Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].Br.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of cis chrysanthemic acid (10 g) in toluene (53 ml) was added a solution of 25% hydrogen bromide-acetic acid (1.3 g) at room temperature under a nitrogen atmosphere. Irradiation with a high pressure mercury lamp (110 W) was made for 30 minutes under stirring. After the irradiation was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (9.6 g). Gas chromatography assay of the product gave the isomer ratio: cis, 8.6%; and trans, 91.4%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(C(Cl)=O)=O.[NH2:22][C:23]1[S:24][C:25]([C@H:28]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:22][C:23]4[S:24][C:25]([C@H:28]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1cnc(N)s1)c1ccc(F)cc1Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (618 mg, 3.0 mmol) in anhydrous CH2C2 (6 mL) was slowly added (COCl)2 (0.3 mL, 3.4 mmol) at −10° C. followed by DMF (3 drops). The reaction mixture was stirred at −10° C. for 0.5 h. The excess (COCl)2 was removed under vacuum. The acid chloride (10.5 mmol) was then dissolved in anhydrous CH2Cl2 (3 mL) and was slowly added to a solution of (R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (648 mg, 1.8 mmol) and Et3N (1.8 mL, 6 mmol) in anhydrous CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with CH2Cl2 and washed with 1N HCl, NaHCO3 and brine. The organic layer was separated from the aqueous layer and dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40-60% EtOAc/Hexane) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)cyclopropanecarboxamide as a colorless solid (680 mg, 69%). 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.60 (dd, J=8.7, 5.9 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.3, 2.6 Hz, 1H), 7.05 (td, J=8.2, 2.6 Hz, 1H), 6.90 (td, J=8.3, 1.7 Hz, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.18 (d, J=4.3 Hz, 1H), 6.04 (s, 2H), 3.90 (d, J=4.3 Hz, 1H), 1.73 (td, J=5.4, 2.0 Hz, 2H), 1.28 (t, J=7.1 Hz, 2H), 1.29 (s, 9H). HPLC ret. time 3.65 min, 10-99% CH3CN, 5 min run; ESI-MS 550.5 m/z (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH2:24])=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:24][C:21]1[N:20]=[C:19]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15](=[O:37])[N:16]([C:25]3[C:26]([F:36])=[C:27]([O:34][CH3:35])[CH:28]=[C:29]([O:32][CH3:33])[C:30]=3[F:31])[CH2:17][C:18]2=[CH:23][N:22]=1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N)nc3N(C3CCNCC3)C2=O)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[7-Amino-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (295 mg, 0.567 mmol) in dichloromethane (5 mL) at 0° C. trifluoroacetic acid (647 μL) was added. The resulting solution was stirred at room temperature for 5 hours. The solution was then concentrated under reduced pressure. The resulting residue was concentrated with toluene (2×50 mL) to give a thick oil. Dichloromethane (2 mL) was added to the oil to produce a white precipitate. To accelerate precipitation diethyl ether (10 mL) was added. The mixture was then filtered to deliver 338 mg (92%) of the title compound as a white powder: mp 200° C.–220° C. (decomposition); MS (APCI) 421.1, 422.2.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH:9]=[C:10]([Cl:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:17][CH:18]1[CH2:24][C:23](=[O:25])[O:22][C:20](=[O:21])[CH2:19]1>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:25])[CH2:24][CH:18]([CH3:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[CH:9]=[C:10]([Cl:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N)ccc1Cl
Reactant: CC1CC(=O)OC(=O)C1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)=Cc1cc(NC(=O)CC(C)CC(=O)O)ccc1Cl
Reaction time: 3 h

Procedure:
5.2 g of 4-chloro-3-(2-chloro-2-ethoxycarbonyl-ethenyl)aniline in 30 ml of dichloromethane were added dropwise at 25° C. to a solution of 2.56 g of 3-methylglutaric anhydride in 50 ml of dichloromethane. After 3 h, the deposited precipitate was removed and washed with dichloromethane. Yield: 5 g; m.p.: 137°-138° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:24].[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N+:8]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=NCCc3ccccc32)cc1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Temperature: 25 °C

Procedure:
The mixture of 1-phenyl-3,4-dihydroisoquinoline (292.0 g) and benzyl bromide (176 ml) in acetonitrile (3 l) was refluxed for 1 hour. After cooling the mixture to room temperature, the solvent was evaporated in vacuo. The residue was triturated with diethyl ether (1 l) to give 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium bromide (471.2 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC1(C)OCC(CO)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To pentafluoropyridine (2.0 g, 12 mmol) dissolved in DMSO was added 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (1.5 mL, 12 mmol) and Cs2CO3 (3.8 g, 12 mmol). The slurry was heated in an oil bath at 60° C. for 1 day. The reaction was partitioned with water and ethyl acetate, washed with water and brine, dried (Na2SO4) and the solvent was removed to give 2,3,5,6-tetrafluoro-4-[[(2,2-dimethyl)dioxolan-4-yl]methoxy]pyridine (3.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:13]([O:12][CH3:11])=[O:14])[CH:3]=[C:4]2[CH:10]=[N:9]1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cnc3[nH]ncc3c2)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00 g, 10.10 mmol), 3-(methoxycarbonyl)phenylboronic acid (2.20 g, 12.12 mmol), sodium bicarbonate (2.2 g, 6.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.250 g, 0.202 mmol) in dioxane/water (40 mL/10 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded methyl 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (8) (1.65 g, 65% yield) as yellow solids. S: m/z 254.0 (M+H+).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(Br)=CC=2)C)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:27].O=O>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2([CH2:1][C:2](=[O:27])[CH3:3])[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: O
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Product: CC(=O)CC1(c2ccc(F)cc2)CCNC(=O)O1
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl) -1,3-oxazinan-2-one (5 g, 12 mmol) and CuCl (2.75 g, 27.8 mmol) in dry DMF (50 mL) was added H2O (20 mL) and PdCl2 (950 mg, 3.2 mmol) at room temperature. The mixture was vigorously stirred under a balloon of oxygen for 24 h. After TLC showed the starting material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (S)-3-(S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (5.25 g, 92%), which was purified by column chromatography. 1H NMR (CDCl3): 1.47 (s, 3H), 2.06 (s, 3H), 2.10-2.36 (m, 3H), 2.58 (m, 1H), 2.90 (m, 2H), 5.58 (m, 1H), 6.69 (m, 1H), 6.79 (m, 1H), 7.02 (m, 2H), 7.19-7.33 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:25][CH:26]([O:28][C:29]([O:31][CH:32](Cl)[CH:33]([CH3:35])[CH3:34])=[O:30])[CH3:27]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][CH:32]([O:31][C:29]([O:28][CH:26]([CH3:27])[CH3:25])=[O:30])[CH:33]([CH3:35])[CH3:34])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)OC(=O)OC(Cl)C(C)C
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl)C(C)C
Yield: 66.6 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (0.4 g, 0.99 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.57 g (3.0 mmol) of 1-chloro-(2-methylpropyl) (methylethoxy)formate in the presence of 0.33 g (1.1 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.37 g of a mixture of the title compound (47a) and (3R)-4,4-dimethyl-3-(1,1,2,2-tetramethyl-1-silapropoxy)-3,4,5-trihydrofuran-2-one (4a). MS (ESI) m/z 583.12 (M+Na)+.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: OC(CCc1ccccc1)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of racemic 1,3-diphenyl-1-propanol (1.26 g; 5.94 mmol) was dissolved in 10 mL of acetone, and Jones reagent was added until persistence of the orange color. After stirring for 30 min, the reaction was quenched by adding 2 mL of 2-propanol. The solvent was decanted away from the precipitated solids, which were washed with ethyl acetate. The combined organic fractions were washed with 2×20 mL of water, dried and concentrated. The crude product was filtered through a plug of silica gel, eluting with 25% ethyl acetate/hexane, to obtain 1.07 g (86%) of 1,3-diphenylpropanone as a white crystalline solid, 1H NMR (360 Mhz; CDCl3): d 3.09 (t, 2H, J=8.1); 3.33 (t, 2H, J=8.1); 7.29 (m, 5H); 7.49 (m, 3H); 7.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.C(OC(O)C)C.Cl.N1C=CC=CC=1.[CH3:24][NH:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)=[O:27]>>[CH3:24][NH:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:6]3[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)=[O:27]
Reactant: CNC(=O)n1ccc2cc(N)ccc21
Reactant: N#Cc1cnc(N)cc1Cl
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)n1ccc2cc(Nc3cc(N)ncc3C#N)ccc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
2-Amino-4-chloro-5-cyanopyridine (123 mg, 0.80 mmol) synthesized in Production example 215-3, ethoxyethanol (3 ml) and pyridine hydrochloride (186 mg, 1.60 mmol) were added to N1-methyl-5-amino-1H-1-indolecarboxamide (198 mg, 1.05 mmol) synthesized in Production example 218-2; and the reaction mixture was stirred at 130° C. for 3 hours. After allowing to be cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate in this order) to yield the title compound (110 mg, 0.359 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][NH2:20].Cl.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:20]([CH2:19][CH:18]([F:21])[F:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)F
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)F
Temperature: 110 °C
Yield: 60.3 %

Procedure:
3-(Benzyloxy)-2-methyl-4H-pyran-4-one (432 mg, 2.0 mmol) was mixed with 2,2-difluoroethylamine (655 mg, 8.0 mmol) and triethylamine hydrochloride (1.10 g, 8.0 mmol) in pyridine (6 mL) in a sealed vial. The reaction mixture was heated at 110° C. for overnight. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was mixed with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine. The product was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-1-(2,2-difluoroethyl)-2-methylpyridin-4(1H)-one (337 mg) as pale-yellow solid. Yield=60%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.66 (d, J=7.1 Hz, 1H), 7.16-7.55 (m, 5H), 6.46 (d, J=7.1 Hz, 1H), 5.55 (t, J=55.0 Hz, 1H), 4.45 (t, J=14.8 Hz, 1H) and 2.20 (s, 3H); MS m/z 280 [M+1]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[CH2:6]([O:13][C:14](=[O:23])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:19][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(CO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
Under ice cooling, methanesulfonyl chloride (2.1 mL, 27 mmol) was added to a solution of 4-hydroxymethylbenzoic acid benzyl ester (Reference Compound No. 7-1, 6.0 g, 24.8 mmol) and triethylamine (7.6 mL, 54 mmol) in dichloromethane (60 mL), and then the reaction mixture was stirred at room temperature for 50 minutes. Brine (0.30 L) was added to the reaction solution, and the mixture was extracted with chloroform (0.15 L) four times. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5.8 g of the title reference compound as yellow oil. (Yield 73%)
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]([C:9]1[S:10][C:11]([C:14]2[N:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[CH:12][CH:13]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH2:26][CH2:25][CH2:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3[S:10][C:9]([C:7]([NH2:6])=[O:8])=[CH:13][CH:12]=3)=[CH:15][N:16]=2)[N:19]=1
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cnc4ccc(NCCCN5CCCC5=O)nn34)s2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To 50 mg (0.094 mmol) of N-(2,4-dimethoxybenzyl)-5-(6-((3-(2-oxopyrrolidin-1-yl)propyl)amino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxamide dissolved in 1 mL DCM was added 5 mL of TFA. The resulting solvent was stirred at rt for 0.5 hr and then concentrated. It was purified in the PREP HPLC to obtain 26 mg (72%) of the desired product. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04 (quin, J=7.39 Hz, 4H) 2.33-2.41 (m, 2H) 3.45-3.60 (m, 6H) 6.76 (d, J=9.85 Hz, 1H) 7.64-7.72 (m, 2H) 7.75 (d, J=4.04 Hz, 1H) 7.94 (s, 1H); LRMS (ESI) m/e 385.0 [(M+H)+, calcd for C18H20N6O2S 384.0].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.C1([C:25](=[O:34])[CH2:26][C:27]2[CH:28]=[C:29](C)[CH:30]=[CH:31][CH:32]=2)C=CC=CC=1>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:25](=[O:34])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:3][CH:4]=1
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution of 4-bromobiphenyl (683 mg, 2.9 mmol) in anhydrous THF (5 mL) was added n-BuLi (1.2 mL, 2.9 mmol) dropwise at −78° C. After being stirred at the temperature for 0.5 h, a solution of N-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 of Intermediate 4) (500 mg, 2.8 mmol) in anhydrous THF (5 mL) was added via a syringe, and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=20:1) to give 1-(biphenyl-4-yl)-2-phenylethanone (180 mg, yield 24%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[CH2:17][CH2:16][N:15]([C@H:18]([CH:26]([CH3:28])[CH3:27])[C:19](OC(C)(C)C)=[O:20])[C:14]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C.ClC(OCC)=O.C[Si](C)(C)[O:57][NH2:58].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[CH2:17][CH2:16][N:15]([C@H:18]([CH:26]([CH3:27])[CH3:28])[C:19]([NH:58][OH:57])=[O:20])[C:14]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)[C@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](C(=O)NO)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
t-Butyl (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (102 mg; 0.23 mmol) was dissolved in CH2Cl2 (2 ml) and cooled to 0° C. Trifluoroacetic acid (TFA; 1 ml) was added, and the mixture was stirred for 2 h. The solvents were removed under reduced pressure, and the residue was taken up in tetrahydrofuran (THF; 2 ml). DIEA (0.16 ml; 0.93 mmol) and ethyl chloroformate (67 μl; 0.69 mmol) were added. After stirring at RT for 2 h, O-trimethylsilylhydroxylamine (0.10 ml; 1.39 mmol) was added. The mixture was stirred for 15 h, HCl (6N, 0.30 ml) was added, and then the solvents were removed under reduced pressure. Purification of the residue by preparative HPLC resulted in (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (8 mg, 0.02 mmol). MS: 398.15 (M+H); Rt: 1.46 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][C:13]#[N:14].C([OH:17])C.[ClH:18]>CCOCC>[ClH:18].[CH3:11][C:4]1[CH:5]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:12][C:13](=[NH:14])[OH:17]
Reactant: CCO
Reactant: Cc1cc(C(C)C)cc(C)c1CC#N
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(C(C)C)cc(C)c1CC(=N)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 2,6-dimethyl4-isopropylphenylacetonitrile (Example 4c); (0.2 g, 1.07 mmol) in anhydrous ether (20 mL) was added absolute ethanol (0.05 g, 1.07 mmol) and an excess of HCl gas was passed into the solution with cooling in an ice bath. The resulting solution was allowed to stir at 0° C. for 2 hours and kept in a refrigerator for 4 days. The white solid was collected by filtration, washed with ether (2×5 mL) and dried to give 0.12 g (42%) of 2-(2,6-dimethyl-4-isopropylphenyl)acetimidate hydrochloride as a white solid, mp 231-233° C. A solution of ethylenediamine (0.053 g, 0.89 mmol) in absolute ethanol (1 mL) was added to a solution of the imidate hydrochloride (0.12 g, 0.44 mmol) in absolute ethanol (4 mL) cooled at ice-bath temperature. After stirring at 0° C. for 2 hour, the solution was heated at reflux for 20 minutes. The solvent was evaporated and the oily residue was washed with water (2×1 mL) and extracted with methylene chloride (3×10 mL). The solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford the free base of the title compound as a white solid (mp 112-114° C.). A solution of the free base in anhydrous ether was treated with dry HCl gas. The crude salt was collected and recrystallized from ethanol/ether to give 0.08 g (65%) of the title compound as a white solid. mp 296-298° C.; Anal. C15H22N2.HCl.0.1H2O: C, H, N.