Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Br:40]C1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[Br:40][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Br)cc2)CC1
Yield: 84 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.8 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 6.2 g (0.03 mole) of 1-(4-bromophenyl)piperazine in a total of 200 ml of tetrahydrofuran gave a pale yellow semisolid. The material was triturated with ethyl ether to give 7.7 g (84%) of the title compound as a white solid, m.p. 133°-135° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16](=O)[NH2:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:29][CH:30]1[C:53](=[O:54])[N:32]2[C:33]([C:50]([OH:52])=[O:51])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12>O1CCCC1.CC(C)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[N:17])[C:10]([NH:29][CH:30]2[C:53](=[O:54])[N:32]3[C:33]([C:50]([OH:52])=[O:51])=[C:34]([CH2:37][S:38][C:39]4[N:43]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Yield: 38.6 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 1.35 g.), N,N-dimethylformamide (0.814 g.) and phosphoryl chloride (1.71 g.) in tetrahydrofuran (13.4 ml.) and a solution of 7-amino-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.95 g.) in 50% aqueous acetone (20 ml.) were treated in a similar manner to that of Example 9-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)(O)=[O:2].[CH3:33]C1(C)OC(=O)CC(=O)O1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1.C(O)(=O)C.O>[O:2]=[C:1]([CH3:33])[CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2 g) in dichloromethane (20 ml) was added in turn 2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg), 1,3-dicyclohexylcarbodiimide (1.1 g) and 4-dimethylaminopyridine (720 mg) at 0° C. A reaction mixture was allowed to warm to ambient temperature and stirred for overnight. Precipitate was removed by filtration, and mother liquor was washed with 1N-aqueous hydrochloric acid and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in a mixture of acetic acid (15 ml) and water (15 ml), and which was refluxed for 10 hours. A reaction mixture was extracted with ethyl acetate (200 ml) and organic layer was separated, which was neutralized with saturated sodium hydrogen carbonate in water. Organic phase was separated, washed in turn with saturated sodium hydrogen carbonate in water (50 ml) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (100 g) eluting in turn with 33%, 50%, 80% ethyl acetate in n-hexane and ethyl acetate to give 3-[2-{2-(2-oxopropyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.5 g).
Reaction SMILES: S[C:2]1[O:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[Cl-].[CH2:29]([O:36][C:37]([C@@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][NH2+:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.CN(C)C=O>[CH3:14][O:13][C:11]([C:10]1[C:4]2[O:3][C:2]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][C@H:39]3[C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])=[N:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: COC(=O)c1cccc2nc(S)oc12
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cccc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc12
Yield: 23.4 %

Procedure:
2-Sulfanyl-7-(methoxy)carbonyl-1,3-benzoxazole (1.00 g) [see Preparation 49] was added to thionyl chloride (4.9 ml) followed by dimethylformamide (0.37 ml) and the mixture heated at reflux for 10 minutes. The mixture was cooled and the solvent removed at reduced pressure, the residue was azeotroped twice with xylene to afford a tan solid. This solid was immediately dissolved in acetonitrile (20 ml) and N-ethyldiisopropylamine (3.3 ml) and (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride (1.22 g) was added and the mixture was then heated at reflux for 7 hours. The reaction was cooled, the solvent removed at reduced pressure, and the residue dissolved in ethyl acetate and washed sequentially with 1M aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, brine, then dried over magnesium sulfate and the solvent removed at reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 5:1, by volume, hexane: ethyl acetate to afford benzyl (2S)-1-[7-(methoxy)carbonyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate (0.44 g) as an orange gum.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH2:46][CH2:45][C:44]4[C:43]5[CH2:42][C:41]([CH3:48])([CH3:47])[CH2:40][C:39]=5[S:38][C:37]=4[C:36]3=[O:49])[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[CH2:46][CH2:45][C:44]3[C:43]4[CH2:42][C:41]([CH3:48])([CH3:47])[CH2:40][C:39]=4[S:38][C:37]=3[C:36]2=[O:49])=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(sc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(sc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A 25 mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 145a (97 mg, 1.0 eq., 0.14 mmol), NaBH4(16 mg, 3.0 eq., 0.42 mmol), and MeOH (10 mL). The mixture was stirred at room temperature for 1 h. The residue was purified by reverse-phase prep-HPLC to afford 145 (61 mg, 63%). LCMS: [M+H]+ 682.3. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.5, 1H), 8.50 (d, J=5.0, 1H), 7.97 (d, J=2.5, 1H), 7.84 (s, 1H), 7.80 (d, J=2.5, 1H), 7.37 (d, J=5.0, 1H), 7.30 (dd, J=3.0, 9.0, 1H), 6.81 (d, J=9.0, 1H), 4.82-4.79 (m, 1H), 4.71-4.61 (m, 5H), 4.45-4.31 (m, 2H), 3.85-3.80 (m, 1H), 3.71 (s, 3H), 3.54-3.46 (m, 2H), 3.07 (d, J=5.0, 2H), 2.98-2.93 (m, 2H), 2.79 (s, 2H), 2.60-2.46 (m, 5H), 2.21-2.18 (m, 1H), 1.28 (s, 6H), 0.98 (d, J=6.0, 3H)
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][O:30][CH3:31])C1C=CC=CC=1.C1CCCCC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][O:30][CH3:31]
Reactant: CCCOc1ncnc(COCc2ccccc2)c1-c1ccc(OC)cc1OCOC
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCOc1ncnc(CO)c1-c1ccc(OC)cc1OCOC

Procedure:
A solution of 6-benzyloxymethyl-5-(2-methoxymethoxy-4-methoxyphenyl)-4-propoxy-pyrimidine (3.41 g, 8.04 mmol), cyclohexene (35 ml), Pd(OH)2 (3.4 g) and ammonium formate (3.4 g) in ethanol (100 ml) was kept at reflux for 3 d. After cooling the mixture was filtered through celite and concentrated to an oil. (2.42 g, 90%).
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:26])[CH3:25]>>[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:26])[CH3:25]
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(C)C)cc2)c1
Yield: 50 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg), sodium hydride (60% in oil, 98 mg) and 4-isopropoxybenzenesulfonyl chloride (201 mg), a procedure as in Example 38 was performed to give the title compound as pale-red crystals (yield 47 mg, 45%).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:2]=1.[H-].[Na+].[CH3:20]I>C1(C)C=CC=CC=1>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH3:20])[C:9](=[O:11])[CH3:10])[CH:2]=1
Reactant: CI
Reactant: CC(=O)NCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N(C)Cc1cccc(-c2ccccc2)c1
Reaction time: 8 h
Yield: 107.8 %

Procedure:
N-biphenyl-3-ylmethyl-acetamide (860 mg, 3.8 mmol) was dissolved in 10 mL of toluene. To this was added 611 mg of 60% NaH (mineral oil) and MeI (0.48 mL, 7.6 mmol). The resulting mixture was stirred overnight then filtered. The solvent was removed under vacuum to yield 980 mg (108% yield) of N-biphenyl-3-ylmethyl-N-methyl-acetamide. HRMS ((M+H) calcd for C16H18N): 240.1389; found: 240.1398. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 2.17 (s), 2.19 (s), 2.96 (s), 2.99 (s), 4.60 (s), 4.66 (s), 7.15-7.60 (overlapping m). 13C NMR (125 MHz, CDCl3) δ: 21.55, 21.91, 33.84, 35.61, 50.66, 54.33, 125.05, 125.16, 126.25, 126.55, 126.85, 127.00, 127.20, 127.23, 127.42, 127.65, 128.79, 128.90, 129.06, 129.45, 137.19, 137.95, 140.65, 140.95, 141.64, 142.12, 170.79, 171.08.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].[Cl:9][C:10]1[CH:15]=C(Cl)[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[N:19]1[C:23](=[O:24])[N:22]([CH2:25][CH2:26][CH3:27])[N:21]=[N:20]1.BrC1C(OC)=CC(N2C(=O)N(CCC)N=N2)=C(Cl)C=1>CN(C)C(=O)C.[Cu]I>[Cl:9][C:10]1[CH:15]=[C:3]([C:2]([F:7])([F:6])[F:1])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[N:19]1[C:23](=[O:24])[N:22]([CH2:25][CH2:26][CH3:27])[N:21]=[N:20]1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCCn1nnn(-c2cc(OC)c(Cl)cc2Cl)c1=O
Agent: [Cu]I
Agent: CCCn1nnn(-c2cc(OC)c(Br)cc2Cl)c1=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCn1nnn(-c2cc(OC)c(C(F)(F)F)cc2Cl)c1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 6.0 g (0.044 mole) of sodium trifluoroacetate and 4.18 g (0.022 mole) of copper(I) iodide in 40 mL of N,N-dimethylacetamide was heated at 150° C. To the hot mixture was added 3.3 9 (0.011 mole) of 1-(4-bromo-2-chloro-5-methoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (compound 12). After complete addition, the hot mixture was stirred for 3 hours then allowed to cool to room temperature. The mixture was filtered and the filtrate diluted with ice water to form a precipitate. The solid was collected by filtration and purified, first by column chromatography on silica gel eluting with methylene chloride:heptane (80:20), then by recrystallization from heptane to yield 0.7 g of 1-(2-chloro-5-methoxy-4-trifluoromethylphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one, mp 82°-83° C.
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH2:7]1[CH2:11]OC[CH2:8]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC(C)C>CN(C=O)C.[NH4+].[Cl-].O.CCOC(C)=O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([CH:7]([CH3:11])[CH3:8])[N:3]=1
Reactant: Ic1cc[nH]n1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)I
Product: CC(C)n1ccc(I)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3-iodo-1H-pyrazole (250 mg, 1.29 mmol) was added as a solution in DMF (0.8 mL) to a 1.0 M THF solution of NaHMDS (1.5 mL, 1.5 mmol) that had been pre-cooled in an ice water bath. Additional portions of DMF (2×0.35 mL) were used to ensure complete transfer. 2-iodopropane was added in one portion and the reaction mixture was allowed to warm to r.t. After 3.5 h, the reaction mixture was diluted with saturated aqueous NH4Cl (5 mL), water (20 mL), and EtOAc (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography to provide 3-iodo-1-isopropyl-1H-pyrazole (7.01). LCMS-ESI+ (m/z): [M+H]+ calcd for C6H10IN2: 236.99; found: 236.94.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(O)=[O:11].C([O-])=O.Cl>CC#N.CO>[OH:11][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=CO
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: CC#N
Product: Cc1oc(=O)oc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 310.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): δ 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([OH:23])[C:17](=[CH:21][CH:22]=1)[C:18]([OH:20])=[O:19])=[O:12])[CH2:7][CH2:8][CH3:9].S([O-])([O-])(=O)=O.[Zn+2:29]>>[CH2:6]([O:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([OH:23])[C:17](=[CH:21][CH:22]=1)[C:18]([O-:20])=[O:19])=[O:12])[CH2:7][CH2:8][CH3:9].[Zn+2:29].[CH2:6]([O:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([OH:23])[C:17](=[CH:21][CH:22]=1)[C:18]([O-:20])=[O:19])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)Nc1ccc(C(=O)O)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCOC(=O)Nc1ccc(C(=O)[O-])c(O)c1
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To 400 ml of an aqueous solution containing 8.4 g of sodium hydrogen carbonate, 25.3 g of 4-(n-butyloxycarbonylamino)salicylic acid was gradually added and dissolved at room temperature. The solution obtained was dropwise added to 200 ml of an aqueous solution containing 14.9 g of zinc sulfate 7 hydrate over 20 minutes at room temperature. After finishing dropwise addition, the mixture was further stirred for 30 minutes. Precipitated crystals were filtered, washed with water, and dried to obtain 26 g of desired zinc 4-(n-butyloxycarbonylamino)salicylate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[OH-].[Na+:17]>C(O)C>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O-:9])=[O:8].[Na+:17]
Reactant: O=C(O)c1ccccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1OCC(F)(F)F
Reaction time: 1 h

Procedure:
2-(2,2,2-Trifluoroethoxy)benzoic acid is dissolved in ethanol and treated with an equimolar amount of sodium hydroxide dissolved in a minimum amount of ethanol and stirred for one hour. The solvent is removed by evaporation in vacuo to give sodium 2-(2,2,2-trifluoroethoxy)benzoate.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 3-fluorophenylhydrazine hydrochloride (488 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (201 mg, 25%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][NH:22][CH:23]1[CH2:29][O:28][CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:21][N:22]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH:23]1[CH2:29][O:28][CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CNC1COCCN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4COCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1

Procedure:
A solution of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg (0.36 mmol) 107.a, of tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate (84 mg (0.36 mmol) X.3, and DIEA (0.127 mL (0.730 mmol) in DMF (2.8 mL) was heated at 90° C. in a sealed tube for 18 hr. The mixture was diluted with H2O and extracted with EtOAc (2×). The combined organics were washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo, absorbing onto 4 g SiO2. Purification by flash column chromatography (ISCO 24 g SiO2, 10% EtOAc/hexanes then gradient to 80% EtOAc/hexanes) afforded tert-butyl 6-(methyl-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1,4-oxazepane-4-carboxylate (0.142 g) 107.4 as a yellow glassy solid. LCMS (ESI) m/z: 502.20 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH:19]4[CH2:20][CH2:21][CH:15]3[CH2:16][O:17][CH2:18]4)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH:19]5[CH2:20][CH2:21][CH:15]4[CH2:16][O:17][CH2:18]5)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2C3CCC2COC3)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3C4CCC3COC4)n(C)c2n1
Temperature: 120 °C
Yield: 52.4 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[2-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)ethyl]-9H-purine (75 mg, 0.19 mmol), 2-ethylbenzimidazole (31 mg, 0.21 mmol), Pd2(dba)3 (4.4 mg, 2.5 mol %), Xphos (9.1 mg, 10 mol %) and Cs2CO3 (93 mg, 0.29 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 18 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 511 (50 mg, 52%) as an off white solid. LCMS: (Method I): RT 2.49 min; [M+H]+ 503.2. 1H NMR (400 MHz, CHCl3-d): δ 8.02-7.97 (m, 1 H), 7.77-7.73 (m, 1 H), 7.29-7.22 (m, 2 H), 4.52-4.20 (m, 4 H), 3.86 (t, J=4.7 Hz, 4 H), 3.82 (s, 3 H), 3.79-3.65 (m, 2 H), 3.58-3.50 (m, 2 H), 3.35 (q, J=7.5 Hz, 2 H), 3.18-3.09 (m, 2 H), 3.09-2.99 (m, 2 H), 2.90-2.76 (m, 2 H), 2.07-1.88 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H)