Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
8.2 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 86 ml of THF is stirred with 8.6 ml of 3,4-dihydro-2H-pyran and 820 mg of p-toluenesulfonic acid hydrate for 2.5 hours at room temperature. Then, 0.5 ml of triethylamine is added, it is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 7.8 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(1 0)-trien- 17-one is obtained as foam.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][S:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1>C1COCC1>[C:5]1([C:4](=[O:11])[CH2:19][C:18]2[CH:22]=[CH:23][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CSc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(CC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution ot N-methoxy-N-methylbenzamide (409 mg, 2.27 mmol) in THF (22mL) was added a THF solution (5.0 mL, 0.5 M) of 4-(methylthio)benzylmagnesium chloride (J.Org. Chem. 42, 1914, 1977). The mixture was stirred at 0° C. for 3 h, NH4OAc was added and the mixture was extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 2.5% EtOAc/toluene) gave 501 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3Br)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:42][N:43](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:40][C:26]1[N:25]=[CH:24][C:23]2[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)=[C:20]([C:42]#[N:43])[O:21][C:22]=2[C:27]=1[O:28][C@@H:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30]
Reactant: CN(C)C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)c(C#N)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of [4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.0299 mmol), zinc cyanide (4.2 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (1 mL) was degassed and refilled with nitrogen (3×). The reaction was heated at 150° C. using a microwave reactor for 2 min. The solution was passed through a PL-Thiol SPE cartridge to remove metals. The material was then dissolved in dioxane and EtOH, charged with 4M HCl in Dioxane (0.2 mL) and stirred at rt for 4 h. The solution was concentrated in vacuo, redissolved in DMF (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.93 (d, J=6.8 Hz, 3H), 2.30-2.40 (m, 4H), 3.18-3.26 (m, 2H), 3.59 (d, J=13.4 Hz, 2H), 4.64-4.71 (m, 1H), 6.43 (q, J=6.8 Hz, 1H), 7.21-7.27 (m, 1H), 7.42 (dd, J=9.0, 4.9 Hz, 1H), 8.11 (s, 1H), 8.33-8.39 (m, 2H). MS (ES+): m/z 515.06/517.07 (100/68) [MH+]. HPLC: tR=2.78 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=2[CH:4]=[N:3]1.[CH3:16][C:17]([CH3:40])([CH3:39])[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=2[CH3:38])[CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.ClCCl.C(N(CC)CC)C>[CH3:16][C:17]([CH3:40])([CH3:39])[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:7]3[CH2:6][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:11]=4[NH:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)=[O:34])=[CH:31][C:30]=2[CH3:38])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)O)ccc1OCCN1CCN(CCC(C)(C)C)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCN1CCN(CCC(C)(C)C)CC1
Yield: 4 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (20 mg, 0.15 mmol) were added to a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (37 mg, 0.20 mmol) and 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid from Example E40 (53 mg, 0.15 mmol) in dichloromethane (5 ml) and triethylamine (to pH9). The mixture was heated at re-flux for 2 days then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% chloroform) to give an off-white solid identified as the title compound (3.5 mg, 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10]C2=O)=[CH:4][CH:3]=1.[C-]#N.[K+]>C1C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:12]([C:11]([OH:16])=[O:10])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O

Procedure:
To a mixture of m-naphthoxybenzaldehyde (0.43 g), 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (0.5 g), and potassium cyanide (0.23 g) in benzene (about 10 ml), with stirring, is added benzyl triethyl ammonium chloride (about 0.1 g). The reaction mixture is stirred for about 50 hr. The reaction is then worked up by taking up in ether, washing with water and brine, drying over sodium sulfate and evaporating. The concentrate is plated, prep. TLC, eluting with 20% ether/hexane to yield the m-naphthoxy-α-cyanobenzyl ester of N-(4-chlorophenyl)valine, MS m/e 484 (M+).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:34]1[CH:35]=[CH:36][C:37]([CH:40]([F:42])[F:41])=[N:38][CH:39]=1>C1COCC1.O.Cl[Pd]Cl.O>[F:41][CH:40]([F:42])[C:37]1[CH:36]=[CH:35][C:34]([CH:1]=[CH2:2])=[CH:39][N:38]=1
Reactant: FC(F)c1ccc(Br)cn1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)F)nc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a stirred suspension of potassium vinyltrifluoroborate (3.32 g, 24.8 mmol), PdCl2 (0.1 g, 0.56 mmol) and PPh3 (0.45 g, 1.71 mmol) in 60 mL of THF—H2O (9:1) were added Cs2CO3 (20.2 g, 62 mmol) and 5-bromo-2-(difluoromethyl)pyridine (4.3 g, 20.7 mmol). The resulting reaction mixture was heated to 80° C. and stirred for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 5% Et2O/pentane) to afford the title compound (2.46 g, 75% yield). MS: 156 [M+1]+; 1H-NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 7.86 (d, 1H, J=8.3 Hz), 7.60 (d, 1H, J=8.3 Hz), 6.74 (dd, 1H, J=18, 11.2 Hz), 6.63 (t, 1H, J=55.6 Hz), 5.91 (d, 1H, J=18 Hz), 5.48 (d, 1H, J=11.2 Hz).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=[C:16]([CH3:25])[CH:15]=1)/[CH3:4].[OH-].[CH3:28][O:29]C(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:28][O:29][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[C:16]([CH3:25])[CH:15]=2)=[C:7]([C:6]2[O:1][N:2]=[C:3]([CH3:4])[N:5]=2)[CH:12]=1
Reactant: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Reactant: C/C(=N/O)NC(=O)c1ccccc1Nc1cc(C)nn1-c1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc(C)nn2-c2ccccc2)c(-c2nc(C)no2)c1
Temperature: 25 °C
Yield: 3.7 %

Procedure:
To a solution of the crude N-[(1Z)-N-hydroxyethanimidoyl]-2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]benzamide (257 mg, 0.41 mmol) in THF (3 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent) (145 mg, 0.61 mmol). The flask was flushed with argon and refluxed for 3 h under argon. The reaction mixture was the cooled to rt, filtered through a small plug of silica gel, and the plug was eluted with EtOAc. The filtrate was concentrated under reduced pressure, and the residue purified by preparative TLC on silica gel using EtOAc/Hex (1:2, v/v) to give the title product as a solid (5.5 mg, 4% overall). 1H NMR (400 MHz, CD3CN). δ 2.30 (s, 3H), 2.32 (s, 3H), 3.82 (s, 3H), 6.16 (s, 1H), 7.09 (dd, 1H), 7.21 (d, 1H), 7.38-7.42 (m, 1H), 7.42-7.50 (m, 3H), 7.50-7.58 (m, 2H), 9.46 (br, s, 1H). ES-MS m/z 362.2 (MH+); HPLC RT (min) 3.28.
Reaction SMILES: [OH:1][P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH2:15](O)[CH2:16][OH:17]>>[OH:3][P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][CH2:5][C:6]([O:8][CH2:15][CH2:16][OH:17])=[O:7])=[O:1]
Reactant: O=C(O)CCP(=O)(O)c1ccccc1
Reactant: OCCO
Product: O=C(CCP(=O)(O)c1ccccc1)OCCO

Procedure:
Except that the recrystallization-purified 3-[hydroxy(phenyl)phosphinyl]propionic acid obtained in Comparative Example 3 was used in lieu of the rinse-purified 3-[hydroxy(phenyl)phosphinyl]propionic acid, the procedure of Comparative Example 4 was repeated to provide 102.81 g of an ethylene glycol solution of hydroxyethyl 3-[hydroxy(phenyl)phosphinyl]propionate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][NH2:24]>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:24][CH2:23][C:19]3[O:18][CH:22]=[CH:21][N:20]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCc1ncco1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ncco1
Yield: 25 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 25% yield: 1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.84 (t, J=5.7 Hz, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.12 (s, 1H), 6.26 (dd, J=8.0, 2.5 Hz, 1H), 5.82 (d, J=2.5 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 333.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[CH:6]=1.S(Cl)([Cl:16])(=O)=O>C(Cl)(Cl)Cl>[Cl:16][C:6]1[C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3][C:2]=1[CH3:1]
Reactant: Cc1cc2cc(C#N)ccc2o1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc2ccc(C#N)cc2c1Cl
Yield: 24.3 %

Procedure:
A solution of 2-methylbenzofuran-5-carbonitrile (J. Het. Chem., 4, 441, 1967) (1.52 g) and sulphuryl chloride (1.49 g) in chloroform (25 ml) was heated under reflux for 9 hours and then cooled. The solution was washed successively with water, dilute sodium hydroxide solution, water and then dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised twice from methanol to give 3-chloro-2-methylbenzofuran-5-carbonitrile (0.45 g), m.p. 131.5°-133.5°.
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=4)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.[H-].[Na+].Br[CH2:35][CH3:36]>CN(C=O)C>[CH2:35]([N:21]([C@@H:18]1[CH2:19][CH2:20][N:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:31])([CH3:30])[CH3:1])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:17]1)[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1)[CH3:36]
Reactant: CCBr
Reactant: C[Si](C)(C)CCOCn1ccc2c(N3CC[C@@H](Nc4ccc(C#N)cn4)C3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccc(C#N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino)nicotinonitrile (200 mg, 0.46 mmol) in DMF (5.0 mL) was added NaH (55 mg, 2.3 mmol) in portions at 0° C. The reaction mixture was stirred at ambient temperature for 30 minutes, bromoethane (60 mg, 0.55 mmol) was then added dropwise and the reaction mixture was stirred at ambient temperature for additional 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 464 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([O:10]C)=[O:9])(=[O:5])[CH:2]([CH3:4])O.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:4][CH:2]1[O:10][C:8](=[O:9])[CH2:7][O:6][C:1]1=[O:5]
Reactant: COC(=O)COC(=O)C(C)O
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC1OC(=O)COC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Methoxy-2-oxoethyl lactate (123 mg, 0.76 mmol), prepared as described in Example 1, was added to 25 mL of refluxing toluene containing (1S)-(+)-10-camphor-sulfonic acid (8.8 mg, 0.038 mmol). The refluxing toluene was made to pass through ca. 8 mL of crushed molecular sieves (type 4A) before returning to the reaction vessel. After 6 hr, the reaction mixture was cooled to room temperature, applied to a 40 mL silica gel column equilibrated in toluene and eluted with ethyl acetate. The ethyl acetate was evaporated and the title compound was identified as a component of the recovered material by GC (Method A) and GC/MS: HRMS calcd for C5H6O4 130.0266, obsd 130.0265.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[F:1][CH:2]([F:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of methyl 4-(difluoromethyl)-1-naphthalenecarboxylate (450 mg, 1.91 mmol) in methanol (5 ml) was added 2N aqueous sodium hydroxide solution (1.9 ml, 3.8 mmol), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to the reaction solution (5 ml) and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-(difluoromethyl)-1-naphthalenecarboxylic acid (344 mg, 81%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][OH:13])[C:6]=2[N:7]=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:19]=[C:18]([F:27])[C:17]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.O>C(O)C.CC#N>[F:27][C:18]1[CH:19]=[C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:21]=[C:16]([F:15])[C:17]=1[N:28]1[CH2:29][CH2:30][N:31]([C:2]2[NH:3][C:4](=[O:14])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][OH:13])[C:6]=3[N:7]=2)[CH2:32][CH2:33]1
Reactant: COCCOc1cc(F)c(N2CCNCC2)c(F)c1
Reactant: O=c1[nH]c(Cl)nc2c1ccn2CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: COCCOc1cc(F)c(N2CCN(c3nc4c(ccn4CCO)c(=O)[nH]3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 31.2 %

Procedure:
A solution of 2-chloro-7-(2-hydroxyethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (150 mg, 0.70 mmol, 1.00 equiv), 1-[2,6-difluoro-4-(2-methoxyethoxy)phenyl]piperazine (192 mg, 0.71 mmol, 1.00 equiv) and DIEA (182 mg, 1.41 mmol, 2.00 equiv) in ethanol (2 mL) was placed in an 8-mL sealed tube. The reaction mixture was irradiated with microwave radiation for 30 min at 140° C. and then cooled back to room temperature. The crude product was collected by filtration then purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column: XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase: water with 10 mmol NH4HCO3 and MeCN (MeCN 35.0%, MeCN up to 50.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 35.0% in 2 min); Detector, UV 254/220 nm to yield 98.3 mg (31%) of 2-[4-[2,6-difluoro-4-(2-methoxyethoxy)phenyl]piperazin-1-yl]-7-(2-hydroxyethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one as a white solid. 1HNMR (400 MHz, DMSO-d6) δ□ ppm 3.09-3.06 (m, 4H), 3.28 (s, 3H), 3.69-3.61 (m, 8H), 4.02-3.99 (m, 2H), 4.08-4.06 (m, 2H), 4.85 (t, J=5.6 Hz, 1H), 6.23 (d, J=3.2 Hz, 1H), 6.72 (d, J=11.2 Hz, 2H), 6.81 (d, J=3.2 Hz, 1H), 10.81 (s, 1H). LC-MS calcd. for C21H26F2N5O4 [(M+H)+] 450, obsd. 450.3.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)C(=O)OC(C)(C)C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {[(1S,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}methylcarbamate (12.02 g, 41.2 mmol), accessed via the method of Preparation 13A, was dissolved in 200 mL DCM with 6.2 mL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (28.0 g, 66.0 mmol, 1.6 eq) in 200 mL DCM at ambient temperature for 3 h. The reaction mixture was diluted with 1 L diethyl ether and treated with 400 mL 1N NaOH at ambient temperature for 30 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (1:4)) to give the title compound (10.7, 36.9 mmol, 89%). 1H NMR (400 MHz, CDCl3) δ9.77-9.65 (m, 1H), 7.33-7.23 (m, 5H), 3.75-3.63 (m, 2H), 2.72-2.50 (m, 3H), 2.26-2.19 (m, 1H), 1.87-1.81 (m, 1H), 1.65-1.61 (m, 1H), 1.31-1.18 (m, 9H). LCMS m/z 312.2 (M+Na).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:21][CH2:22][CH2:23][N:24]1[C:28]([CH3:30])([CH3:29])[C:27](=[O:31])[NH:26][C:25]1=[O:32].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[C:28]([CH3:29])([CH3:30])[C:27](=[O:31])[NH:26][C:25]2=[O:32])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: CS(=O)(=O)c1ncc(Br)c(-c2nc3ccncc3s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2nc3ccncc3s2)n1
Temperature: 160 °C
Yield: 4.5 %

Procedure:
A microwave tube was charged with 2-(5-bromo-2-(methylsulfonyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (300 mg, 0.81 mmol), 1-(2-Aminoethyl)-5,5-dimethyl-imidazolidine-2,4-dione (138 mg, 0.81 mmol), isopropanol (3 mL) and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol). The vessel was sealed and heated in a microwave reactor at 160° C. for 1000 seconds. The resulting solid was filtered off and washed with methanol (4×10 mL). The solid was then dissolved in dimethylsulfoxide (4 mL) and purified by reverse phase HPLC. Product fractions were combined and loaded onto an SCX cartridge, washed with methanol (4 mL), then free based and eluted with 2 M ammonia in methanol (4 mL). The solvent was evaporated in vacuo to yield 1-(2-(5-bromo-4-(thiazolo[5,4-c]pyridin-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (17 mg, 5%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 1.50 (s, 6H), 3.67 (br. s., 2H), 3.75 (br. s., 2H), 4.32 (br. s., 1H), 6.89 (s, 1H), 7.49 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.91 (d, J=5.1 Hz, 1H), 9.71 (s, 1H): HRMS (M+H)+ Calcd. C17H16BrN7O2S 462.0348. found 462.0339.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:24][C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[S:29][C:28]([S:30]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:32])=[O:31])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(N)c2)C[C@H](C)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(NS(=O)(=O)c3ccc(Br)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]aniline (D39) (300 mg, 0.96 mmol) in dichloromethane (5 ml) and pyridine (5 ml) was added 5-bromo-2-thiophenesulfonyl chloride (505 mg, 1.93 mmol) and the mixture stirred at room temperature for 4 hours. The mixture was then reduced in vacuo and the residue purified by SCX (eluting with methanol then ammonia 2M in methanol). The appropriate fractions were combined and reduced and the residue purified by trituaration with methanol to afford the title compound (D42). MS (ES+) m/e 536/538 [M+H]+.