Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.C[O:7][P:8]([CH2:12][P:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O:15]CC)=[O:14])(=[O:11])[O:9]C.C(N(CCCC)CCCC)CCC.[Na+:41].[I-].CC(C)=O>O.CO>[Na+:41].[Na+:41].[Na+:41].[CH2:18]([P:13]([CH2:12][P:8](=[O:7])([O-:11])[O-:9])([OH:15])=[O:14])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Agent: C[Si](C)(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCP(=O)(O)CP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Bromotrimethylsilane (2 mL, 15.15 mmol) was added dropwise to ((n-decyl)ethoxyphosphinyl)methylphosphonic acid dimethyl ester (0.6 g, 1.68 mmol) in a 30 vial. A large exotherm was noted which resulted in a clear solution that was stirred for 14-16 hours at ambient temperature. Excess bromotrimethylsilane was then removed by passing a steady stream of nitrogen over the solution for 2 hours. The solution was then placed under high vacuum for 3 hours to remove any residual bromotrimethylsilane. A tacky solid was obtained. Tributylamine (0.936 g, 5.05 mmol), methanol (10 mL) and deionized water (0.5 mL) was then added to the vial and a clear solution was obtained. This solution was then added dropwise to a 0.5 M solution of NaI in acetone (10.1 mL, 5.05 mmol). A white solid precipitated immediately which was then washed with 20 mL of acetone. The solid was filtered under vacuum and then washed several times with acetone. The white solid recovered was placed under vacuum to dry for a period of 12-16 hours to give the desired product (0.481 g, 78% yield). 1H NMR (400 MHz D2O): δ 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (m, 2H), 1.0 (m, 14H), 0.5 (t, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC.C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][CH2:31]1)=[O:9]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCCCCBr
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCCCCBr)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25 g (0.128 mol) of 6-bromohexanoic acid and 12.7 g (0.125 mol) of triethylamine in 150 ml of ether was cooled (0°) and treated dropwise with 28.5 g (0.263 mol) of ethyl chloroformate. The reaction mixture was stirred for 1 hr and then filtered. To the cooled (0°) filtrate was added a solution of 21 g (0.129 mol) of N-phenylpiperazine in 50 ml of ether. The reaction mixture was then allowed to warm to room temperature for 30 min and was then washed once with 1 N NaOH solution and once with water. The dried (Na2SO4) organic layers were concentrated in vacuo to give a yellow oil which was dissolved in benzene and chromatographed on silica gel (500 g). The column was eluted with benzene-ethyl acetate mixtures, the product appearing in the benzene-ethyl acetate (8.5:1.5) mixtures. Evaporation of those combined mixtures gave 1-(6-bromohexanoyl)-4-phenylpiperazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:8][C:7]([CH2:13][C:14]#[CH:15])([C:9]([F:12])([F:11])[F:10])[O:6][CH:5]([OH:16])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.CC(=CC)C.C1C[O:30]CC1.Cl([O-])=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C.O>[OH:6][C:7]([C:9]([F:12])([F:11])[F:10])([CH2:13][C:14]#[CH:15])[CH2:8][C:2]([C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([OH:30])=[O:16])([CH3:21])[CH3:1]
Reactant: C#CCC1(C(F)(F)F)CC(C)(C)c2ccccc2C(O)O1
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C#CCC(O)(CC(C)(C)c1ccccc1C(=O)O)C(F)(F)F
Reaction time: 6 h
Yield: 87.3 %

Procedure:
To a solution of 5,5-dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-ol (2.50 g, 8.38 mmol) in tert-BuOH (75 mL) was added a 2.0 M solution of 2-methyl-2-butene in THF (58 mL, 117 mmol). To this solution was added a solution of sodium chlorite (4.74 g, 42.0 mmol) and sodium hydrogen phosphate (11.57 g, 84.0 mmol) in water (37.5 mL). The reaction mixture was stirred for 6 hours then the volatiles were removed in vacuo. The aqueous mixture was then acidified to pH=1 with aqueous 1M HCl, extracted with 300 mL of ethyl acetate, dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography (120 g SiO2, hexanes to 1:1 hexanes:EtOAc) to give 2-(3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid (2.30 g, 87%). MS (ES+) m/z 315 [M+H]+.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]([N:37]2[CH:41]=[N:40][N:39]=[CH:38]2)[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C.O.CN(C)C(=O)C>[S:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]([N:37]2[CH:41]=[N:40][N:39]=[CH:38]2)[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:21]2[CH:26]=[CH:25][C:24]([O:27][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: N#Cc1ccc(N(C(c2ccc(O)cc2)c2ccc(O)cc2)n2cnnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(C(c2ccc(OS(N)(=O)=O)cc2)c2ccc(OS(N)(=O)=O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (5 mL, 0.7 M, 3.5 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 1 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-{[Bis-(4-hydroxy-phenyl)-methyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB2070, 250 mg, 0.65 mmol) was added to the colourless solution and the mixture was stirred for 18 h at, room temperature. Ethyl acetate (50 mL) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate and precipitated by addition of hexane. The white powder was filtered off and dried under high vacuum. Yield: 299 mg (85%).
Reaction SMILES: [NH:1]1[C:9]2C(=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O>>[Br:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:3][CH2:2][NH:1][CH3:9])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Product: CNCCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s, 1 H), 8.26 (d, J=1.2 Hz, 2 H), 7.47-7.37 (m, 4 H), 4.31 (t, J=5.2 Hz, 2 H), 2.88 (t, J=5.2 Hz, 2 H), 2.39 (s, 3 H); MS (ESI) m/z 486.0 (M−H)−; MS (ESI) m/z 487.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1.I[CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 36 %

Procedure:
A mixture of [3-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamino]methyl]phenyl]acetic acid methyl ester (68 mg), 1-iodobutane (37 μL), potassium carbonate (45 mg) and dimethylformamide (1 mL) was stirred at 80° C. for 3.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The residue was purified by column chromatograph on silica gel to give the title compound (28 mg). Yield: 36%.
Reaction SMILES: C(=O)C1C=CC=CC=1.C(N)(C)(C)C.C(=NC(C)(C)C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+].C(=O)=O.[C:40]([N:44]1[CH:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:45]1)([CH3:43])([CH3:42])[CH3:41]>C1(C)C=CC=CC=1.O.CC(C)=O>[C:40]([N+:44]([O-:45])=[CH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)N1OC1c1ccccc1
Agent: CC(C)(C)N=Cc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: CC(C)(C)[N+]([O-])=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a dry 3 liter, 3-necked, round bottom flask equipped with a mechanical paddle stirrer, a nitrogen gas flow, and a condenser was added 87 gm (83.5 ml; 0.82 moles) of benzaldehyde and 63 gm (90.5 ml; 0.86 moles) of t-butylamine. The mixture was stirred for about 4 hours at room temperature to allow complete formation of N-benzylidene-t-butylamine. After removal of the nitrogen gas flow and the condenser, the reaction flask was evacuated under an aspirator (about 24″ Hg vacuum) for about 15 minutes. The aspirator was detached and 288 gm (3.428 moles) of sodium bicarbonate followed by 500 ml of water and 500 ml of acetone were added to the 3-liter flask. The condenser was reattached to the flask and carefully about 600 gm (0.98 moles) of Oxone® was added portion-wise through a powder-addition funnel to the stirring reaction over a period of about 10 minutes. The reaction began to slowly foam from the evolution of carbon dioxide and turn to a bluish tinge as the temperature rose to about 35° C. The reaction was stirred for one hour after the Oxone® addition, and a GC analysis revealed a trace amount of starting imine (3.72 minutes) and a large peak representing 2-t-butyl-3-phenyl oxaziridine (4.45 minutes). The reaction was poured into a beaker containing a 2-phase solution of 3000 ml water and 300 ml toluene. Insoluble salts were filtered out and the aqueous layer separated in a separatory funnel. The upper toluene layer was placed in a 1-liter single-neck, round bottom flask and concentrated over a 30-minute period on a rotary evaporator at 50° C. under vacuum (about 24″ Hg) to remove traces of acetone and water. Several silicon carbide boiling chips were added to the concentrated oxaziridine and the oxaziridine/toluene solution was refluxed at 115° C. -125° C. for 2-3 hours to form the desired N-t-butylphenylnitrone product. The excess toluene was removed under vacuum and the resulting clear brown liquid N-t-butylphenylnitrone was poured into a crystallizing dish and placed in a fume hood. Crystallization was almost immediate, affording 113.1 gm of crude crystalline N-t-butylphenylnitrone (78% theoretical yield).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[N:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:17]([Cl:20])[C:18]#[CH:19]>O>[Cl:20][CH2:17][C:18]1[O:16][N:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#CCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CCl)on1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
21.2 g (210 mmol) of triethylamine were added dropwise to a stirred mixture of 30 g (198 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate and 150 ml of propargyl chloride cooled to 10-15° C. and, after stirring at room temperature for 1 h, water was added, the mixture was extracted with ether, and the organic phase was dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was distilled under 0.5 torr, the product distilling over at 116-122° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cnc(NC(=O)c3cccc(OC)c3)c(Cc3ccccc3)n2)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 82.5 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (800 mg, 2.75 mmol) in pyridine (10 mL) were successively added 4-(dimethylamino)pyridine (33.6 mg, 275 μmol) and m-anisoyl chloride (18) (773 μL, 5.50 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 22 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 100 g, dichloromethane/ethyl acetate=9/1). The residue was recrystallized from ethyl acetate to give Compound 11y (967 mg, 2.27 mmol, 82.5%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 611), 4.19 (s, 2H), 7.05-7.12 (AA′BB′, 2H), 7.14-7.28 (m, 6H), 7.42-7.49 (m, 2H), 7.53 (d, 1H, J=7.5 Hz), 8.06-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.77 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 41.5, 55.3, 55.4, 112.5, 114.3 (2C), 118.6, 119.3, 126.7 (2C), 128.1, 128.55, 128.61 (2C), 128.5 (2C), 129.6, 135.0, 136.8, 137.7, 143.3, 149.2, 149.9, 159.8, 160.9, 165.7; IR (KBr, cm−1) 700, 746, 833, 1022, 1040, 1117, 1179, 1254, 1300, 1325, 1373, 1416, 1441, 1501, 1607, 1655, 2936, 3265; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.55; H, 5.36; N, 9.86.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24].O.N>C(O)CCC>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N:12]1[CH2:13][CH2:14][CH2:15][N:16]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[C:2]1=[NH:1]
Reactant: Cc1cccc(C)c1NCCCNc1c(C)cccc1C
Reactant: N#CBr
Agent: N
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(C)c1N1CCCN(c2c(C)cccc2C)C1=N
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A solution of 0.75 g (7.1 mmoles) of cyanogen bromide in 10 ml of n-butanol is added dropwise, within about 0.5 hours, to a stirred solution of 2.0 g (7.1 mmole) of 1,3-bis(2',6'-dimethylphenyl-amino)-propane in 20 ml of n-butanol at 110° to 115° C. After the addition the mixture is stirred for further 2 hours at the same temperature. Thereafter the mixture is cooled, shaken five times with 10 ml of water each, the aqueous solutions are combined, and the pH of the mixture is adjusted to 8.0 to 8.5 with concentrated aqueous ammonia. The separated unreacted starting substance (0.4 g, m.p.: 68°-71° C.) is filtered off, the aqueous filtrate is rendered alkaline with 2 n aqueous sodium hydroxide solution, and the aqueous-alkaline phase is extracted thrice with 30 ml of chloroform each. The organic phases are combined, washed with water, dried over potassium carbonate, and the solvent is distilled off. 0.8 g (36.7%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-hexahydro-pyrimidine are obtained; m.p.: 181°-183° C. (after recrystallization from aqueous isopropenol).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in 130 mL CH2Cl2 was added methanesulfonyl chloride (10 mL, 129 mmol) in 20 mL CH2Cl2 dropwise at 0° C. After addition, the reaction was stirred for 2.5 h at rt, then quenched with sat. NaHCO3 (aq.), and extracted with CH2Cl2. The extract was dried and concentrated to give the desired product (22.7 g, 100% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>O1CCOCC1.O>[C:7]1([CH:2]([NH:1][S:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])(=[O:26])=[O:25])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.=218-219° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[OH:20]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=[N+]([O-])c1cccnc1CBr
Product: Cc1ccc(OCc2ncccc2[N+](=O)[O-])c(C)c1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-dimethylphenol, the titled compound was obtained as yellow solid. (Yield: 78%)
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:68])[C@H:53]([OH:67])[C@H:54]([NH2:66])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:64])[F:63])[CH3:50]>C(Cl)Cl>[CH2:49]([O:51][C:52]([C@H:53]([OH:67])[C@H:54]([NH:66][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:63])[F:64])=[O:68])[CH3:50]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1C(F)(F)F
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1C(F)(F)F)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 34.6 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol, 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-2-hydroxy-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl and the product was extracted with DCM, dried, evaporated, and purified by preparative HPLC to yield the title compound (40 mg, 100% purity). MS m/z [M+H]+ calc'd for C24H26F3NO6, 482.17. found 482.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][OH:32])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[N:28]=[N:27]2)=[O:14])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CO)nn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CO)nn1)c1csc(N)n1)C(=O)O
Yield: 28.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.145 mmol), DCM (4 mL) and TFA (1 mL, 13 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×100 mm, 5 μm, C18 column; acetonitrile-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (22 mg, 29%) as a white solid. LCMS: m/z=530.9 (M−1); 1H NMR (400 MHz, DMSO-d6): δ 12.50 (br s, 1H), 9.36 (d, J=9.2 Hz, 1H), 7.97 (s, 1H), 7.50 (br s, 2H), 6.70 (s, 1H), 5.28 (dd, J=8.8, 5.2, Hz, 1H), 4.86 (dd, J=14.4, 4.0 Hz, 1H), 4.69 (dd, J=14.8, 7.2 Hz, 1H), 4.48 (s, 2H), 4.27-4.21 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.N1C=CC(NC(=O)C(C)=C)=CC=1>>[CH3:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc2cnccc2nc1O
Agent: C=C(C)C(=O)Nc1ccncc1
Agent: Cc1cc2cnccc2[nH]c1=O
Product: CC1Cc2cnccc2NC1=O

Procedure:
2-Hydroxy-3-methyl-1,6-naphthyridine, the tautomeric form of 3-methyl-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Ogata et al. [Chem Pharm Bull. 20, 2264 (1972)] in two steps by first photocylization of N-(4-pyridinyl)methacrylamide to produce 1,2,3,4-tetrahydro-3-methyl-2-oxo-1,6-naphthyridine and then dehydrogenating said tetrahydro compound by heating it in acetic acid.