Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[C:22]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[C:22]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:3](=[O:5])[C:2]([CH3:1])([S:7]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH3:6])[O:28][N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(CN)on1
Reactant: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CNC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 43.9 %

Procedure:
Activation of 51 mg (0.22 mmol) of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.04 mL) and DMF (1 drop) in DCM (2 mL) at room temperature for 1 h. The reaction is concentrated under reduced pressure. The crude acid chloride is dissolved in DCM (1 mL) and added dropwise to a solution of (3-tert-butyl-1,2-oxazol-5-yl)methanamine (42 mg, 80%, 0.22 mmol) and N,N-diisopropylethylamine (114 μL, 0.66 mmol) in DCM (2 mL). The reaction is concentrated under reduced pressure. The residue is purified twice by column chromatography (silica, eluent: heptanes, 0-50% ethyl acetate then DCM, 20% ethyl acetate), followed by preparative HPLC (neutral method) to give 36 mg of N-(3-tert-butyl-isoxazol-5-ylmethyl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 44%; ES-MS: m/z 373 [M+H]. Compounds in Table 4 amide method D are made according to this procedure.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([SH:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:5]([S:17][CH2:2][CH2:3][OH:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCSCCO
Temperature: 22 °C
Reaction time: 10 h
Yield: 76.5 %

Procedure:
A mixture of 2-bromoethanol (6.08 g, 48.7 mmol), dodecanethiol (9.86 g, 48.7 mmol) and potassium carbonate (11 g) in dry N,N-dimethylformamide (100 ml) was stirred at 22° C. for 10 h. The reaction mixture was then diluted with toluene (400 ml) washed with water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residue was filtered through a silica gel pad (toluene -ethyl acetate 95:5) and distilled under vacuum to give 9.18 g (77%) of 2-(dodecylthio)ethanol as a clear oil which solidified on standing: b.p. 100-105° C./0,01 torr (bulb to bulb distillation, air bath temperature); m.p. 31-32° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=[O:13])[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc2ccncc12
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 2-(isoquinolin-8-yl)acetate (1.8 g) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed to give a residue which was adjusted to pH 3-4 with aqueous ammonia. The precipitate was filtered off and washed with water. The final product was purified (silica gel coulumn chromatography) to afford 2-(isoquinolin-8-yl)acetic acid as a solid (1.2 g, 87%). LC-MS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (DMSO-d6, 400MHz): δ13.0 (brs, 1H), 9.65(s, 1H), 8.61(d, 1H, J=4.8Hz), 8.16 (d, 1H, J=4.8Hz), 8.05 (d, 1H, J=6.8Hz), 7.92 (t, 1H), 7.72 (d, 1H, J=6.8Hz), 4.29 (s, 2H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>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.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(-c2cccc3nc(N)nn23)cc1
Temperature: 150 °C

Procedure:
5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2 g, 9.4 mmol), 4-methoxybenzeneboronic acid (1.71 g, 11.26 mmol), potassium phosphate (3.98 g, 18.77 mmol) and tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) were added to a microwave tube containing a stirrer bar. Dimethylacetamide (12 mL) and water (4 mL) were then added and the reaction was heated to 150° C. for 10 min. The reaction was filtered through silica and washed through with methanol and concentrated under reduced pressure. The crude was suspended in diethyl ether and the solid collected and was used without further purification. Yield: 1.70 g, 71%; LCMS method: 1, RT: 3.43 min, MI: 241 [M+1]. NMR 1H (DMSO): 3.82 (s, 3H), 6.16 (brs, 2H), 6.96 (d, 1H), 7.06 (d, 2H), 7.29 (d, 1H), 7.46 (t, 1H), 7.92 (d, 2H).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH2:27])[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1cc(F)cc(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (44 mg), 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 24 (66 mg), DMAP (36 mg), EDC.HCl (120 mg), and Et3N (120 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification of the crude product by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 78 mg of the title compound as a solid.
Reaction SMILES: [Cl-].[CH2:2]([O:4][P:5](=O)([OH:9])[O:6][CH2:7][CH3:8])[CH3:3].[OH-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15]>O>[CH2:13]([O:16][P:5](=[O:9])([O:6][CH2:7][CH3:8])[O:4][CH2:2][CH3:3])[C:14]#[CH:15]
Reactant: CCOP(=O)(O)OCC
Reactant: C#CCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOP(=O)(OCC)OCC
Reaction time: 0.25 h
Yield: 70 %

Procedure:
1 mol of phosphoric acid diethyl ester chloride and 1.07 mols of 50% strength sodium hydroxide solution were added dropwise to 3.33 mols of propargyl alcohol (233% excess) at 15°-20° C. The mixture was stirred for 15 minutes, water was added to dissolve the salt and the mixture was extracted with 800 ml of chloroform. On distillation, 70% of phosphoric acid diethyl propargyl ester was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[S:9])[NH2:8].C([CH:12](Br)[C:13](=O)[C:14]([O-:16])=[O:15])C.[CH2:19](O)[CH3:20]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:19][CH3:20])=[O:15])[N:8]=1
Reactant: CCO
Reactant: COCCOCC(N)=S
Reactant: CCC(Br)C(=O)C(=O)[O-]
Product: CCOC(=O)c1csc(COCCOC)n1
Yield: 81 %

Procedure:
To a solution of 2-(2-methoxyethoxyl)ethanethioamide (Example 6B, 3.26 g, 21.85 mmol) in ethanol (60 mL) was added dropwise ethylbromopyruvate (3.7 mL, 29.5 mmol) and the mixture was refluxed for 18 hours. The reaction was then concentrated under vacuum, diluted with ethyl acetate, washed with water (1×), brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (3.5×10 cm, 30% ethyl acetate/CH2Cl2) to give the title material (4.36 g, 81%) as an oil. LC (Method F): 1.791 min. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.16 (s, 1H), 4.87 (s, 2H), 4.41 (q, J=7.10 Hz, 2H), 3.74-3.77 (m, 2H), 3.57-3.60 (m, 2H), 3.39 (s, 3H), 1.39 (t, J=7.10 Hz, 3H).
Reaction SMILES: ICCCC(OC)=O.N1CCCC1.[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1.[ClH:26]>C1C=CC=CC=1>[ClH:26].[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)CCCN1CCCC1
Agent: COC(=O)CCCI
Agent: Cl
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: O=C(O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g. (0.13 mole) of Methyl γ-iodobutyrate (Blicke et al., J. Am. Chem. Soc. 63, 2488 (1941)) was combined with 36 g. of pyrrolidine in 300 ml. of benzene, heated at 60°C. for 0.5 hour and stirred at room temperature for 16 hours. A dark orange layer formed. The benzene solution was decanted, concentrated and distilled (b.p. 100°C. at 15 mm Hg) to give 10 g. of colorless liquid. The infrared and nuclear magnetic resonance spectra indicated the product to be methyl γ-pyrrolidino-butyrate. This material was dissolved in 100 ml. of 18% hydrochloric acid and heated at reflux for 28 hours. The solution was concentrated under reduced pressure to give a semi-solid which was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 8.3 g. (33%) of the desired acid hydrochloride as colorless crystals, m.p. 126°-127°C. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.[N:15](OS(=O)(=O)O)=O.[CH3:22][NH:23][CH3:24].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:22][N:23]([CH3:24])[N:15]=[N:11][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: Cc1csc2c(N)cc([N+](=O)[O-])cc12
Reactant: O=NOS(=O)(=O)O
Reactant: CNC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc2c(N=NN(C)C)cc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.05 mole of 3-methyl-5-nitro-7-aminobenzothiophene is dissolved in 100 ml of concentrated sulphuric acid, while cooling with ice, and is diazotised at 10° C. by dropwise addition of 0.05 mole of nitrosylsulphuric acid. After 15 minutes, the mixture is poured onto 700 g of ice, 0.06 mole of dimethylamine (40% strength aqueous dimethylamine solution) is added and the mixture is rendered alkaline with 20% strength sodium hydroxide solution. The triazene is then extracted by shaking with methylene chloride and the organic solution is washed with water and dried over Na2SO4. The crystalline residue obtained after filtration and evaporation of the solvent is taken up in a little methylene chloride and chromatographed on Al2O3 (eluting agent: methylene chloride/cyclohexane (1:1)). The product obtained after evaporation of the eluate is recrystallised from isopropanol.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Br:17][C:18]1[C:22]([Br:23])=[C:21](Br)[N:20]([CH3:25])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:23][C:22]1[C:18]([Br:17])=[N:19][N:20]([CH3:25])[C:21]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cn1nc(Br)c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(Br)c(Br)nn3C)c(C)nc12
Temperature: 130 °C
Yield: 32 %

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (300 mg, 1.4 mmol), 3,4,5-tribromo-1-methyl-1H-pyrazole (700 mg, 2.1 mmol) and cesium carbonate (900 mg, 2.8 mmol) are stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 (14 mg) is added and the mixture heated to 130° C. overnight. The mixture is added to water and extracted twice with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the title product (204 mg, 32% yield). ES-MS (m/z): calc'd for C17H21Br2N5: 455.2. found 455.9 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.51 (s, 3H), 2.45 (s, 3H), 1.84 (m, 4H), 0.88 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH2:20]([O:22][CH:23]([O:31][CH2:32][CH3:33])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:32]([O:31][CH:23]([O:22][CH2:20][CH3:21])[C:24]1[S:28][C:27]([CH2:29][N:8]2[S:7](=[O:13])(=[O:12])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:10](=[O:11])[CH2:9]2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: CCOC(OCC)c1ccc(CO)s1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.9 g, 48.5 mmol), (5-diethoxymethyl-thiophen-2-yl)-methanol (10.5 g, 48.5 mmol) and triphenylphosphine (19.1 g, 72.2 mmol) are dissolved in dry THF (300 mL) and the mixture is cooled to 0° C. Diethyl azodicarboxylate (12. g, 72.7 mmol) is added dropwise over 3 min and the mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is taken up in Et2O (100 mL). The solution is cooled to 0° C. and the precipitate is filtered and discarded. The filtrate is concentrated to dryness and the residue is chromatographed on silica gel using 0→100% EtOAc in hexane as the eluent to afford 5-(5-diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as an orange oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].[F:15][C:16]([F:20])=[C:17]([F:19])[F:18].[OH-].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:17]([F:19])([F:18])[CH:16]([F:20])[F:15])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4]
Reactant: FC(F)=C(F)F
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(F)(F)C(F)F)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
A solution of 72 g of N-methyl-2-nitrobenzenesulfonamide, 35 g of tetrafluoroethylene and 4 g of powdered potassium hydroxide in 150 ml of dimethylformamide was heated at 85° for 3 hours in a pressure vessel. The reaction mixture was cooled to 25° and poured into 800 ml of water. A heavy oil was separated and the aqueous layer extracted with 150 ml of 1-chlorobutane. The heavy oil, the 1-chlorobutane extract and an additional 300 ml of 1-chlorobutane were combined and washed three times with water. The organic solution was dried over magnesium sulfate and concentrated in-vacuo to yield 85.1 g of N-methyl-N-(1,1,2,2-tetrafluoroethyl)-2-nitrobenzenesulfonamide as a viscous orange oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:21]1[N:26]=[C:25]([OH:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>C(O)C>[N+:28]([C:24]1[C:25](=[O:27])[NH:26][C:21]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:22][CH:23]=1)([O-:30])=[O:29]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Solvent: CCO
Product: O=c1[nH]c(NCCCOc2cccc(CN3CCCCC3)c2)ncc1[N+](=O)[O-]

Procedure:
A solution of 3-(3-piperidinomethylphenoxy)propylamine (8.20 g; 33.0 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (6.20 g; 32.5 mmoles) [prepared according to the procedure described in U.S. Pat. No. 4,241,056] in 35 ml of ethanol was stirred at reflux temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was placed on 250 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions were combined and evaporated, and the product was recrystallized from tetrahydrofuran to give the title compound, mp 161°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH2:33]C)=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: OB(O)c1cc2cc(Cl)ccc2o1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of 5-chlorobenzofuran-2-ylboronic acid (281 mg, 1.43 mmol) in dioxane (6 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 3 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (152 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([N:30]=[C:31]=[O:32])=[O:29])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31]([NH:30][C:28](=[O:29])[O:27][CH2:25][CH3:26])=[O:32])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N=C=O
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (540 mg, 1.57 mmol) in 30 ml of freshly distilled tetrahydrofuran at 0° C. is added dropwise 194 μl (1.88 mmol) of ethoxycarbonyl isocyanate. The reaction mixture is stirred for 10 minutes at 0° C. and concentrated in vacuo. The residue is purified by column chromatography on silica using an ethyl acetate:methylene chloride gradient (15:85 to 1:1). Recrystallization from methylene chloride:hexane gives pure [[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]carbamic acid, ethyl ester (68%); mp 147.5°-148° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(C)(=O)=O)C1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Methane sulfonyl chloride (204 mg, 1.78 mmol) was added to a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (300 mg, 1.62 mmol) and Et3N (197 mg, 1.94 mmol) in DCM (6 mL) at 0-5° C.; stirring was continued at 20-35° C. for 2 h. The reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford 250 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O-:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.F[C:48]1[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=1[F:58]>C(OCC)(=O)C>[Cl:21][C:20]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17](=[O:22])[N:18]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=2[F:58])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([O-])ncc2Cl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3F)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A two liter round bottom flask was charged with tetrabutylammonium 4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g, 158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene (30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for 12 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (500 mL) and distilled water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the residue was added 500 mL of 20% ethyl acetate in diethyl ether and the mixture was stirred for 12 hours at room temperature. The slurry was then cooled to 4° C. and stirring was continued for additional 1 hour. The solid was collected by filtration and dried under vacuum for 4 hours at 45° C. to yield t-butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (58 g, 70% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.85-7.89 (m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m, 1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m, 4H), 1.48 (s, 9H); MS m/e 501.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]3[CH2:20][CH:15]2[C:16](=[O:21])[O:17]3)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:22][CH2:23][N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].[OH2:31]>>[CH:25]([N:24]([CH:28]([CH3:30])[CH3:29])[CH2:23][CH3:22])([CH3:27])[CH3:26].[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]([OH:17])[CH2:20][CH:15]2[C:16]([OH:21])=[O:31])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Reactant: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Temperature: 40 °C

Procedure:
To a solution of 3 (800 mg, 2.73 mmol) in water (15 mL) in a 20 mL microwave reaction vessel was added DIPEA (1.2 mL, 6.8 mmol) and a stir bar. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave oven cavity. After 1 min of pre-stirring, the reaction was irradiated for 40 min to a set temperature of 100° C. After cooling to 40° C., the transparent solution was concentrated in vacuo, and the residual brown oil co-evaporated 3 times with MeCN to remove any residual water. The crude product 4, in the form of a DIPEA salt, was immediately taken forward to the next step. LC/MS (Method A): tR=1.29 min, >95%, m/z (ESI+)=312 (MH+).