Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:20]3[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:39]([O:43][C:44]([N:46]1CC[CH2:48][C@H:47]1[C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=1)C(O)=O)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C([O:69]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:42])([CH3:41])[CH3:40])[C:48]([N:36]2[CH2:35][CH2:34][N:33]([C:19]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[C:20]=34)[CH2:38][CH2:37]2)=[O:69])=[CH:56][CH:57]=1
Reactant: OC[C@H](O)COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H](O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.055 mL, 0.32 mmol) was added to a solution of (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.050 g, 0.079 mmol, see Example 15), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.027 g, 0.079 mmol, see Example C) and TBTU (0.031 g, 0.095 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2 M) was added. The mixture was stirred for 10 minutes. Ethyl acetate (20 mL) was then added, and the organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 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, 2 N) was added. The solvent was then removed. The residue was dissolved in MeOH (3 mL), and an aqueous LiOH solution (3 mL, 2 N) was added. The mixture was stirred for 5 minutes, and then extracted with DCM (20 mL) and dried over sodium sulfate. Removal of the solvent provided (S)-2-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone (0.011 g, 24% yield) as a solid. MS APCI (+) m/z 591.2 detected.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CC(F)(F)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of (3,3-difluorocyclobutyl)methanol (500 mg, 4.09 mmol, 1.00 equiv), triethylamine (662.6 mg, 6.55 mmol, 1.60 equiv), and 4-dimethylaminopyridine (750 mg, 6.14 mmol, 1.50 equiv) in CH2Cl2 (5 mL) under argon at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.01 g, 5.30 mmol, 1.30 equiv) in portions. The resulting mixture was stirred overnight at ambient temperature. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified using flash column chromatography (silica gel, EtOAc/Hexanes (1:5)) to yield 1.1 g (97%) of a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ ppm 7.77 (d, J=7.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.03 (d, J=6.5 Hz, 2H), 2.75-2.50 (m, 2H), 2.50-2.36 (m, 4H), 2.36-2.08 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[S:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([S:20][C:21]([F:24])([F:22])[F:23])=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(SC(F)(F)F)c(F)c1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 3-fluoro-4-trifluoromethylsulfanyl-aniline to afford a white crystalline solid. HPLC (Condition 4) tR=6.71 min, UPLC-MS (Condition 3) tR=1.34 min, m/z=429 [M−H]−.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:17])[CH:10]([CH:12]([C:14](O)=[O:15])[OH:13])[OH:11]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:14](=[O:15])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1C
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Yield: 77.5 %

Procedure:
Benzylamine (75 g, 0.70 mol) and (−)-tartaric acid (100 g, 700 mol) were heated in boiling xylene (1.0 L) in a Dean-Stark apparatus. After cooling, the product was collected, washed with acetone, and recrystallized from EtOH to afford the product (120 g, 77%). 1H NMR (300 MHz, CDCl3) δ 7.39-7.20 (5H, m), 6.27 (2H, d), 4.58 (1H, d), 4.52 (1H, d), 4.38 (2H, m).
Reaction SMILES: Cl.C(O[C:5](=[NH:37])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:22][N:21]=[C:20]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:19]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:18]=4[C:17]=3[N:36]=2)=[CH:8][CH:7]=1)C.[CH3:38][CH:39]1[CH2:44][NH:43][CH2:42][CH:41]([CH3:45])[NH:40]1>C(O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:18]2[C:17]3[N:36]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([C:5]([N:43]5[CH2:42][CH:41]([CH3:45])[NH:40][CH:39]([CH3:38])[CH2:44]5)=[NH:37])=[CH:7][CH:8]=4)[N:14]=[CH:15][C:16]=3[CH2:22][N:21]=[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:19]=2[CH:31]=1
Reactant: CCOC(=N)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Reactant: CC1CNCC(C)N1
Agent: Cl
Solvent: CCO
Product: CC1CN(C(=N)c2ccc(Nc3ncc4c(n3)-c3ccc(Cl)cc3C(c3c(F)cccc3F)=NC4)cc2)CC(C)N1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
A mixture of the ethyl benzimidate (100 mg, 0.17 mmol), 2,6-dimethylpiperazine (200 mg, 8.8 mmol), and absolute ethanol (1 mL) was submitted to microwave irradiation (300 W) for 7.5 minutes at 120° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected and purified by column chromatography (silica gel, 0.25% NH4OH/2% MeOH/97.75% CH2Cl2 to 2.5% NH4OH/20% MeOH/77.5% CH2Cl2) to yield I-251 as a pale yellow solid (30 mg, 30%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]C1.[CH3:13]N(C)C=O>[Cu]I>[CH:4]1([C:5]2[NH:6][C:7]3[C:8]([CH:13]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:1][CH2:3]1
Reactant: CN(C)C=O
Reactant: C(#CC1CC1)Nc1ccccc1
Agent: [Cu]I
Product: c1ccc2[nH]c(C3CC3)cc2c1

Procedure:
0.54 g of copper(I) iodide is added to a solution of 0.42 g of 2-cyclopropylethynylphenylamine in 20 ml of N,N-dimethylformamide under argon. The reaction mixture is refluxed for 2 hours, and is then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 200 ml of water and 100 ml of dichloromethane, filtered through Celite®, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 50 g column of 20-45 μm silica, elution being carried out with a 50/50 v/v cyclohexane/dichloromethane mixture. 0.18 g of 2-cyclopropylindole is thus obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC.CCOC(C)=O.O>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29][NH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([CH3:15])=[N:4]2)=[CH:9][CH:10]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Cc1nn(-c2ccc(N)cc2)c(C)c1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)c(C)c1Cl
Yield: 31.6 %

Procedure:
The 4-(4-Chloro-3,5-dimethyl-pyrazol-1-yl)-phenylamine (130 mg, 0.58 mmol) and 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (120 mg, 0.43 mmol) is heated in N,N-dimethylformamide (10 mL) at 100° C. for 4 h. EtOAc (100 mL) and H2O (20 mL) is then added. The EtOAc layer is washed with H2O (3×20 mL) and brine (15 mL) and dried over MgSO4. Upon removal of EtOAc, precipitate formed and the precipitate is collected and washed with MeOH and Et2O and dried to provide the title compound (64 mg, 32%). 1H NMR (400 MHz, DMSO) δ 12.56(1H, d, J=12.4 Hz), 11.46 (1H, s), 8.98 (1H, d, J=12.4 Hz), 8.50 (1H, s), 7.43-7.94 (6H, m), 2.30 (3H, s), 2.21 (3H, s); MP: 290-291° C.; Anal. Cacl. for C21H16BrClN4O2: C, 53.47; H, 3.42; N, 11.88. Found: C, 51.49; H, 2.94; N, 11.31.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:12](=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:31])[CH:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>CC#N>[CH2:18]([O:19][C:20](=[O:31])[CH:21]([N:4]1[C:3]([CH3:11])=[C:2]([Cl:1])[C:6]([C:7]([F:9])([F:10])[F:8])=[N:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH3:12]
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Reactant: Cc1n[nH]c(C(F)(F)F)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(c1cccc(OC)c1)n1nc(C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole (610 mg, 3.3 mmol) was taken into dry CH3CN (15 ml), dry potassium carbonate (1.15 g) was added to this and the resulting mixture stirred at room temperature for 1 h under nitrogen. Bromo-(3-methoxy-phenyl)-acetic acid methyl ester (900 mg, 2.8 mmol) in CH3CN (5 ml) was then added to the mixture through a syringe. The reaction was then heated at reflux for 10 h, cooled and then filtered through a celite filter bed. The filtrate was concentrated to obtain (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid ethyl ester that was purified by column chromatography on silica (pet ether/ethyl acetate)
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]1.[I:31][CH2:32]I>C1COCC1>[I:31][CH2:32][C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:17][CH2:18][N:13]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:14]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ICI
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CI)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A solution of diisopropylamine (14.6 mmol, 2.05 mL) in THF (15 mL) was cooled to −78° C. N-butyllithium (1.6 M in hexane) (16 mmol, 10 ml) was added dropwise and the solution was stirred for 30 minutes at 0° C. After cooling to −78° C. a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (14.6 mmol, 3.75 g) in 20 ml THF was added and the solution was stirred for 3 h at −78° C. A solution of diiodomethane (16 mmol, 1.3 mL) in THF (10 mL) was added and the solution was stirred for 2 days at room temperature. The reaction was quenched by the addition of water and extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 10 to 50%) yielding the title compound (C1) (4.5 g, 74%). MS (ES) C14H24INO4 requires: 397. found: 420.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:17][O-:18].[Na+]>CO>[ClH:1].[CH3:17][O:18][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[O-]
Reactant: CC(C)NCC(O)COc1nccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1OCC(O)CNC(C)C
Product: Cl

Procedure:
7.5 g of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine and 3.2 g of sodium methylate in 150 ml of methanol are boiled for 10 hours under reflux. The reaction mixture is then evaporated in a waterpump vacuum. The residue is partitioned between 2 N hydrochloric acid and ether. The acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The crude base is thus obtained, from which 3-methoxy-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine hydrochloride, melting point 152°-153° C., is obtained by reaction with ethereal hydrochloric acid in methanol.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of kojic acid (28 g) in DMF (200 ml) was added potassium carbonate (32 g), and the mixture was stirred at room temperature for 30 minutes. After benzyl chloride (25 g) was added, the mixture was further stirred for 60 minutes. The solvent was evaporated. The residue was then extracted acetate, was acetate, washed with water and dried. After the solvent was evaporated, the residue was crystallized from ethyl acetate to give 5-benzyloxy-2-hydroxymethyl-4-oxo-4H-pyran (34.6
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: CS(=O)(=O)Nc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NS(C)(=O)=O)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 1-iodo-3-methanesulfonamidobenzene (0.19 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as a tan solid (0.18 g, 58%), m.p. 59-62° C.
Reaction SMILES: 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.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([NH2:50])([C:47](=[O:49])[NH2:48])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:51][C:52]1[CH:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55]>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:42][CH2:43][C:44]([C:47](=[O:49])[NH2:48])([NH:50][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:59]([C:61]([F:62])([F:63])[F:64])=[CH:60][C:52]=2[F:51])[CH2:45][CH2:46]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(C(F)(F)F)cc2F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
HATU (939 mg, 2.47 mmol) and DIPEA (525 μL, 3.09 mmol) were added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.06 mmol) and 2-fluoro-4-trifluoromethyl-benzoic acid (514 mg, 2.47 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 19 hours and then quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was diluted with EtOAc, and the organic layer was then washed with H2O and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was triturated with n-hexane and EtOAc and then collected by filtration to give 4-carbamoyl-4-(2-fluoro-4-trifluoromethyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH2:23])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.94 g (3.36 mmol) of 3-(2-trifluoromethoxyphenyl)-benzoic acid in 17 Ml of DMF was added 0.55 g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction was stirred at RT for 4 h. To the reaction mixture was added. 2.6 g (33.6 mmol) of ammonium acetate and the reaction mixture was stirred over night at RT. The reaction mixture was partitioned between ethyl acetate and water and the organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% successively EtOAc: hexanes) to give the title compound. Mass Spectrum (ESI) m/e (M+1): 282.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].N1C=CC=CC=1.[S:14](Cl)(Cl)(=[O:16])=[O:15].Cl.N1C=CC=CC=1>ClCCl.C(=O)=O.CC(C)=O>[S:14]1(=[O:16])(=[O:15])[N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: OC[C@@H]1CCCN1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=S1(=O)OC[C@@H]2CCCN21
Temperature: -40 °C
Yield: 72.7 %

Procedure:
To a solution of (S)-pyrrolidin-2-yl-methanol (25.0 g, 0.247 mol) in dichloromethane (165 ml) was added pyridine (41 ml, 0.508 mol). The solution was stirred while being cooled in dry ice/acetone bath until the temperature of the mixture was below −68° C. Sulfuryl chloride (20 ml, 0.247 mol) was added over 45 minutes while maintaining the reaction temperature below −60° C. The reaction temperature was allowed to warm to −40° C. and held for two hours while pyridine hydrochloride precipitates. The reaction mixture was allowed to warm to ambient temperature and was stirred for an additional 50 minutes. The reaction mixture was poured onto ice water (300 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (150 ml). The combined organic layers are washed with 1N HCl (100 ml), water (100 ml) and saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (32.4 g in the form of a orange resin) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 6:4) to afford 29.3 g (72.7% of theory) of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide as a white solid m.p. 46-50° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9](OC)=[O:10])(=O)[CH3:6].C[O-].[Na+]>CO>[CH3:6][C:5]1[NH:4][C:2](=[S:3])[NH:1][C:9](=[O:10])[C:8]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=S)[nH]c(=O)c1CC(=O)O
Yield: 72.9 %

Procedure:
Thiourea (4.00 g; 52.5 mmol) and dimethyl acetylsuccinate (9.41 g; 50 mmol) were added at room temperature to a solution of sodium methoxide (22.87 ml; 100 mmol) in methanol (18 ml) and the mixture is stirred under reflux for 18 h. After cooling, the precipitate was filtered off and added with stirring to a hydrochloric acid solution (12N) at 0° C. The white precipitate was filtered, washed with water and dried under reduced pressure over phosphorus pentoxide to give 7.3 g (73%) of title compound as a white powder.
Reaction SMILES: C[Si](C)(C)O[NH:4][OH:5].CN1CCOCC1.[CH3:15][O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][C:23](Cl)=[O:24]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:5][NH:4][C:23](=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18][CH:17]([O:16][CH3:15])[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)ONO
Reactant: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(CC=CC=CC(=O)NO)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred solution of trimethylsilyloxy hydroxylamine (132 μL, 1.08 mmol) and N-methylmorpholine (44 μL, 0.40 mmol) in CH2Cl2 (5 mL) at 0° C. was added dropwise a solution of acid chloride 5 (101 mg, 0.36 mmol) via cannula. The reaction mixture was stirred for 1 h, and then was allowed to warm to rt over 1 h. After being stirred for an additional 1 h, the reaction mixture was diluted with CHCl3: MeOH (20 mL: 1 mL), washed with saturated NaHCO3 solution and then water, and the organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash silica gel chromatography (5-10% MeOH in CHCl3) gave the desired hydroxamic acid 6 (30 mg, 30%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 3H), 6.87 (d, J=7.5 Hz, 2H), 5.60-6.20 (m, 3H), 4.10 (m, 1H), 3.79 (s, 3H), 3.16 (s, 3H), 2.61 (m, 1H), 2.43 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 41.6, 55.2, 56.4, 82.7, 113.8, 117.9, 127.8, 130.4, 133.1, 139.3, 141.7, 159.2, 165.5.