Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)[Cl:55]>CO>[ClH:55].[ClH:55].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15](=[O:16])[CH:14]=[N:13][C:12]5[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]4=5)[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Product: Cl
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (150 mg, 0.494 mmoles) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (82 mg, 0.496 mmoles) in anhydrous DCM (10 ml) and anhydrous MeOH (1 ml) was stirred at rt for 5 minutes. Sodium triacetoxyborohydride (316 mg, 1.49 mmoles) was added and the mixture was stirred, under argon, for 18 h, treated with sat. aq. NaHCO3 solution (5 ml) and 10:1 DCM:MeOH (10 ml). The layers were separated and the aqueous layer was washed with 10:1 DCM:MeOH (5 ml). The organic extracts were combined, washed with brine, passed through a hydrophobic frit and evaporated to an orange gum. Purification on a 20 g silica column eluted with a 0% to 30% DCM/MeOH gradient elution gave the free base of the title compound as a colourless gum (128 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=Cc1c(F)cccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-bromo-6-fluorobenzaldehyde (3.3 g, 16 mmol) and (trimethylsilyl)acetylene (4.5 mL, 32 mmol) in anhydrous N,N-dimethylformamide (60 mL) was treated with triethylamine (3.5 mL, 25 mmol), copper(I) iodide (0.3 g, 1.6 mmol), and Pd(PPh3)2Cl2 (0.6 g, 0.80 mmol) under argon atmosphere. The mixture was stirred at RT for 2.5 h. The mixture was poured into water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×75 mL), brine (100 mL) then dried over anhydrous sodium sulfate and evaporated to yield the crude product which was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 2-fluoro-6-(2-(trimethylsilyl)ethynyl)benzaldehyde 2-bromo-6-fluorobenzaldehyde as a brown oil. MS (ESI, pos. ion) m/z: 221 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[CH:4][CH:3]=1.[OH-:13].[Na+].C(O)C[O:17]CCO.Cl>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]([OH:17])=[O:13])=[CH:4][CH:3]=1
Reactant: OCCOCCO
Reactant: [OH-]
Reactant: Cc1ccc(C(C)(C)C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(C)(C)C(=O)O)cc1

Procedure:
A solution of 2-(4-methylphenyl)-2-methylpropionitrile (53.61 g), sodium hydroxide (40.4 g), diethylene glycol (160.8 ml) and water (60.6 ml) was refluxed for 18 hr. The reaction mixture was poured into water (3000 ml) and conc. hydrochloric acid (90 ml) was added. The generated crystals were collected by filtration to give the title compound (60.0 g) as pale-brown crystals, m.p.=78-81° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][N:26]=[CH:25]1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:31][CH2:30][CH2:29][C:28]4[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: Cn1cncc1CCN
Product: Cn1cncc1CCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Yield: 31.8 %

Procedure:
The product was synthesized as described in Example 109 using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (142.5 mg, 0.45 mmol) and 3-methylhistamine 100 mg, 0.5 mmol). The product was purified by semipreparative HPLC (20-80% acetonitrile gradient over 30 minutes at 20 mL/min) to yield the title compound (52 mg, 32% yield). 1H NMR (DMSO-d6) δ 8.85 (s, 1H), 8.5 (s, 1H), 8.05 (m, 2H), 7.9 (d, 1H), 7.7 (d, 1H), 7.4 (m, 3H), 3.9 (s, 3H), 3.6 (m, 2H), 3.0 (m, 2H). ES-MS m/z 364 [M+1]+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][S:7][C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])[CH2:4][CH2:3][CH2:2]1.[OH:37]OS([O-])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O.[OH2:56]>CO>[N:1]1([CH2:5][CH2:6][S:7]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:37])=[O:56])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN2CCC2)cc(C(F)(F)F)c1
Reactant: O
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCN2CCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cold solution of 3-(2-(azetidin-1-yl)ethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 96.2 μmol, example 259) in MeOH (2 mL) and water (0.5 mL) was added Oxone® (148 mg, 241 μmol) and the white suspension was stirred at room temperature for 3 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The crude product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 98:2). Colorless solid (0.017 g; 32%). MS (ESI): m/z=552.16 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1O
Yield: 112.3 %

Procedure:
Using the procedure of J. Org. Chem. 59(15) 1994, 4301, 4-benzenesulfonyl-phenol (5.348 g, 22.8 mmol) was added to 3.07 mL of conc. H2SO4 with stirring. Concentrated HNO3 (1.28 g) was added dropwise via addition funnel, and the reaction mixture was stirred under nitrogen for 4 hours. The reaction mixture was then poured over ice, and the resulting suspension was extracted four times with 50 mL of methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield an oil which slowly solidified. The solid was washed with 1:1 EtOAc:hexanes to yield 4-benzenesulfonyl-2-nitro-phenol (6.37 g, quantitative) as a crude solid. MS: 235 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][OH:25])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[H-].[Na+].CN(C=O)C.Br[CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][O:25][CH2:35][CH2:36][CH3:37])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(-n3cnc4cc(CO)sc4c3=O)cc2)C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOCc1cc2ncn(-c3ccc(N4CCC(N(C)C)C4)cc3)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one (50.0 mg), sodium hydride (5.24 mg) and DMF (1 mL) was stirred at 0° C. for 15 min. Then 1-bromopropane (22.0 mg) was added, the solution was warmed to room temperature and stirred for 2 h. Water and ethyl acetate were added and the aqueous phase was extracted with ethyl acetate several times. The combined organic phase was dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 412.55 (C22H28N4O2S) was obtained in this way; MS (ESI): 413 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[OH-].[NH4+:21]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:21])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: Clc1ncnc2c1c(Br)cn2CCN1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1c(Br)cn2CCN1CCOCC1
Temperature: 100 °C
Yield: 68 %

Procedure:
To 5-bromo-4-chloro-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (240 mg, 0.694 mmol) in a 5 mL sealable vial was added ammonium hydroxide (1.5 mL, 38.5 mmol). The reaction vial was capped and heated at 100° C. overnight. The reaction was cooled and solid formed. The solid was isolated by filtration and the solid was washed with NH4OH. The solid was air dried to isolated the desired product 5-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg, 68.0% yield) as an off white solid. LC-MS (ES) m/z=326.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 8.10 (s, 1H), 7.47 (s, 1H), 6.69 (br. s., 2H), 4.22 (t, J=6.44 Hz, 2H), 3.52 (t, J=4.42 Hz, 4H), 2.65 (t, J=6.44 Hz, 2H), 2.41 (d, J=4.04 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[CH:6]=[C:7]([C@@:11]3([CH3:16])[CH2:15][CH2:14][CH2:13][NH:12]3)[NH:8][C:9]=2[CH:10]=1.CC#N.[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[CH:6]=[C:7]([C@@:11]3([CH3:16])[CH2:15][CH2:14][CH2:13][N:12]3[CH2:27][C:26]([O:25][CH3:24])=[O:29])[NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(F)cc2[nH]c([C@@]3(C)CCCN3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.9 %

Procedure:
To a stirred mixture of (R)-methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (1.0, 1.27 mol), CH3CN (50 ml) and methylbromoacetate (0.58 g, 3.82 mmol) was added DIPEA (0.82 g, 6.35 mmol). The reaction mixture was stirred at room temperature for about 20 hours. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4 and concentrated to give 0.85 g of (R)-methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate. 1H NMR (CD3OD-d4) δ 7.47 (dd, 1H, J=2.4, 12.0 Hz), 7.27 (dd, 1H, J=2.4, 9.0 Hz), 6.89 (s, 1H), 3.95 (s, 3H), 3.66-3.68 (m, 1H), 3.64 (s, 3H), 3.16-3.17 (m, 2H), 2.72-2.75 (m, 1H), 1.88-2.02 (m, 4H), and 1.44 (s, 3H). MS (ESI) m/e [M+1]+ 349.0.
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][O:22][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propan-1-ol (12.9 g, 32.1 mmol), p-toluenesulfonyl chloride (24.6 g, 129 mmol) and triethylamine (37 mL, 270 mmol) in methylene chloride (300 mL) was stirred at ambient temperature under nitrogen. After 2 hours, a second portion of p-toluenesulfonyl chloride (12.1 g, 63.5 mmol) was added. The reaction was stirred for 2 more hours and then concentrated. The residue was partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 20-50% ethyl acetate in hexane, 100% ethyl acetate and then 100% methylene chloride (due to limited solubility). A yellow solid (13.0 g, 73.0%) was obtained as toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester: MP: 162-4° C.; Mass Spectrum (−EI, [M−H]−) m/z 554. 1HNMR (500 MHz, DMSO-d6): δ8.52-8.54 (m, 1H), 8.31 (d, 1H, J=8.18 Hz), 8.09-8.11 (m, 1H), 7.97-8.00 (m, 2H), 7.62-7.73 (m, 5H), 7.35 (d, 2H, J=7.93 Hz), 6.92 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.73 (d, 1H, J=2.80 Hz), 5.22 (s, 2H), 4.09 (t, 2H, J=5.98 Hz), 3.79-3.82 (m, 2H), 2.29 (s, 3H), 1.91-1.97 ppm (m, 2H). Elemental Analysis for C27H25NO8S2: Calcd: C, 58.37; H, 4.54; N, 2.52; Found: C, 58.13; H, 4.43; N, 2.41.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27]CC)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[N:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([OH:27])=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[N:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2nc(OCC)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2n1
Temperature: 65 °C
Yield: 25 %

Procedure:
A solution containing ethyl 3-{[(benzyloxy)carbonyl]amino}-7-ethoxy-1,8-naphthyridine-2-carboxylate (47 mg, 0.12 mmol) and lithium hydroxide monohydrate (25 mg, 0.59 mmol) in THF (2.0 mL) and water (1.0 mL) was heated at 65° C. in a sealed vial for 2 h. A precipitate was filtered off and washed with EtOAc to afford the sub-title compound (11 mg). The filtrate was diluted with water (1 mL) and the solution was extracted with EtOAc (2×5 mL). The combined organic extract were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give additional sub-title compound (30 mg). The crude product was used directly in the subsequent reaction. LCMS (ESI) calc. for C19H18N3O5 [M+H]+: m/z=368.1. found: 368.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])=[C:11]([CH3:27])[O:10][N:9]=2)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.O[N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=CC=2N=N1.CCN(CC)CC.C1(N)CC1>CN(C=O)C>[CH:45]1([CH2:44][NH:40][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:13]([C:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[N:9][O:10][C:11]=4[CH3:27])=[O:14])=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[O:25])[CH2:47][CH2:46]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)O)ccc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)NCC3CC3)ccc12
Yield: 71.9 %

Procedure:
A solution of 62 mg (0.17 mmol) 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-indole-6-carboxylic acid, 41 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide, 23 mg (0.17 mmol) 1-hydroxy benzotriazole, 59 uL (0.43 mmol) Et3N and 0.26 mmol cyclopropylamine in DMF (1 mL) was reacted at room temperature overnight. After evaporation the mixture was subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water (0.05% NEt3) gradient to afford 51 mg of the title compound in 72% yield as a white solid. (m/e): 418.1 (MH+; 100%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1.O>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: O
Solvent: C1COCCO1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (60 mg, 0.20 mmol, 1.00 equiv), 1H-indol-5-ylboronic acid (100 mg, 0.62 mmol, 3.05 equiv), Pd(PPh3)4 (23.6 mg, 0.02 mmol, 0.10 equiv), K3PO4 (174 mg, 0.82 mmol, 4.01 equiv), 1,4-dioxane/H2O (4/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 55% in 8 min, hold 55% in 3 min, up to 100% in 0.1 min, hold 100% in 0.9 min); Detector, UV 220 & 254 nm. This resulted in 25 mg (33%) of 2-(1H-indol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.Cl>[C:12]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[OH:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(=O)OC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
10 g (57.9 mmol) 5-chlorosalicylic acid was weighed in a 100-mL round-bottomed flask, followed by the addition of acetic anhydride (12.8 mL, 115.9 mmol). The mixture was stirred for 5 minutes before adding concentrated sulfuric acid (2 drops). The reaction was refluxed for 3 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature and poured into a beaker containing 2N HCl (200 mL) to precipitate the product out. The product was collected via vacuum filtration. A purity check by HPLC revealed the presence of impurities. The precipitate was stirred in water (150 mL) overnight in a 200-mL round-bottomed flask. The insoluble solid was collected via vacuum filtration. An impurity check by HPLC revealed that the crude product was free of the impurities. The product was dried overnight in vacuo to yield 12 g of O-acetyl-5-chlorosalicylic acid (56 mmol, 97% yield)
Reaction SMILES: [CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2Br)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2[C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Br)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1c(-c2ccncc2)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 170.7 %

Procedure:
A mixture of (4-benzyl-4-hydroxypiperidin-1-yl)(5-bromo-1,3-benzodioxol-4-yl)methanone (0.50 g), pyridine-4-boronic acid (0.22 g), sodium carbonate (0.38 g), tetrakis(triphenylphosphine)palladium(0) (0.069 g), water (0.50 mL) and DME (2.5 mL) was stirred at 150° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.85 g).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])([OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[F:35][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][C:11]1([OH:15])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCNCC3)c(F)c2)C(=O)O1

Procedure:
A solution of 334 mg 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester (MW: 495.55, 0.674 mmol) in 3 ml of a 1.25 M anhydrous hydrogen chloride solution in methanol was stired at 35° C. for four hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 4 ml water and the water layer neutralized to pH 7 with a saturated sodium bicarbonate solution. The water was evaporated and the residue dissolved in 30 ml of a 9/1 dichloromethane/methanol mixture. The unsoluble salt were filtered and the filtrate evaporated to dryness to afford off white solid. Yield 266 mg, quant. MS: 395.8 (M+H)+, 440.6 (M+HCOO−), Method ESI+, ESI−.