Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].Br[C:20]1[N:24]2[N:25]=[C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>O1CCOCC1.O>[F:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([C:12]3[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[C:10]([F:18])[CH:11]=3)=[CH:21][N:22]=2)[N:25]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc3ccc(N4CCCC4c4cc(F)ccc4F)nn23)cc1F
Temperature: 150 °C

Procedure:
In step 12-1, [Pd(Dppf)2]Cl2 (90 mg, 0.11 mmol), sodium carbonate (0.41 g, 3.9 mmol), and 4-cyano-3-fluorophenylboronic acid (0.36 g, 2.2 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (0.42 g, 1.1 mmol) in 3 mL of dioxane and 1 mL of DI water. The reaction mixture was heated in a microwave for twenty minutes at 150° C., and the slurry was then cooled to room temperature and filtered through a 0.2 μM nylon fit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in dichloromethane (DCM). This solution was loaded onto a 12 g silica gel column and eluted using a 0-10% methanol in DCM gradient over 30 minutes. The solvent was removed from the desired fractions to yield 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile. m/z=420.2 [M+1].
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH3:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=1.Cl>CO>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19](=[O:20])[CH2:21][CH:33]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: C1=NCCCC1
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Product: O=C(CC1CCCCN1)C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 1,1-diphenylacetone, 63.0 g (0.3 moles), is added and the mixture is stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 30.0 g (0.36 moles) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirring continued at room temperature for a period of 6 days under an atmosphere of carbon dioxide. The reaction mixture is poured into 375 ml of concentrated HCl on 400 g of ice and the resulting mixture is extracted with methylene dichloride. The extracts are combined, dried over anhydrous sodium sulfate and the solvent is removed. The crude oil is recrystallized twice from an aqueous isopropyl alcohol solution to yield 37.9 g (37% yield) of 1,1-diphenyl-3-(2-piperidyl)propan- 2-one as the hydrochloride salt having a M.P. of 197-9°C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Cl)ccc1O
Yield: 97.4 %

Procedure:
To a stirred solution of 1.7 g (9.96 mmol) of 1-(5-chloro-2-hydroxyphenyl)ethanone in 20 mL of CH2Cl2 and 11.34 g (99.47 mmol) of trifluoroacetic acid, slowly add 3.46 g of (29.82 mmol) of triethylsilane. Stir resulting solution at room temperature for 18 hours, and remove volatiles and excess reagents under reduced pressure to give 1.52 g (97.4%) of 4-chloro-2-ethylphenol as an oil. 1H NMR (500 MHz, CDCl3) δ 7.09 (d, J=2.6 Hz, 1H), 7.03-7.01 (m, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.82 (s, 1H), 2.58 (q, J=7.6 Hz, 2H) and 1.21 (t, J=7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 151.85, 131.82, 129.62, 126.62, 125.60, 116.28, 22.81 and 13.60. MS m/e 157. The 4-chloro-2-ethylphenol can be used in Preparation 13b.
Reaction SMILES: Cl.[Br:2][C:3]1C=C[C:6]([CH2:7]N)=[CH:5][CH:4]=1.C([N:13]([CH2:16][CH3:17])CC)C.[N:18]1[C:27]2[C:22](=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]([OH:30])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Br:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:17]=1[CH2:16][NH:13][C:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[N:24][CH:23]=2)[N:18]=1)=[O:30]
Reactant: CCN(CC)CC
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1Br)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a stirring solution of 4-bromobenzylamine hydrochloride (97.8 mg, 98%, 0.431 mmol) in anhydrous DMF (5 ml) was added triethylamine (60.1 ul. 0.431 mmol), After 5 min, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol) was sequentially added. The resulting mixture was allowed to stir at room temperature for overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (97 mg, 99%): m.p. 149-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.2 %

Procedure:
1-Bromo-4-iodobenzene (20.0 g, 70.7 mmol), bis(triphenylphospine)palladium(II) dichloride (PdCl2(PPh3)2) (250 mg), and CuI (68 mg) were suspended in 50 mL triethylamine (NEt3) and 100 mL tetrahydrofuran (THF). The suspension was treated with 3 cycles of evacuation and refilling with N2. Phenylacetylene (7.21 g, 7.75 mL, 1.0 eq) was added in 0.5 mL portions every 5 minutes to the stirred suspension. The solution was then stirred at room temperature for 22 hours. The solvents were then evaporated. Methylene chloride (100 mL) and 1 M HCl (aqueous) (50 mL) were added, the organic layer was retained, and then was washed again with 1 M HCl (aqueous) (50 mL) and 2×50 mL water, dried (MgSO4), filtered, and the solvent evaporated in vacuum to give 18 g of the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[NH:40]1[CH2:48][CH2:47][CH2:46][CH:42]([C:43]([NH2:45])=[O:44])[CH2:41]1>>[C:43]([CH:42]1[CH2:46][CH2:47][CH2:48][N:40]([C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])[CH2:41]1)(=[O:44])[NH2:45]
Reactant: NC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Product: NC(=O)C1CCCN(C(=O)c2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)C1

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and nipecotamide (18 mg, 0.14 mmol) the title compound was obtained (18 mg, 37%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.36(m, 2H), 8.29(dt, 1H), 7.95–7.76(m, 4H), 7.44(dd, 1H), 4.02(m, 1H), 3.18(bm, 2H), 2.87(bm, 2H), 1.70–1.38(m, 4H). MS 536.8 m/z (M−H)−.
Reaction SMILES: CC(C)(C)CC(Cl)=O.NC1C=CC(OC)=NC=1.C(OCC)C.Cl.C[O:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=1>O1CCCC1.CO>[OH:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:28][CH:27]=1
Reactant: COc1ccc(NC(=O)CC(C)(C)C)cn1
Agent: CC(C)(C)CC(=O)Cl
Agent: COc1ccc(N)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)CC(=O)Nc1ccc(O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
3,3-Dimethylbutyroyl chloride (4.04 g, 30.0 mmol) was added dropwise to a stirred solution of 5-amino-2-methoxypyridine (3.72 g, 30.0 mmol) in tetrahydrofuran (25 mL). After stirring for 1 hour at room temperature, diethyl ether was added and the solid material was isolated by suction. The N-(6-methoxy-pyridin-3-yl)-3,3-dimethyl-butyramide hydrochloride (4.13 g, 15.96 mmol) was heated at 180° C. for 15 minutes. After cooling to room temperature the product was dissolved in methanol. Partial evaporation of the solvent yielded the title compound (1.15 g, 35% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]=[C:16]1[CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]=[C:16]1[CH2:25][CH3:26])=[O:11]
Reactant: CCc1nc2sccc2c(=O)n1N
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Product: CCc1nc2sccc2c(=O)n1NC(=O)C[C@@H]1CC[C@H]2C[C@@H]1C2(C)C

Procedure:
The product from Example 1C and 3-amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one (Enamine) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 1H) 1.07 (s, 3H) 1.16-1.23 (m, 6H) 1.45-1.64 (m, 1H) 1.79-2.06 (m, 6H) 2.27-2.46 (m, 2H) 2.53-2.67 (m, 1H) 2.66-2.82 (m, 1H) 7.38 (d, J=7.1 Hz, 1H) 7.59 (d, J=5.6 Hz, 1H); MS (ESI+) m/z 360 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH3:21])([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(OCC)C>[CH3:7][C:8]([CH3:21])([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=1
Reactant: CC(C)(C)CCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)CCOc1ccc(CN)cc1
Temperature: 0 °C
Yield: 88.1 %

Procedure:
Mix lithium aluminum hydride (1.0 g, 26.6 mmol) and anhydrous ethyl ether (70 mL) under nitrogen atmosphere. Stir and cool to 0° C. in an ice bath. Add dropwise a solution of 4-(3,3-dimethylbutoxy)-benzonitrile (1.8 g, 8.87 mmol) in anhydrous ethyl ether (20 mL). Stir for 2 h at 0° C., remove the ice bath and stir at ambient temperature for 18 h. Cool the reaction flask in an ice bath and add carefully dropwise and sequentially water (1 mL), 2N aqueous NaOH (1 mL), and water (2 mL). Stir for 30 min. filter, separate the organic layer, dry over Na2SO4 and concentrate in vacuo to obtain the title compound (1.62 g, 88%). MS (ES+) m/z: 191 M+H−NH3)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15]Cl>>[OH:17][CH:14]([CH2:13][OH:18])[CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: OCC(O)CCl
Product: O=C1CCc2ccc(OCC(O)CO)cc2N1

Procedure:
In the same manner as described in Example 7, 7-hydroxy-3,4-dihydrocarbostyril was reacted with glycerol α-monochlorohydrin to give 7-(2,3-dihydroxy)propoxy-3,4-dihyrocarbostyril as white needle-like srystals having a melting point of 143° - 144° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](Cl)=[N:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>CN(C=O)C>[CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Reactant: CC(C)(N)CO
Solvent: CN(C)C=O
Product: Cn1c(=NC(C)(C)CO)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Yield: 50.6 %

Procedure:
A solution of 3-Benzyl-2-(biphenyl-4-ylmethyl)-6-chloro-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (9.5 mg, 0.022 mmol) and 2-amino-2-methyl-1-propanol (21 μL, 0.22 mmol) in DMF (2 mL) is heated at 110° C. overnight. The reaction mixture is then purified by chromatography to give 5.5 mg product (Yield: 52%). MS (FAB) m/z 494.4 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH2:24][C:25](=[O:33])[CH2:26][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:34]([CH2:36][C:37](OCC)=[O:38])#[N:35]>CO>[C:34]([C:36]1[C@@H:19]([C:18]2[CH:21]=[CH:22][C:15]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:16][CH:17]=2)[C@H:26]([N+:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25](=[O:33])[NH:24][C:37]=1[O-:38])#[N:35]
Reactant: NC(=O)C[n+]1ccccc1
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CC1=C([O-])NC(=O)[C@@H]([n+]2ccccc2)[C@@H]1c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
Triethylamine (3.06 mL, 21.98 mmol) was added to a mixture of 4-phenoxybenzaldehyde (3.96 g, 19.98 mmol), 1-(2-amino-2-oxoethyl)pyridinium chloride (3.45 g, 19.98 mmol) and ethyl 2-cyanoacetate (2.260 g, 19.98 mmol) in methanol (80 mL) at room temperature. The resultant yellow solution was stirred at room temperature for 15 h to give a suspension. The yellow solid was collected by filtration, washed with methanol (2×20 mL), toluene (2×20 mL), hexanes (2×20 mL) and dried under vacuum to give trans-3-cyano-6-oxo-4-(4-phenoxyphenyl)-5-(pyridinium-1-yl)-1,4,5,6-tetrahydropyridin-2-olate (7.00 g, 91% yield). MS (ES+) m/z: 384 (M+H); LC retention time: 2.472 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][S:28]1(=[O:37])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][S:28]3(=[O:36])=[O:37])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: O=S1(=O)Cc2ccccc2N1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4CS3(=O)=O)[C@H](C)[C@H]12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (25.5 mg, 0.07 mmol), 1,3-dihydro-benzo[c]isothiazole 2,2-dioxide (13 mg, 0.077 mmol), and triphenylphosphine (28 mg, 0.105 mmol) in anhydrous tetrahydrofuran (0.4 mL) was cooled in an ice bath and treated with diethyl azodicarboxylate (0.017 mL, 0.105 mmol). The mixture was stirred at 0-5° C. for 30 minutes, then streaked onto a 1 mm×20 cm×20 cm silica gel GF plates. The plates were developed with 5% ethyl acetate in dichloromethane. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-(2,2-dioxo-2,3-dihydro-benzo [c]isothiazol-1-yl-methyl)-1-methyl-carbapen-2-em-3-carboxylate (15 mg) as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC[C@H](C)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 17 h
Yield: 90 %

Procedure:
Lithium bis(trimethylsilyl)amide (3.23 g, 19.3 mmol) was added to 8 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (1.16 g, 7.73 mmol) in 1 mL of tetrahydrofuran to the reaction solution was followed by addition of (S)-1-bromo-3-methyl-pentane (2.05 g, 12.4 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 25 mL of 1 N NaOH, washed with 25 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3× 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 1.63 g (90%) of a clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.83 (m, 6H) 1.20 (m, 5H) 1.57 (s, 3H) 1.98 (m, 2H) 7.35 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N+:31]([O-])(OCCC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]2[C:3]=1[CH:18]=[N:31][NH:17]2
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: Cc1c(N)cc(Oc2ccc(F)cc2F)cc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Fc1ccc(Oc2cc(Br)c3cn[nH]c3c2)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
3-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine (5.31 g, 16.9 mmol) was dissolved in 50 mL dry benzene, and acetic anhydride (5.17 g, 50.7 mmol) and potassium acetate (1.69 g, 17.2 mmol) were added. The reaction mixture was placed under nitrogen atmosphere and heated to 80° C. with stirring for 10 minutes. Isoamyl nitrate (3.39 mL, 25.4 mmol) was added dropwise over 30 minutes, after which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Water (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added, and the mixture was heated to 55° C. Methanol (100 mL) was added, and the mixture was heated to 80° C. The mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned betwee methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 3.18 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:31])[C:10]=1[C:11](=[O:30])[NH:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[N:21]=[C:15]2[CH:14]=1)=[O:5])C.CO.O.[Li+].[OH-]>C1COCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:15]3[CH:14]=[C:13]([NH:12][C:11]([C:10]4[N:9]([CH3:31])[N:8]=[CH:7][C:6]=4[C:4]([OH:5])=[O:3])=[O:30])[CH:18]=[CH:17][N:16]3[N:19]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(OC)c3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.5 g, 8.33 mmol) in a mixture of THF (20 ml), MeOH (14 ml) and water (7 ml) was added LiOH×H2O (1.0 g, 25.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 4 h. Solvents were removed in vacuum and the resultant crude material was diluted with water (150 ml). The aqueous layer was washed with ether (2×100 ml), cooled to 0° C., and slowly acidified (pH 5) with aqueous 1N HCl solution under stirring. The resultant precipitated solid was filtered and dried under vacuum to give 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid as white solid (5.9 g; crude, quant). LC-MS: m/z=393.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ncc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cn1

Procedure:
By carrying out the operation analogously to example 213, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.ClCCl.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
A solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.12 mmol) in thionyl chloride (50 mL) was stirred for 3 hr at reflux and then concentrated in vacuo to give a residue, which was dissolved in dichloromethane (10 mL) and then added dropwise to a solution of anisole (6.51 g, 60.28 mmol) and AlCl3 (11.97 g, 90.00 mmol) in dichloromethane (120 mL). The resulting solution was stirred for 3 h at room temperature, then diluted with water (100 mL), extracted with dichloromethane (3×80 mL), dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with (1%˜2% ethyl acetate in petroleum ether) to afford 1,2-bis(4-methoxyphenyl)ethanone as a white solid (6.5 g, 84%).