Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:20]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:21]3[N:25]([CH3:26])[CH:24]=[N:23][N:22]=3)[CH:9]=2)[N+:4]=1[CH2:34][C:35](=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH:20]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:9]=3)[N:4]3[CH:34]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:2]=[C:3]3[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)C[n+]1c(N)cc(-c2cccc(Cl)c2)c2cc(C(c3ccc(Cl)cc3)c3nncn3C)ccc21
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cn2c(cc(-c3cccc(Cl)c3)c3cc(C(c4ccc(Cl)cc4)c4nncn4C)ccc32)n1
Yield: 27.3 %

Procedure:
A mixture of intermediate (67) (0.0006 mol), obtained in Example A12 g, in ethanol (3 ml) was stirred and refluxed for 18 hours. Potassium carbonate 10% was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (0.3 g) was purified by column chromatography over kromasil (eluent: CH2Cl2 100 to CH2Cl2/CH3OH 90/10; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.12 g, 33%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 0.091 g (25%) of ethyl 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-imidazo[1,2-a]quinoline-2-carboxylate, mp. 220° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([NH:42][C:29]4[C:30]5[O:34][CH2:33][O:32][C:31]=5[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])=[CH:36][C:28]=4[F:27])=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COCC#Cc1cc(F)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 71.6 %

Procedure:
This was prepared using the, method described in the example 4 using 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (150 mg, 0.40 mmol), 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (97 mg, 0.43 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 0.83 ml) in DMF (2.5 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (162 mg, 72%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.98 (quintet, 2H), 1.99 (s, 3H), 2.34 (m, 2H), 2.40 (m, 2H), 2.50 (t, 2H), 3.37 (s, 3H), 3.44 (m, 4H), 3.94 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 566.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[CH3:15][N+:16]([O-:18])=[O:17].CC(=O)OCC>CC(O)=O.O>[CH3:13][C:4]1([CH3:14])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8](/[CH:11]=[CH:15]/[N+:16]([O-:18])=[O:17])[CH:9]=[CH:10][C:5]1=2
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)OB(O)c2cc(/C=C/[N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (1.14 g, 6 mmol) and NH4OAc (47 mg, 0.6 mmol) in AcOH (10 mL) at rt was added CH3NO2 (10 mL). The reaction mixture was stirred at 100° C. for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel by elution with PE:EA (2:1 to 1:1) to give (E)-3,3-dimethyl-6-(2-nitrovinyl)benzo[c][1,2]oxaborol-1(3H)-ol as a yellow solid (750 mg, yield 53%). 1F1 NMR (500 MHz, CDCl3) δ 9.18 (s, 1H), 8.18 (s, 2H), 8.01 (s, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 1.46 (s, 6H) ppm; MS: m/z=234.1 (M+1, ESI+).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[NH:9][C:10](=[O:18])[CH2:11][C:12](OC)([O:14][CH3:15])[CH3:13])(=[O:4])[CH2:2][CH3:3]>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[NH:9][C:10](=[O:18])/[CH:11]=[C:12](\[O:14][CH3:15])/[CH3:13])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1cccc(NC(=O)CC(C)(OC)OC)c1
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Reaction time: 72 h
Yield: 47.2 %

Procedure:
A solution of 42.8 g of m-propionamido-3,3-dimethoxy-butyranilide in 500 ml of toluene was heated at 140° C. for 1 hour and was then let stand for 72 hours. The toluene was decanted and the residue was added to acetone. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 18 g of m-propionamido-3-methoxycrotonanilide melting at 155° C. Crystallization from ethyl acetate did not change the melting point.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=2)[CH2:30][CH2:31]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-(1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.35 (s, 1H), 7.68-6.82 (m, 11H), 5.58-5.48 (m, 1H), 3.64-3.50 (m, 2H), 3.01-2.94 (m, br, 2H), 2.92-2.54 (m, 4H), 2.48-2.32 (m, br, 2H), 2.20-2.04 (m, 1H), 2.01-1.80 (m, 5H), 1.70-1.54 (m, 1H), 1.54-1.36 (m, 3H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C34H40ClF5N2O2.0.6MeOH: C, 63.12; H, 6.49; N, 4.25; Found: C, 63.38; H, 6.61; N, 3.95. ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)C.Cl.[F:6][C:7]([F:37])([F:36])[C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][NH:12][CH:13]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[C:14]([OH:16])=[O:15].C([O-])(O)=O.[Na+]>CO>[F:37][C:7]([F:6])([F:36])[C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][NH:12][CH:13]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[C:14]([O:16][CH3:1])=[O:15]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a magnetically stirred solution of 100 ml of methanol cooled in an ice-acetone bath at ca. -15° C., was treated dropwise with acetyl chloride (27.3 g, 350 mmol, 35 eq) over a six-minute period as a convenient way to generate HCl in situ. The solution was stirred at ambient temperature for 45 minutes, then solid α-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid was added which formed a dark rose colored solution. After stirring for 22 hours the reaction mixture was poured into 100 mL of saturated NaHCO3 solution containing 100 mL of crushed ice, basified with additional solid NaHCO3 powder until the rose color dissipated and extracted twice with ether. The combined organic extracts were washed with saturated NaHCO3 (1×75 mL), saturated brine (1×100 mL), dried with anhydrous NaSO4 and concentrated in vacuo. Flash chromatography with 100 g of silica gel using ethyl acetate-hexane (1:2) afforded 4.07 g of the title compound as a golden oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(=O)[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(CC(=O)Nc2ccsc2C(=O)NNC(C)=O)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccsc2-c2nnc(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
To a solution of N-(2-(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (300 mg, 0.86 mmol) in anh. acetonitrile (6 mL) was added diisopropylethylamine (0.8 mL, 4.84 mmol) and triphenylphosphine (396 mg, 1.51 mmol). After 5 min, hexachloroethane (292 mg, 1.23 mmol) was added to the reaction mixture and then stirred at room temperature overnight under N2(g) inlet. The reaction mixture was evaporated under reduced pressure, partitioned between ethyl acetate and H2O, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40:60 ethyl acetate/hexane) gave 2-(4-methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)acetamide (25 mg, 9%). See James, C. A. et al., Tet. Lett. 47 (2006) 511-514. Method [7] m/z 330.0 (M+H); retention time=4.805. 1H-NMR (CDCl3) δ 10.15 (broad s, 1H), 8.18 (d, J=5.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 7.31 (d, J=7.6 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[ClH:39]>CC#N>[ClH:39].[ClH:39].[CH2:27]1[C:25]2([CH2:28][CH2:29][NH:30][CH2:31][C@@H:24]2[O:23][C:21]2[N:22]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][N:6]=3)[CH:18]=[N:19][CH:20]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: Cl
Solvent: CC#N
Product: Brc1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (314.5 mg, 0.538 mmol) in HCl (5.0M in IPA; 3.0 mL, 15.00 mmol) was stirred under argon at 80° C. for 1 h. The reaction was cooled to RT, diluted with CH3CN (3.0 mL), and vacuum filtered. The collected solid was washed with CH3CN (2×2 mL) and dried in vacuo to provide (R)-3-(6-(6-azaspiro[2.5]octan-4-yloxy)pyrazin-2-yl)-5-bromo-1H-indazole dihydrochloride (256a 205.2 mg, 0.434 mmol, 81% yield) as a yellow solid: MS (ESI, pos. ion) m/z: 400.1/402.1 (M+1).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl.O1CCOCC1>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C(NOCCO)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (24.0 mg, 0.05 mmol) in methanol (0.5 mL) and dichloromethane (1.0 mL) was added 4M HCl in 1,4-dioxane (30 μL, 0.1 mmol, 2.5 eq.), and the reaction was stirred at ambient temperature under N2 for 2 h. The reaction mixture was concentrated in vacuo then poured into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, water, and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 25%, methanol in dichloromethane) to afford the title compound as yellow solid (11.6 mg, 51%). 1H NMR (MeOD, 400 MHz) δ ppm 8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (dd, J=10.20, 1.82 Hz, 1H), 7.48 (d, J=8.41 Hz, 1H), 6.61 (t, J=8.53 Hz, 1H), 4.05 (t, J=4.80 Hz, 2H), 3.78 (t, J=4.80 Hz, 2H)); LCMS (method E1): RT=4.33 min, [M+H]+=458.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:17]1[CH:16]=[CH:15][C:14]([C:28]2[CH:33]=[N:32][C:31]([NH2:34])=[N:30][CH:29]=2)=[C:13]([F:12])[CH:18]=1
Reactant: NCCOc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: NCCOc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)ethanamine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=0.9, 2H), 8.29 (s, 1H), 7.58-7.54 (m, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, J=8.0, 1.4, 1H), 7.39-7.34 (m, 2H), 7.15 (d, J=8.1, 1H), 7.09-7.05 (m, 1H), 6.86 (s, 2H), 4.13 (t, J=5.4, 2H), 3.05 (t, J=5.4, 2H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH:11](O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[Br:2][CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrP(Br)Br
Reactant: CCCCC(O)c1ccccc1
Solvent: CCOCC
Product: CCCCC(Br)c1ccccc1

Procedure:
PBr3 (0.171 mL, 1.82 mmol, Aldrich) was added to a solution of 1-phenylpentan-1-ol (0.500 g, 3.04 mmol, Alfa Aesar) in Et2O (3.2 mL) at 0° C. The reaction was allowed to reach ambient temperature and then was quenched with ice water and diluted with hexanes. The layers were separated and the organic layer was washed with water and then with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with hexanes afforded product (0.15 g, 22%).
Reaction SMILES: [F:1][C:2]1[C:10](F)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[OH-:15].[K+].Cl>O>[F:1][C:2]1[C:10]([OH:15])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(O)c(F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a 1 L reactor equipped with mechanical stirrer, addition funnel, thermocouple, reflux condenser and nitrogen inlet was charged 4,5-Difluoro-2-nitrobenzoic acid (82 g, 0.4 mol, 1 eq) and water (120 mL) to form a suspension. The suspension was heated to about 50° C. Solution of KOH in water (45 wt. %, 161 g, 1.3 mol, 3.25 eq) was slowly added over about 20 min so that the temperature of the exothermic reaction mixture was kept at 80-90° C. After addition, the mixture was stirred at about 80° C. for about half hour, until HPLC sample showed complete conversion. The mixture was cooled down to room temperature, acidified to pH 1 with concentrated HCl solution (105 ml, 1.26 mol, 3.2 eq), and extracted with 2-methyltetrahydrofuran (630 mL). The layers were separated. The upper organic layer was washed with water (150 mL), and distilled under vacuum to minimum volume. The dark brown residue was stirred in 200 mL of mixed solvent of toluene/methylcyclohexane (v/v, 2:1) to give a suspension. The slurry was filtered. The desired product, 4-fluoro-5-hydroxy-2-nitrobenzoic acid, was obtained as an off-white solid after drying under vacuum (68 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz) δ 13.64 (br, 1H), 11.84 (br, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.25 (d, J=12.1 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz) δ 166.0, 151.6, 150.3, 150.2, 149.1, 138.4, 138.3, 127.0, 117.3, 113.7, 113.5.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-])=O)[CH2:9][CH2:10]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.Cl>>[CH2:1]([N:8]1[C:12]2[C:13](=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[NH:19][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N(CCI)Cc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Brc1ccc2c(c1)NCCN2Cc1ccccc1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
A stirred mixture of benzyl-(4-bromo-2-nitro-phenyl)-(2-iodo-ethyl)-amine (23.55 g, Reference Example 7), tin(II) chloride dihydrate (41.48 g), hydrochloric acid 12N (21.28 ml) and distilled water (45 ml) was heated to 80° C. for 1 hour then cooled to room temperature and then treated with distilled water (200 ml). The reaction mixture was neutralized to pH 7-8 by addition of an 32% aqueous ammonia solution (50 ml) and filtered through a pad of celite. The filter pad was washed three times with dichloromethane (250 ml). The filtrate and washings were combined. The organic phase was separated, then washed four times with distilled water (200 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (14.47 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting initially with a mixture of cyclohexane and ethyl acetate (9:1, v/v) and then with a mixture of cyclohexane and ethyl acetate (7:3, v/v) to give the title compound (3.28 g) as a tan solid. 1H NMR, 300 MHz, (CD3)2SO: δ3.1 (broad s, 4H); 4.2 (s, 2H); 5.6 (broad s, 1H); 6.1 (d, J=8 Hz, 1H); 6.2 (dd, J=8 Hz and J=1.5 Hz, 1H); 6.3 (d, J=1.5 Hz, 1H); 7.25 (m, 5H). MS (EI): M+ 304 and 302 (100%), 213 and 211 (100%), 132 (85%), 91 (60%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[N:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1>C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[N:21]=[CH:20][NH:19][C:16]2=[N+:17]([O-:9])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2[nH]cnc2c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cc(Br)cc2nc[nH]c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
m-Chloroperbenzoic acid (25 wt % water content, 2.77 g, 12.0 mmol) was gradually added dropwise to 6-bromo-3H-imidazo[4,5-b]pyridine (1.58 mg, 7.98 mmol) in ethyl acetate (15 mL), and the reaction mixture was stirred at room temperature for one day. The precipitated solid was collected by filtration and washed with ethyl acetate and diethyl ether and dried under reduced pressure to give the title compound as a pale yellow solid (1.67 g, yield 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:1]3[CH:21]=[CH:25][CH:24]=[CH:23]3)[CH:11]=2)[NH:6][C:7](=[O:15])[C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Yield: 66.6 %

Procedure:
0.9 g (3.5 mmol) of 7-amino-1-ethyl-6-nitro-2,3(1H,4H)-quinoxalinedione and 0.58 g (4.4 mmol) of 2,5-dimethoxytetrahydrofuran in 20 ml of acetic acid were refluxed for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: toluene/acetone/acetic acid=10:10:1) to yield 0.7 g (68%) of the product. Melting point >300° C.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([CH3:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])C1C=CC=CC=1>CC(N(C)C)=O.[Pd]>[OH:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([CH3:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24]
Reactant: Cc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Cc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Yield: 33.9 %

Procedure:
The hydrogenation of 2-benzyloxy-5-methyl-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.3 mmol, from Example P) was performed in the presence of 10% Pd/C (0.1 g) in DMA (20 mL). Purification of crude product by column chromatography (silica gel using 10% methanol in dichloromethane) gave 0.1 g of the title compound, mp 251-253° C.;
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([F:12])[C:7]([Si](C)(C)C)=[C:6]([F:17])[CH:5]=1>CN(C)C=O.CCCCCCC.O>[Cl:3][C:4]1[CH:5]=[C:6]([F:17])[CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11]
Reactant: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: CCCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(F)cc(F)cc1Cl
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
CsF (approximately 0.2 g) was added to a mixture of crude 6-chloro-2,4-difluoro-3-(trimethylsilyl)benzaldehyde (10.5 g, approximately 42 mmol) in dimethylformamide (15 mL)/H2O (2 mL). After stirring for 10 min the reaction was diluted with heptane and H2O. The phases were separated and the aqueous extracted with further heptane. The combined organic layers were washed with H2O, dried over MgSO4 and concentrated in vacuo to a yellow oil. Purification by column chromatography (1:4 EtOAc:heptane) followed by trituration with pentane gave the title compound as a white solid (3.0 g, 17.0 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15](OCC)(=O)[C:16]([NH2:18])=[O:17].C[O-].[Na+]>C(O)CO>[N:1]1[C:2]2=[N:3][C:4]3[C:9]([CH:10]=[C:11]2[C:12](=[O:13])[NH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: CCOC(=O)C(N)=O
Reactant: NC(=O)c1cc2ccccc2nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: OCCO
Product: NC(=O)c1nc2nc3ccccc3cc2c(=O)[nH]1
Temperature: 170 °C

Procedure:
A mixture of 2-aminoquinoline-3-carboxamide (2.0 g., 1.15 millimoles) ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) and sodium methoxide (10 mg.) is heated at 170° C. for 1 hour. The product is precipitated by slow addition of ice cold methanol (50 ml.) to the hot reaction mixture followed by chilling in an ice bath. It is filtered off, washed with cold methanol and dried in vacuo. Yield = 0.768 g. (28%). M.P. 320° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C@H:2]1[CH2:3][O:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1COCCO1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate.