Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl.O>CN(C=O)C.C(OCC)(=O)C>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[CH:12]=[N:13]3)=[C:9]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1nc2nc(N3CCOCC3)nc(N3CCOCC3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2nc(N3CCOCC3)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
As shown in Scheme 5 above, 2,6-dicloropyrimidine (1 g, 5.29 mmol) was dissolved in morpholine (5 mL) in a sealed tube. The tube was heated to 120° C. for 5 hours then cooled to room temperature. Water (100 mL) was added and the resulting precipitate was filtered and washed with water to give 2,6-di-morpholin-4-yl-7H-purine (1.33 g, 87%). 2,6-Di-morpholin-4-yl-7H-purine (1.33 g, 4.58 mmol) was dissolved in DMF (50 mL). NaH (0.22 g, 5.50 mmol, 60% dispersion in oil) was added and the reaction was stirred at room temperature for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.92 g, 5.50 mmol) was added dropwisely and the reaction was stirred for 18 h at room temperature. Water (200 mL) then ethyl aceate (200 mL) were added. The ethyl acetate extracts were washed with water (3×100 mL), dried over MgSO4, filtered and evaporated to dryness. The resulting residue was purified by silicagel column chromatography eluting with a gradient of 1:1 ethyl aceate to ethyl acetate to produce 2,6-Di-morpholin-4-yl-7-(2-trimethylsilanylethoxymethyl)-7H-purine (1.51 g, 78% yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:24]C(=O)OCC2C=CC=CC=2)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:24][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)=[C:9]([OH:8])[CH:10]=1
Reactant: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2ccc(N)cc2O)cc1
Reaction time: 11 h
Yield: 76.6 %

Procedure:
To a solution of 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g) and triethylamine (1.3 mL) in 1,4-dioxane (10 mL) was added a solution of diphenylphosphoryl azide (1.3 g) in 1,4-dioxane (10 mL), and the mixture was stirred at 100° C. for 1 hour. Benzyl alcohol (1.6 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 7 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give benzyl N-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]carbamate (1.4 g). To a solution of obtained benzyl N-[3-benzyloxy-4-(4-ethyl-benzyl)phenyl]carbamate (1.4 g) in methanol (15 mL) was added 10% palladium-carbon powder (0.28 g), and the mixture was stirred under a hydrogen atmosphere for 11 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 5-amino-2-(4-ethylbenzyl)phenol(0.54 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:23][CH2:22][C:10]3([CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C([Cl:27])(=O)C>C(O)C>[ClH:27].[ClH:27].[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:23][CH2:22][C:10]3([CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)CC2)C1
Solvent: CCO
Product: Cl
Product: c1cc(N2CCC3(CCNC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (5.671 mmol, 1 equiv.) was placed in ethanol p.a. (20 ml). Acetyl chloride (28.355 mmol, 3 equiv.) was then added at 0° C., and the resulting mixture was stirred for 16 hours at 25° C. The solvent was concentrated in vacuo and the residue was dried under a high vacuum to yield the desired product. Yield: 1.48 g (90%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2.[OH-].[K+].[I:20]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:20]
Reactant: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc3[nH]nc(I)c3c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.4 %

Procedure:
To a solution of 5-(3-chlorophenoxy)-1H-indazole (152 mg, 621 μmol) in DMF (2.36 mL) at 25° C. was added potassium hydroxide (105 mg, 1.86 mmol) and iodine (237 mg, 932 μmol). The reaction mixture was stirred at 25° C. for 75 min then quenched with 10% Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (3×), then the combined organics were washed with water and brine (2×), dried over MgSO4 and concentrated to afford a pale yellow oil which was purified by chromatography (silica, 115 g, 50 μm from Analogix, 0 to 30% EtOAc in hexanes, 15 min) to give 5-(3-chlorophenoxy)-3-iodo-1H-indazole (194 mg, 524 μmol, 84%) as an off-white solid. MS (M+H)+=370.8; 1H NMR (CDCl3) δ: 7.73 (d, J=8.7 Hz, 1H), 7.28 (d, J=5.3 Hz, 1H), 7.22-7.25 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.08 (dt, J=7.9, 0.9 Hz, 1H), 6.98 (t, J=2.3 Hz, 1H), 6.89 (dd, J=8.3, 2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2([CH2:31][CH2:32]OC)[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)[CH3:2].[Cl-].C[Al+]C>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:32][CH2:31][C:15]3([CH2:20][CH2:19][N:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])(=[O:22])=[O:23])[CH2:17][CH2:16]3)[C:13]2=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C2(CCOC)CCN(S(=O)(=O)c3ccccc3Cl)CC2)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)Cc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 25 °C

Procedure:
(4-{[1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (2.47 g) in toluene (50 ml) was treated with dimethylaluminium chloride in heptane (1 molar, 5 ml) under an argon atmosphere at RT, and then refluxed for 3 hours. The reaction was then cooled to RT partitioned between AcOEt and 1N aqueous HCl/water. The layers were separated, the organic layer dried over sodium sulphate and the solvent was removed in vacuo to give the desired {4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-phenyl}-acetic acid ethyl ester as a light brown solid. MS (EI): 491.2 (M+).
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1.O1CCOCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:33]1[C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (4.4 g, 11.21 mmol, 1 eq.) in 30% aqueous THF/dioxane was treated with lithium hydroxide (0.81 g, 33.63 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a brown oil
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C.C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:36][C@@H:32]4[CH2:33][CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 120 °C
Yield: 113.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.77 mmol), (R)-1-benzyl-3-aminopiperidine (175 mg, 0.92 mmol), diisopropylethylamine (197 μl, 1.16 mmol) in propan-2-ol (5 ml) was heated in a microwave reactor at 120° C. for 10 minutes. The mixture was diluted with DCM and then purified by column chromatography on silica gel (gradient: 0 to 40% ethyl acetate in cyclohexane) affording 429 mg of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-piperidin-3-yl)amine, which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.58 min, m+H=492.5; 1H NMR (400 MHz, CDCl3) δ: 9.53 (br s, 1H), 9.10 (s, 1H), 8.19-8.15 (m, 2H), 7.69-7.33 (m, 9H), 6.68-6.61 (m, 1H), 4.24-4.15 (br m, 1H), 3.54 (s, 2H), 2.77-2.27 (br m, 4H), 1.88-1.74 (br m, 3H), 1.69-1.52 (br m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2ccn(Cc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 130 °C

Procedure:
A mixture of 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352, Example 1; 50 mg, 0.19 mmol), 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine (45 mg, 0.40 mmol), sodium phenoxide (35 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg, 0.003 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=Xanthphos (7 mg, 0.012 mmol) in dioxane (2 ml) was heated under an argon atmosphere in the microwave to 130° C. for 15 min. The mixture was diluted with water, extracted with dichloromethane and the product purified by chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as a light yellow solid (Yield=42%). MS ISP (m/e): 378.4 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[CH:9][N:8]=[N:7]1)=[O:4].ClCCl.[C:41]([OH:44])(=[S:43])[CH3:42].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>O.C1(C)C=CC=CC=1>[C:41]([S:43][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[N:8][CH:9]=1)(=[O:44])[CH3:42]
Reactant: CC(O)=S
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (6.27 g) in a mixed solvent of dichloromethane (100 ml) and toluene (100 ml) were added thioacetic acid (3.62 ml) and N,N-dimethylformamide dineopentyl acetal (14.0 ml). After the mixture was stirred at room temperature for 1 hour, water was added thereto and products were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by purification of the residue by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (2:1:1) as an eluent afforded crude (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (4.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9](=[O:18])[NH:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C(N(CC)CC)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:18][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(=O)c(C#C[Si](C)(C)C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc2occc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6Oxo-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester described in Preparation Example P-3 (545 mg, 2.07 mmol) and copper(I)iodide (5.9 mg, 31 μmol) were suspended in ethanol (7 mL) and triethylamine (3 mL), and the mixture was stirred at 75° C. for 20 hours. The reaction mixture was cooled to room temperature, then, potassium carbonate (572 mg, 4.14 mmol) was added to the reaction mixture, which was further stirred at 75° C. for 5 hours. The reaction mixture was cooled to 0° C., then, water was added, the precipitated solid was filtered, and the title compound (303 mg) was obtained as a brown solid. In addition, ethyl acetate was added to the mother liquor for extraction, the organic layer was washed with brine, then, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (33 mg, 0.17 mmol) was obtained as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([O:10][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:9]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
Thionyl chloride (50 mL, 680 mmol) was added to 2,4,5-trifluorobenzoic acid (10 g, 57 mmol) and the mixture stirred at 55° C. for 18 hours. After cooling, the excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL) and the residue redissolved in DCM (50 mL), then cooled to 0° C. with an ice bath. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was allowed to warm up to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were combined, washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL). The organic layer was dried over magnesium sulfate and concentrated to provide a crude solid, which was purified by silica gel chromatography eluting with 5% EtOAc in heptane to provide the title compound (10.08 g, 66%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13].[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC1CCN(c2ccn(C)n2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1CCN(c2nn(C)cc2[N+](=O)[O-])C1=O
Temperature: 0 °C

Procedure:
To a solution of 3-methyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (97 mg) in acetic anhydride (1.2 mL) was added fuming nitric acid (45 μL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13].OC1C(O)=C(C)C=CC=1C=O>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH:10]1[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1)[CH3:13]
Reactant: Oc1cccc(O)c1O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(C=O)c(O)c1O
Solvent: Cc1ccccc1
Product: CCOC1Oc2cccc(O)c2O1
Temperature: 150 °C
Yield: 72.6 %

Procedure:
A 500 mL round bottom flask was charged with pyrogallol (25 g, 0.198 mol), triethyl orthoformate (40 mL, 35.6 g, 0.240 mol), toluene (250 mL) and Amberlyst-15 (2.40 g). A 40 cm long B24 reflux condenser was attached and on top of this a distillation head was connected to a condenser, receiver adaptor and 100 mL collecting flask. The reaction mixture was stirred and heated under reflux at a metal block temperature of 150° C. for 1 h. The water flow to the is reflux condenser was stopped and the water to the distillation condenser was turned on. Distillate boiling point up to 78° C. was collected over 4 h, after which the block temperature was increased to 260° C. for 30 min and finally 170° C. for 30 min. The toluene/ethanol azeotrope (43 mL) was collected and contained 68% ethanol. The red mixture was filtered through celite and the filtrate was evaporated to dryness. The residue was absorbed onto 60 mL of flash silica then applied to a column of 300 mL flash silica made up in heptane/EtOAc (9:1). Elution with this solvent mixture afforded 37 (26.2 g, 73%) as a very pale yellow oil:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[CH:14]1([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:19][N:18]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH:14]1([C:17]2[N:18]=[CH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][N:28]([S:10]([CH2:9][C@@:2]3([CH3:1])[NH:3][C:4](=[O:8])[NH:5][C:6]3=[O:7])(=[O:12])=[O:11])[CH2:27][CH2:26]4)=[CH:21][N:22]=2)[CH2:16][CH2:15]1
Reactant: c1cc2c(cc1-c1cnc(C3CC3)nc1)CCNC2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.020 g, 0.087 mmol) in anhydrous THF (0.40 mL) was added dropwise to a stirred solution of 6-[2-(cyclopropyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline (0.023 g, 0.091 mmol), DIPEA (0.022 mL, 0.13 mmol) and dry THF (0.50 mL) at RT. After the addition was complete, the solution was stirred at RT for 2 h and then taken up in water-brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give a crude product. Purification by preparative HPLC afforded 0.021 g (50%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1.N1C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([NH:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1cc2c(cc1F)COB2O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 2-fluoro-4-nitrobenzene-1-sulfonyl chloride (1.336 g, 5.57 mmol) and 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.93 g, 5.57 mmol) in 20 mL of ACN was added pyridine (900 uL, 11.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, and concentrated to give 1.84 g of the title compound as a yellow residue. MS calcd for (C13H9BF2N2O6S): 370.0. MS found (ESI negative): (M−H)−=368.9
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[Cl:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: FC(F)(F)c1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) and potassium carbonate (0.31 g) and 2-chloro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (melting point: 156.0°-159.0° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1(C)CCNc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CC1(C)CCN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 250 °C
Reaction time: 1 h

Procedure:
1b (0.762 g, 4.73 mmol), ortho-fluoronitrobenzene (0.88 g, 5.67 mmol, 1.19 eq), and 2,4,6-collidine (0.66 mL, 1.05 eq) were pre-stirred 40s in a conical microwave container. It was then heated with stirring at a Personal Chemistry Microwave reactor with normal absorption at 250° C. for 1 h. The crude mixture was dissolved in CHCl3, and was purified by flash chromatography (hexanes/EtOAc) to give 0.66 g of crude 1c. LC-MS ESI 283 (M+H).