Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27][CH2:28][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCOS(C)(=O)=O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCN2C(=O)c3ccccc3C2=O)C1
Temperature: 55 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
Potassium phthalimide (7.79 g, 42.1 mmol) is added to a stirred solution of racemic 3-(3-methanesulfonyloxypropyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 28.0 mmol) in DMF (60 mL). The mixture is allowed to stir at 55° C. for 16 hours. At room temperature, the mixture is concentrated, the oil is diluted in ethyl acetate (50 mL), and the solution is washed with water (50 mL). The organic layer is concentrated and the crude product is chromatographed on silica gel, eluting with ethyl acetate in hexane 0-25%, to give 3-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-piperidine-1-carboxylic acid tert-butyl ester (9.84 g, 94% yield). A stirred solution of this intermediate (9.00 g, 24.2 mmol) in ethanol (400 mL) is treated with hydrazine (4.65 g, 145 mmol). The mixture is heated at 50° C. for 16 hours to form a white suspension. At room temperature the suspension is quickly filtered and the filtrate is concentrated to give the oil containing a small amount of white solid. This mixture is diluted in ethanol (10 mL and diethyl ether (50 mL), filtered, and concentrated to provide the title compound as an oil (5.0 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:21]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19]C)=[O:17].Cl.O1CCOCC1>CO>[NH2:21][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CCOC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of ethyl 6-(2,6-dimethoxyphenyl)-6-(1,1-dimethylethylsulfinamido)hexanoate (5.360 g; 13.41 mmol) in MeOH (100 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (6.7 ml; 26.80 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h50. The obtained yellow solution was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate as a yellow oil. LC-MS (conditions B): tR=0.62 min.; [M+H]+: 282.10 g/mol.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:19]C1C=CC(N2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([I:19])=[CH:7][CH:6]=2
Reactant: O=C1C(=O)N(c2ccc(I)cc2)c2ccccc21
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(I)cc12

Procedure:
Intermediate 26 was prepared as a white powder the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 4-iodo-phenylindoline-2,3-dione. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (1 H, br. s.), 10.52 (1 H, br. s.), 7.33-8.21 (2 H, m), 7.14 (1 H, d, J=8.3 Hz), 4.41 (2 H, q, J=6.9 Hz), 3.34 (1 H, br. s.), 2.51 (1 H, br. s.), 1.33 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 359.9 (M+H), RT=3.48 min (Method A).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[C:19]3[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC=C)=O>C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH3:24]
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2nccc(C)c2c1
Agent: C=COC(=O)Cl
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)c2nccc(C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of 1-benzyl-4-(6-methoxy-4-methylquinolin-8-yl)piperazine (2.0 g, 5.76 mmol), methylene chloride (50 mL) and vinyl chloroformate (0.8 mL, 8.64 mmol) were refluxed for 4 hours. The mixture was concentrated, then dissolved in a 1:1 mixture of dioxane/conc. HCl and stirred at ambient temperature for 18 hours. The reaction mixture was made basic with 2.5 N aqueous NaOH and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.6 g (47%) of the title compound: mp 208-209° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)c(C)c1
Temperature: 25 °C

Procedure:
5.00 g of 4-fluoro-3-methylbenzoic acid was dissolved in 100 mL of ethanol, and 2.59 mL of concentrated sulfuric acid was added thereto, followed by heating under reflux overnight. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was alkalified (pH=8) by addition of an aqueous saturated sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5.86 g of ethyl 4-fluoro-3-methylbenzoate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC#N>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.4 %

Procedure:
Sodium carbonate (1.27 g) was added to a solution of homopiperazine (5.99 g; 5 eq.) and ethyl bromoacetate (2.0 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give [1,4]diazepan-1-yl-acetic acid ethyl ester (1.794 g), which was carried on for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.15 (m, 2H), 3.39 (s, 2H), 2.91 (m, 4H), 2.81 (m, 4H), 1.76 (m, 3H), 1.25 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[S:5][N:4]=1.[ClH:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]2[CH2:28][NH:27][CH2:26]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[ClH:13].[F:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:27]3[CH2:28][CH:25]([CH2:24][S:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)(=[O:23])=[O:22])[CH2:26]3)=[N:4][S:5][C:6]=2[CH:11]=1
Reactant: Fc1ccc2c(CBr)nsc2c1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(CC1CN(Cc2nsc3cc(F)ccc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
3-Bromomethyl-6-fluoro-1,2-benzisothiazole (73 mg, 0.3 mmol) was added to a mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (57 mg, 0.21 mmol) and potassium carbonate (91 mg, 0.66 mmol) in DMF (2 mL) and the resulting mixture stirred at room temperature for 18 h. The mixture was diluted with 0.5M sodium hydroxide solution (20 mL) and extracted with EtOAc (2×10 mL). The organic extracts were washed with saturated brine (10 mL), combined, dried (MgSO4) and concentrated. The residue was purified by preparative thin layer chromatography, eluting with 2.5% MeOH/DCM, to afford an oil which crystallised on standing (35 mg, 41%). The solid was dissolved in EtOAc, the resulting solution heated and treated with 1M HCl in diethyl ether (0.11 mL). The mixture was allowed to cool to give a crystalline solid which was collected under suction to afford the title compound (21 mg). 1H NMR (400 MHz, CD3OD) δ 3.33–3.41 (1H, m), 3.72 (2H, d, J=7.6 Hz), 4.23–4.28 (2H, m), 4.44–4.49 (2H, m), 4.96 (2H, s), 7.35–7.46 (3H, m), 7.87–7.90 (1H, m), 7.99–8.04 (2H, m), 8.10–8.13 (1H, m). (471 MHz, CD3OD)δF −105.2, −112.7. m/z (ES+) 395 (M+H)+.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([N:16]1[CH2:21][CH2:20][C:19]2[N:22]=[C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:18]=2[CH2:17]1)=[O:15]>CN(C=O)C>[CH3:1][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([N:16]1[CH2:21][CH2:20][C:19]2[N:22]=[C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:18]=2[CH2:17]1)=[O:15]
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCc2nc(COc3ccccc3)oc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N2CCc3nc(COc4ccccc4)oc3C2)cc2ccccc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
Methyl iodide (0.01 mL, 0.161 mmol) was added to a suspension of a 60% dispersion of sodium hydride in mineral oils (3.85 mg, 0.096 mmol) and 5-(1H-Indol-2-ylcarbonyl)-2-(phenoxymethyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine (0.03 g, 0.08 mmol) in DMF (2 mL). The mixture was stirred under microwave irradiation at 100° C. for 10 minutes. Then a 60% dispersion of sodium hydride in mineral oils (3.86 mg, 0.096 mmol) and methyl iodide (0.01 mL, 0.161 mmol) were added. The crude product was washed with a saturated solution of sodium hydrogen carbonate and extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by RP HPLC on (C18 XBridge 19×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 100% ACN). The solvents were evaporated to yield 5-[(1-methyl-1H-indol-2-yl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine (17.25 mg, 55% yield) as a white solid. C23H21N3O3 1H NMR (500 MHz, CDCl3) δ ppm 2.82 (br. t, J=5.3 Hz, 2 H), 3.87 (s, 3 H), 4.05 (br. t, J=5.2 Hz, 2 H), 4.87 (s, 2 H), 5.14 (s, 2 H), 6.71 (s, 1 H), 6.98-7.07 (m, 3 H), 7.18 (t, J=7.4 Hz, 1 H), 7.29-7.37 (m, 3 H), 7.39 (d, J=8.4 Hz, 1 H), 7.66 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27](Br)[CH:26]=[C:25](Br)[CH:24]=1.Cl>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:18][O:19][C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:26]=[C:25]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C=Cc1cc(Br)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)cc(-c2ccc(OCc3ccccc3)cc2)c1
Reaction time: 8 h

Procedure:
4.00 g (14.4 mmol) sodium metaborate-octahydrate and 250 mg (0.349 mmol) bis(triphenylphosphine)palladium(II)chloride are stirred for 15 min in 50 ml THF and 50 ml water, and 5.00 g (21.3 mmol) 4-benzyloxybenzene boronic acid, 3.00 g (9.37 mmol) 3,5-dibromo cinnamic acid methyl ester are added and the mixture is stirred overnight at reflux. The mixture is acidified with 2 M hydrochloric acid, the precipitated product is filtered off, suspended in hot ethanol, filtered off and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:41]/[O:42]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S:20][CH2:21][C:22](/[CH:30]=[C:31]2/[C:32](=[O:40])[N:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]/2)=[C:23]3[C:27]([OH:29])=[O:28])=[O:16])[N:13]=1.C([SiH](CC)CC)C>C(OCC)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:41]/[OH:42])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S:20][CH2:21][C:22](/[CH:30]=[C:31]2/[C:32](=[O:40])[N:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]/2)=[C:23]3[C:27]([OH:29])=[O:28])=[O:16])[N:13]=1
Reactant: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(N)n4)[C@H]3SC2)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
16.8 ml (219.4 mmol) Trifluoroacetic acid was cooled to 0° C., and 2.0 g (2.62 mmol) (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-3-[(E)-1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were added portionwise, keeping the temperature below 5° C. After 5 min. at that temperature, 0.96 ml (6.06 mmol) of triethylsilane were added dropwise and the reaction mixture was stirred for 1 h at 0° C. During this time a beige suspension was formed which was poured with stirring into 100 ml of diethyl ether. After 1 h the crystals were collected by filtration and retreated with 50 ml diethyl ether. After 1.5 hours the product was filtered and dried under high vacuum.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:37]=[CH:36][C:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30](OC)=[O:31])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(OC(C)(C)C)=O.O.[OH-].[Na+]>C1COCC1>[CH3:7][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:37]=[CH:36][C:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(OCc3ccc(CO)cc3)cc2)CC1
Temperature: 80 °C

Procedure:
To a slurry of LiAlH4 (4 equivalents) in dry THF, cooled to 0° C. under N2, was slowly added drop-wise a solution of methyl 4-[4-(1-BOC-piperazin-4-yl)phenoxymethyl]benzoate (1 equivalent) in dry THF. Once the addition was complete, the slurry was heated to reflux at 80° C. for 1 hour. The slurry was subsequently cooled to 0° C. and treated with water, 10% aq. NaOH and with water again. The resulting solids were filtered, and the filtrate was diluted with chloroform, washed with brine, dried over MgSO4 and concentrated, providing the crude 4-[4-(4-methylpiperazin-1-yl)phenoxymethyl]benzyl alcohol that was used without purification.
Reaction SMILES: [Br-].C(N(CC)C(=[N+](CC)CC)N(CC)CC)C.O=O.[C:20](=[O:35])([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(O)C=CC=CC=1.[C]=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[C:20](=[O:21])([OH:35])[OH:28].[C:22]1([OH:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:22]1([OH:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CCN(CC)C(N(CC)CC)=[N+](CC)CC
Solvent: Oc1ccccc1
Product: O=C(O)O
Temperature: 65 °C

Procedure:
A phenolic solution (feedstream A) was prepared consisting of 1.7849 g Pd(acac)2 (5.86 mmol), 20.14 g PbO (90.2 mmol; 15.4 equivalents of lead per equivalent of palladium) and 11.4 liters of phenol. A second phenolic solution (feedstream B) was prepared consisting of 1261 g hexaethylguanidinium bromide (4112 mmol) in 3.2 liters of phenol. Each feedstream was maintained at 65° C. and pumped at a rate of 1.5 liters/hour into a stirred, 1-gallon continuous reactor system, maintained at 65° C. and 40 psig. Once the reactor was filled, gas flow of a mixture consisting of 6% oxygen in carbon monoxide was initiated at a rate of 1200 SLPH to achieve a pressure of 1200 psig, after which the reactor temperature was increased to 100° C. These conditions (100° C., 1200 psig, 1200 SLPH of 6% oxygen in carbon monoxide gas mixture, with stirring) were maintained for approximately 7 hours, and weight percent of diphenyl carbonate was determined by high pressure liquid chromatography over the course of the reaction. Only 1.5-2 weight % of diphenol carbonate was produced after 7 hours. A similar batch flow reaction run under the same pressure and oxygen concentration produced 17% diphenyl carbonate in 1.25 hours.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)([CH3:7])[CH3:6].CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:22]([O:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]([O:4][CH3:3])([CH3:7])[CH3:6])[O:9][CH:10]=1)(=[O:24])=[O:23]
Reactant: COC(C)(C)c1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(C)(C)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methoxypropan-2-yl)oxazol-4-yl)methanol (31 mg, 0.18 mmol) in dry CH2Cl2 (1.4 mL) was treated at 0° C. with Et3N (0.03 mL, 0.23 mmol) followed by DMAP (2.2 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 44 mg of crude (2-(2-methoxypropan-2-yl)oxazol-4-yl)methyl methanesulfonate as a yellow oil. LC-MS-conditions 07: tR=0.62 min, [M+H]+=250.00. A solution of this crude material (44 mg) in DMF (0.4 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (203 mg of a 9.6% solution in DMF, 0.17 mmol) in DMF (0.4 mL) pre-treated for 30 min with DIPEA (0.06 mL, 0.34 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (5 mL), followed by EA (5 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.43. LC-MS-conditions 07: tR=0.72 min, [M]+=267.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[NH2:20])([CH3:16])[CH3:15]>>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([NH:20][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: COc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Yield: 12.7 %

Procedure:
Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@:5](NC(OC(C)(C)C)=O)(CCN1CCCC1)[CH2:6][CH2:7][CH2:8][CH2:9]B1OC(C)(C)C(C)(C)O1)C.[ClH:35]>O>[ClH:35].[ClH:35].[C:4]([OH:34])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCOC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: CCCCCC(=O)O
Temperature: 25 °C

Procedure:
A solution of (R)-2-tert-butoxycarbonylamino-2-(2-pyrrolidin-1-yl-ethyl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (98 mg) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-2-[2-pyrrolidin-1-yl)-ethyl]-hexanoic acid dihydrochloride, as a colorless foam (36 mg, 53%); 1H NMR (D2O, 300 MHz) δ 3.47 (m, 2H), 3.24 (m, 1H), 3.07 (m, 1H), 2.88 m, 2H), 2.12 (t, J=8 Hz, 2H), 1.94 (m, 2H), 1.60-1.82 (m, 4H), 1.20 (m, 3H), 1.04 (m, 1H) and 0.59 (t, J=7 Hz, 2H); MS (+CI): m/z for C12H25BN2O4: expected 272.2. found 273.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Br:12][CH2:13][C:14](Cl)=[O:15]>>[Br:12][CH2:13][C:14]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:15]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CBr
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-methylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.[C:30](O)(=[O:34])[CH2:31][CH2:32][CH3:33].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:3][N:4]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:5]1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.05 mmol) was dissolved in dimethyl formamide (0.5 mL); this was added to butyric acid (0.1 mmol), followed by a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate in dimethyl formamide (0.5 mL), and triethylamine (0.5 mmol). The resulting mixture was shaken at ambient temperature for 16 hours. The solvent was removed by distillation under vacuum, and the crude product purified by preparative HPLC to give 3.2 mg of 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-1-yl)butan-1-one. MH+ 537; retention time 9.83 minutes.