Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:29])([O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH2:23][C:24]([OH:26])=[O:25])=[C:16](F)[C:15]=1[F:28])[O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[NH2:30][C:31]1[C:32]([CH3:37])=[CH:33][CH:34]=[CH:35][CH:36]=1>C(OCC)C>[C:1](=[O:29])([O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH2:23][C:24]([OH:26])=[O:25])=[C:16]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:15]=1[F:28])[O:2][C:3]12[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(OC(=O)OC23CC4CC(CC(C4)C2)C3)c(F)c1F
Reactant: Cc1ccccc1N
Solvent: CCOCC
Product: Cc1ccccc1Nc1c(CC(=O)O)cc([N+](=O)[O-])c(OC(=O)OC23CC4CC(CC(C4)C2)C3)c1F
Temperature: 200 °C
Reaction time: 6 h

Procedure:
The compound 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl carbonate is dissolved in excess ortho-toluidine. The reaction mixture is stirred at 200° C. for 6 hours. The mixture is allowed to cool and is dissolved in diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product is purified by flash chromatography as necessary.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[O:21]2)[CH:13]=1)([CH3:11])[CH3:10])(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(Cl)Cl>C1(C)C=CC=CC=1>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:7][CH2:8][C:9]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:21][C:22](=[O:27])[CH2:23][C:24](=[O:26])[CH2:25]2)[CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(CN)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
(2-{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (1.80 g, 3.94 mmol), was stirred with 30% TFA/CH2Cl2 (30 mL), for 2 h. The reaction was diluted with Toluene (30 mL) and stripped of all solvents. The crude product was used without further purification. Yield 3.22 g.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[N:5]/[C:6]1[S:7][C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=1)[CH3:3].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:11]([C:8]2[S:7][C:6](/[N:5]=[CH:4]/[N:2]([CH3:1])[CH3:3])=[N:10][CH:9]=2)=[O:13])[CH2:27][CH2:26]1
Reactant: CN(C)/C=N/c1ncc(C(=O)O)s1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C)/C=N/c1ncc(C(=O)NC2CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL flask was charged 2-{[(1E)-(dimethylamino) methylidene]amino}-1,3-thiazole-5-carboxylic acid 23-2 (0.56 g, 2.37 mmol) and thionyl chloride (5 mL). This suspension was refluxed for 75 minutes. At the end of this time the homogeneous solution was evaporated to dryness and the residue was flushed 2 times with CCl4. This residue was then dissolved in methylene chloride and triethylamine (1.20 g, 11.8 mmol) was added followed by cyclopropylamine (0.47 g, 8.29 mmol). The reaction was stirred overnight at 25° C. A precipitate was filtered off. Hi-Res MS: calc: 239.0961 found: 239.0959. 1H-NMR (DMSO): 8.36 ppm (s, 1H); 8.27 ppm (s, 1H); 7.83 ppm (s, 1H); 3.12 ppm (s, 3H); 2.98 ppm (s, 3H); 2.72 ppm (m, 1H); 0.67 ppm (m, 2H); 0.52 ppm (m, 2H).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([C:24]1[C:29]([NH2:30])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[C:29]([NH:30][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)(=[O:23])[CH3:21]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(cc1NC(=O)c1cccc3ccccc13)OCO2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Into solutions of 149 (5.0 mmol) in 200 mL of dry toluene were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (5 mmol). The mixtures were stirred at 20±2° C. for 24 h and then evaporated. The residues were washed with acetone and EtOH and then recrystallized from acetone or EtOH to form 150. Obtained as a grayish-white solid; mp 143-144° C.; ESI-MS (Positive mode): m/z 334 [M+H]+; 1H-NMR (400 MHz, DMSO-d6, δ): 2.59 (3H, s), 6.20 (2H, s), 7.60-7.68 (4H, m), 7.87 (1H, d, J=7.2 Hz), 8.05-8.07 (1H, m), 8.15 (1H, d, J=8.0 Hz), 8.33-8.38 (2H, m), 12.52 (1H, s); IR (KBr): 1647, 1672 (C═O) cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH3:18].OS(O)(=O)=O.B(O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@H:7]([CH3:11])[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[CH:12][CH:13]=1
Reactant: C[C@@H](Oc1ccc(O)cc1)C(=O)O
Reactant: CCCCCO
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)[C@@H](C)Oc1ccc(O)cc1
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of the (R)-2-(4-hydroxyphenoxy)propionic acid (11 mmole) in toluene (30 ml), 1-pentanol (30 mmole), 98% H2SO4 (0.2 ml) and boric acid (0.1 g) was heated to reflux and water removed by azeotropic distillation on a Dean & Stark apparatus. After 3 hours the excess toluene was allowed to distil. The residue was allowed to cool and diluted with dichloromethane, washed with dilue HCl, water and saturated NaHCO3 solution, dried (MgSO4) and the crude product isolated by evaporation. This was distilled (Kugelrohr b.p. 150°-60° C. at 0.05 mbar) to give PHPP (yield 57%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[NH:29]1[C:28]([NH:27][C:20]([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[N:8]=2)=[O:22])=[N:32][N:31]=[N:30]1
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 55.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-n-butyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (1.7 g), thionyl chloride (15 ml) and 5-aminotetrazole (0.67 g) are reacted to give N-(5-tetrazolyl)-4-n-butyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (1.16 g). M.P. 278°-280° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[CH:6]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.O1CCCC1>[N:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[CH:6]=1)=[C:1]=[S:3]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N=C=S)cc1O
Temperature: 25 °C
Reaction time: 31 h
Yield: 64 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 4-amino-2-hydroxybenzoic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 31 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 3 minutes at 0° C., followed by stirring at 0° C. for further 2.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the obtained residue, ethyl acetate (6 mL), water (2 mL) and sodium hydrogencarbonate (13 mg, 0.15 mmol) were added, and the organic layer was washed twice with water (2 mL) and then concentrated under reduced pressure to dryness. To the obtained residue, chloroform (1 mL) and hexane (3 mL) were added and thoroughly mixed, and then, an insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to dryness to obtain 4-isothiocyanato-2-hydroxybenzoic acid as a brown-colored solid (0.18 g, yield: 64%, HPLC purity: 86%, HPLC retention time: 4.6 min). LC-MS ES-194 (retention time: 4.4 min, condition 1).
Reaction SMILES: [K].[Br:2][CH:3]([CH2:15][Br:16])[CH2:4][O:5][P:6](=[O:14])([OH:13])[O:7][CH2:8][CH:9]([Br:12])[CH2:10][Br:11]>>[P:6]([O:13][CH2:4][CH:3]([Br:2])[CH2:15][Br:16])([O:5][CH2:4][CH:3]([Br:2])[CH2:15][Br:16])([O:7][CH2:8][CH:9]([Br:12])[CH2:10][Br:11])=[O:14]
Reactant: O=P(O)(OCC(Br)CBr)OCC(Br)CBr
Agent: [K]
Product: O=P(OCC(Br)CBr)(OCC(Br)CBr)OCC(Br)CBr

Procedure:
An emulsion containing the potassium salt of bis-(2,3-dibromopropyl) phosphoric acid and tris-(2,3-dibromopropyl) phosphate was formed by adding 25 gms of the emulsion concentrate from Example 2 to 975 gms of water with stirring at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-(3′-fluoro-5-hydroxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3,5-difluorobenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH2:40][CH:41]2[CH2:42][CH2:43]2)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
(5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0444 g, 0.1445 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.05114 g, 0.1445 mmol) were combined in methylene chloride (1.25 mL). They were then treated with diisopropylethylamine (0.07552 ml, 0.4336 mmol), followed by HBTU (0.05495 g, 0.1445 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was chromatographed on SiO2 (Biotage 12M) and eluted with 4% MeOH/MC. The material was concentrated in vacuo to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (67.4 mg, 82%). LCMS (APCI+) [M+H]+ 570.0.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.OC[CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na]>C1(C)C=CC=CC=1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH2:19][CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCCN1CCCCCC1
Reactant: COC(=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCCCCC1)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Yield: 59.9 %

Procedure:
By treating 17.31 g of methyl 2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF3, R"=CH3), 10.5 g of 1-(2-hydroxyethyl)homopiperidine in 130 ml of toluene and in the presence of sodium as described in Example 1, 20.6 g of a crude material are isolated. The recrystallization in diisopropyl ether enables to isolate 13.7 g (yield: 60%) of a whitish solid with m.p. 72°-75° C. and elemental analysis C, H, N, F correct.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3C(C)C)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [CH:1]([C@@H:3]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:4]1)=O.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][N:17]=[CH:1][C@H:3]1[C@H:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:4]1
Reactant: O=C[C@H]1O[C@H]1c1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN=C[C@@H]2O[C@H]2c2ccccc2)c(OC)c1
Reaction time: 12 h

Procedure:
To a solution of (2S,3S)-2-formyl-3-phenyloxirane (430 mg, 2.90 mmol) in 8.0 mL of dichloromethane under nitrogen was added a solution of 2,4-dimethoxybenzylamine (461 mg, 2.75 mmol) in 1.0 mL of dichloromethane via cannula. Residual amine was washed into the reaction flask with 1.0 mL of dichloromethane. Molecular sieves (2.3 g of pellets, 4 Å, activated) were added and the mixture was allowed to stand for 12 hours. This solution was used directly in the cycloaddition after removing and concentrating a small aliquot for spectral analysis: IR (CHCl3) 3016, 1615, 1510 cm-1 ; 1H NMR (CDCl3, 250 MHz) δ 7.40-7.24 (6H, N=CH, ArH), 7.14 (d, 1H, J=8.8 Hz, ArH), 6.52-6.43 (2H, ArH), 4.62 (s, 2H, NCH2Ar), 3.69 (d, 1H, J=1.9 Hz, oxirane CHCHPh), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.62 (dd, 1H, J=1.9, 7.0 Hz, oxirane CHCHPh).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:17]=[O:18].Cl>O1CCCC1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:7][C:6]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1F
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1F
Reaction time: 0.5 h

Procedure:
5-Bromo-2-fluoro-toluene (26 mmol, 5.0 g) was dissolved in tetrahydrofuran (25 ml) and cooled to −78° C. t-Butyllithium (1.7 M in pentane, 31 ml) was added over 10 minutes. After 30 minutes, N,N-dimethylformamide (2.1 ml) was added. The reaction mixture was warmed to ambient over 30 minutes and 6% HCl (100 ml) was added with vigorous swirling. The mixture was extracted with ethyl acetate (200 ml). The organic layer was dried over MgSO4, then concentrated affording the title compound as an oil (3.6 g, ˜quant.).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[N+:6]([O-:11])=[CH:7][NH:8][C:9]=2[N:10]=1.[BrH:13]>>[BrH:13].[N:3]1[C:4](=[O:12])[C:5]2[C:9]([N:8]=[CH:7][N+:6]=2[O-:11])=[N:10][C:2]=1[NH2:1]
Reactant: Nc1nc2[nH]c[n+]([O-])c2c(=O)[nH]1
Agent: Br
Product: NC1=NC(=O)C2=[N+]([O-])C=NC2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-1,9-dihydro-6H-purin-6-one-7-oxide (50 mg, 0.29 mmol) was heated over a steam bath in 5 ml of 1.0M aqueous hydrobromic acid until it dissolved. The solution was filtered and cooled to room temperature for one hour and then allowed to stand at 5° C. overnight whereupon 33 mg of the hydrobromide salt of 2-amino-1,9-dihydro-6H-purin-6-one-7-oxide precipitated as white needles, mp >250° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Sodium hydride (60 wt %, 0.54 g) was added to dimethyl sulfoxide (15 ml), and the mixture was stirred at 70° C. for 30 min and was then cooled to room temperature. 4-Amino-3-nitrophenol (2.07 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.50 g) was added thereto, and the mixture was stirred at 100° C. for 4 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give 0.53 g (yield 23%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.B1([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>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>[S:30]1[C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[C:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[N:27][CH:28]=[N:29]1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ncns4)ccc32)CC1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 0.059 mL, 0.192 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 10 minutes (starting material remained, but moved forward). The reaction mixture was diluted with water, and washed with DCM. Equal partitioning between both layers was observed (and an emulsion formed), so the organic and aqueous were combined and concentrated until just the water remained. The aqueous was washed with DCM (×3) and the organics were then combined and dried using a phase separator. After concentration, the material was purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide tert-butyl 4-(2-(7-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.035 g, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 2.16-2.37 (m, 2 H) 3.51-3.72 (m, 4 H) 3.81-3.90 (m, 2 H) 4.22-4.34 (m, 2 H) 5.84 (br. s., 1 H) 6.38-6.46 (m, 1 H) 7.10-7.17 (m, 2 H) 7.56 (d, J=8.31 Hz, 1 H) 7.65 (d, J=2.05 Hz, 1 H) 7.72 (dd, J=8.41, 2.15 Hz, 1 H) 8.42 (s, 1 H). m/z (ESI) 524.0 (Boc group falls off in LCMS).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:11](OCC)(OCC)OCC>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([CH:11]=[N:9][N:8]=2)[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncc(Br)nc1Cl
Solvent: O
Product: Clc1nc(Br)cn2cnnc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-3-chloro-2-hydrazinylpyrazine (1.24 g, 5.5 mmol) and triethyl orthoformate (20 mL). The resulting mixture was stirred at 130° C. for 2 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 30% EtOAc in petroleum ether, to afford 1.12 g (87%) of the product as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=O)=[C:6]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N+:17]([O-:19])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:16])=[N:8]2
Reactant: CCOC(=O)CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(O)nc2cc(Cl)ccc2[n+]1[O-]
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(5-chloro-2-nitrophenylamino)-3-oxopropanoate (1.5 g, 5.2 mmol) in anhydrous DMF (8 mL) was added dropwise to a solution of potassium tert-butoxide (1.2 g, 10.5 mmol) in anhydrous DMF (5 mL) at 0° C. under nitrogen, after which the mixture was stirred for 2 h. The cold mixture was diluted with water (50 mL), acidified to pH 2 with 2 N HCl and extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with water (45 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (3:7), to provide 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline-1-oxide as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 1H), 7.46 (d, 1H), 7.34 (dd, 1H), 4.55 (q, 2H), 1.45 (t, 3H) ppm; ESI MS m/z 267 [M−H]−.