Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10](I)=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)O1.C(=O)([O-])O.[Na+]>CN(C)C=O.O.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>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10]([C:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=3)=[CH:11][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)c(Cl)cnc32)cc1
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
A mixture of Example 229B (0.808 g, 1.730 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, 0.588 g, 1.903 mmol) and sodium hydrogencarbonate (0.436 g, 5.19 mmol) in degassed N,N-dimethylformamide (10.81 mL) and water (3.6 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (0.121 g, 0.173 mmol) under nitrogen and the mixture was heated at 72° C. for 24 hours. The mixture was cooled to ambient temperature, suspended in 80 mL water, stirred for 30 minutes and filtered. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 0-20% ethyl acetate in hexanes afforded the title compound. MS (ESI+) m/z 522.2 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][N:9]1[C:14](=[O:28])[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][O:26][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]=1[O:24][CH3:25])[C:14]([N:9]1[CH2:10][C@@H:11]([CH2:12][CH3:13])[C@@H:8]1[C:6]([OH:7])=[O:5])=[O:28]
Reactant: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)OC(C)(C)C)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid tert-butyl ester (160 mg, 0.41 mmol, 1 eq.) in dry DCM (3.5 mL) at room temperature was added TFA (1.5 mL). The resulting reaction mixture stirred at room temperature for 2 h. The solvent was removed in vacuo and dried under high vacuum. The residue was dissolved in ether and washed with 2% NaOH solution. The aqueous layer was acidified with 1 M HCl and extracted with EtOAc. The organic layer dried over Na2SO4, filtered, and concentrated in vacuo to afford (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid in 80% yield, which was used without further purification. ESMS: m/z 336.3 [M+H].
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[C:54]([Cl:59])[CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)[C:50]=1[CH3:66].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[N:52]=[C:51]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=1)[C:50]([CH3:66])=[C:49]2[NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH:42]=1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Nc1cncc(N2CCOCC2)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 5-morpholinopyridin-3-amine (0.074 g, 0.42 mmol), 4,8-dichloro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.35 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) and sodium tert-butoxide (0.083 g, 0.87 mmol) in toluene (3.5 mL) at 100° C. for 1.1 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 8-chloro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69-8.73 (2H, m), 7.95-8.06 (3H, m), 7.92 (1H, dd, J=7.4, 1.2 Hz), 7.81 (1H, d, J=2.3 Hz), 7.50-7.56 (3H, m), 6.56 (1H, t, J=2.4 Hz), 3.70 (4H, m), 3.06 (4H, m), 2.25 (3H, s). Mass Spectrum (ESI) m/e=432.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH:16]=[N:15][CH:14]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2cccc3cnccc23)c1
Temperature: 240 °C
Yield: 22.9 %

Procedure:
A sealed tube was charged with 5-hydroxyisoquinoline (0.15 g, 1.03 mmol), 3,5-dibromopyridine (0.24 g, 1.03 mmol), potassium carbonate (0.27 g, 2.0 mmol) and DMF (4 mL). The reaction was heated to 240° C. for 10 minutes in a personal chemistry microwave. The reaction was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (0.071 g, 23%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (d 0.742; 0.0410 mL, 0.235 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.0311 g, 0.0883 mmol, See Example 1), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.020 g, 0.0589 mmol, see Example C) and TBTU (0.0227 g, 0.0706 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.008 g, 24%). MS APCI (+) m/z 501.3 detected.
Reaction SMILES: OC1C=CC(C(O)=O)=CC=1.C(O)C1C=CC=CC=1.O[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=O)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:27]([O:26][CH2:24][C:23]1[CH:34]=[CH:35][CH:20]=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
In the same way as in Example 13, 69.1 g (0.5 mole) of p-hydroxybenzoic acid and 216.2 g (2 moles) of benzyl alcohol were reacted at 120° C. for 4 hours in 138 g of toluene in the presence of 1.44 g of p-toluenesulfonic acid as a catalyst. The yield of benzyl p-hydroxybenzoate was 26%. Dimerization and dehydration of benzyl alcohol occurred simultaneously, and dibenzyl ether was formed in a ratio of as high as 45%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([CH2:28][S:29]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:28][S:29]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Solvent: CCO
Product: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Yield: 85 %

Procedure:
A mixture of 4-[3-(1-naphthylsulfonylmethyl)-4-nitrophenoxymethyl]-piperidine-1-carboxylic acid benzyl ester (0.9 g, 1.6 mmoles) and stannous chloride (1.8 g, 8 mmoles) in ethanol was heated at reflux temperature for 5 hours, cooled and concentrated under vacuum. The concentrate was diluted with water and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated to afford the title compound (0.74 g, 1.36 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:27])[C:10](=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22]([CH3:25])=[CH:21][C:20]2=[O:26])[C:11](=O)[CH3:12].[NH2:28]/[C:29](/[CH3:37])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:10]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:30]([C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32])=[C:29]([CH3:37])[NH:28][C:11]=1[CH3:12])=[O:27]
Reactant: COc1ccccc1C(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CCCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2OC)C1c1cccc2c(=O)cc(C)oc12

Procedure:
240 mg (0.62 mmol) of 1-(2-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 94 mg (0.62 mmol) of n-propyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 108 mg (33% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Clc1ccncc1-c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2-c2ccccc2)cc1
Yield: 48.7 %

Procedure:
4-Chloro-3-phenylpyridine (200 mg, 1.06 mM), paranitrophenol (440 mg, 3.18 mM), Hunig's base (isoPr2EtN, diisopropylethylamine, 1 ml) and 1-methylpyrrolidone (2 ml) were stirred at 160° C. for 2 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1, and then 2:1) to obtain 4-(4-nitrophenoxy)-3-phenylpyridine (150 mg) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-yl-amine (prepared in Example 72, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 86%) as a colorless oil: [α]30589=−18.8° (c=0.16, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 2.05-2.19 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.86-3.94 (m, 1H, ArCH), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.75 (m, 4H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:18])=[CH:16][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2
Reactant: C1CCNCC1
Product: O=C(c1ccc2c(c1)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2)N1CCCCC1

Procedure:
This compound was prepared from 2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; light yellow solid, mp.: 54° C.,
Reaction SMILES: C([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[C@H:16]([CH3:24])[NH:17][P:18]([CH2:22][CH3:23])([CH2:20][CH3:21])=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[CH2:20]([P:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:26])=[O:8])=[O:25])[CH3:24])([CH2:22][CH3:23])=[O:19])[CH3:21]
Reactant: CCP(=O)(CC)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCP(=O)(CC)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The oily diethylphosphoryl-L-alanyl-L-proline benzylester (8.5 g, 20.6 m mole) was dissolved in methanol and palladium-carbon (2 g) was added thereto. The reductive reaction was carried out for 3 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain an oily diethylphosphoryl-L-alanyl-L-proline.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>O.O1CCCC1>[S:13]1[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: Brc1ccc(C=Cc2cc3ccccc3s2)s1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred, chilled (-70° C.) suspension of 2-[2-(5-bromo-2-thienyl)ethenyl]benzo[b]thiophene (15.6 g) and tetrahydrofuran (400 ml) was added n-butyl lithium (21.4 ml of a 2.5M solution in hexanes), under nitrogen over 10 mins. The solution was stirred at -70° C. for 1.5 hr, and was transferred via canula to a flask containing a suspension of dry ice (excess) and tetrahydrofuran (1000 ml). The suspension was stirred for 2 hrs and allowed to warm to room temperature overnight. The mixture was poured into water (500 ml), acidified with hydrochloric acid, and the tetrahydrofuran was removed in vacuo. The resulting suspension was filtered, and the filter cake was washed with water and dried in vacuo overnight. The filter cake was recrystallized from dimethyl sulfoxide/10% hydrochloric acid to yield 10.5 g (75%) of product, mp 236°-237° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36]([NH:39][C:40](=[O:56])[C:41]3[C:46]([F:47])=[CH:45][CH:44]=[C:43]([NH:48][S:49]([CH2:52][CH2:53][CH3:54])(=[O:51])=[O:50])[C:42]=3[F:55])[CH:37]=2)[NH:32][N:31]=1)(C(C)(C)C)(C)C>C1COCC1>[F:55][C:42]1[C:43]([NH:48][S:49]([CH2:52][CH2:53][CH3:54])(=[O:51])=[O:50])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[C:40]([NH:39][C:36]1[CH:37]=[C:38]2[C:30]([CH2:29][CH2:28][CH2:27][OH:26])=[N:31][NH:32][C:33]2=[N:34][CH:35]=1)=[O:56]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(CCCO[Si](C)(C)C(C)(C)C)c3c2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(CCCO)c3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Tetra-n-butylammonium fluoride (“TBAF”; 0.12 mL, 0.12 mmol, 1.0M in THF) was added to a solution of N-(3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.034 g, 0.060 mmol) in THF (4.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was purified by column chromatography, eluting with ethyl acetate, ethyl acetate/MeOH (50:1) to give 2,6-difluoro-N-(3-(3-hydroxypropyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.014 g, 52%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.6 (s, 1H), 7.7 (m, 1H), 7.1 (m, 1H), 3.7 (t, J=7.0 Hz, 2H), 3.1-3.0 (m, 4H), 2.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=452.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C)C=O>[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:37][CH2:36]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2O)CC1
Temperature: 20 °C
Yield: 55 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.02 g), triethylamine (10.5 cc) and 4-(2-hydroxyphenyl)piperazine dihydrobromide (8.5 g) in dimethylformamide (150 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (50-50 vol) as eluant, and recrystallization from acetonitrile (25 cc), 2-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (5.8 g) is obtained, m.p. 128° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH:10]([O:23][C:24]([CH:26]1[N:31]2[C:32](=[O:43])[CH:33]([NH:34][C:35](=[O:42])[CH2:36][C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[C@H:30]2[S:29][CH:28]=[C:27]1[CH2:44]O)=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)Cl>[F:7][CH2:44][C:27]1[CH:26]([C:24]([O:23][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:25])[N:31]2[C:32](=[O:43])[CH:33]([NH:34][C:35](=[O:42])[CH2:36][C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[C@H:30]2[S:29][CH:28]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CF)=CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of 0.322 g of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 is added a solution of 1.04 g of benzhydryl-3-hydroxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate in 50 ml of CH2Cl2. The mixture is stirred for 0.5 hour then poured into 100 ml of H2O and the CH2Cl2 layer dried (MgSO4) and evaporated in vacuo. The residue is chromatographed on silica with CHCl3 to give benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate, which can be purified by recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1.[F:27][C:28]([F:33])([F:32])[C@H:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:31][C@H:29]([CH3:30])[C:28]([F:33])([F:32])[F:27])=[O:26])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: O=C(O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
To a mixture of 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (10.0 mg, 0.028 mmol), (R)-1,1,1-trifluoropropan-2-amine (6.33 mg, 0.056 mmol) and HATU (10.5 mg, 0.045 mmol) in dry DMF (0.2 mL) was added DIEA (15.0 μL, 0.084 mmol). The reaction vessel was flushed with nitrogen, sealed, and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was directly purified by reverse phase column chromatography (0-50% CH3CN/H2O) to provide the title compound (6.50 mg, 51% yield) as a white solid. MS (apci) m/z=453.0 (M+H).