 ml, 268 mmol) was added dropwise, and the mixture stirred at 20° C. for 72 hours under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and filtered. The filtrate was stripped and the residue washed with ethyl acetate. The combined solid residues were dried in the vacuum oven for 2 hours to give the title compound as an off white solid (5.3 g). LCMS (System C): tRET=0.76 min; MH+ 252, 253