Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](/[CH:13]=[C:19]2/[C:18](=[O:20])[NH:17][C:16](=[O:21])[S:15]/2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)/C(=C/c2ccc(-c3ccccc3Cl)o2)S1

Procedure:
The titled compound was prepared by the condensation of 5-(5-(2-chloro-phenyl)furan-2-aldehyde (1.0 g) with 2,4-thiazolidinedione (0.68 g) using the procedure described in Step B of EXAMPLE 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:27][CH2:26][CH2:25][C:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]([Cu])#[N:29].C(N)CN>CN1C(=O)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:28]#[N:29])=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: N#C[Cu]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(C#N)cc1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (1 g, 2.1 mmol) (Example 1) and CuCN (0.45 g, 5 mmol) in NMP was heated to 180° C. for 6 h. After cooling, the reaction mixture was poured on a mixture of ice and ethylene diamine and extracted twice with DCM. The brown residue was chromatographed over silica gel to yield 4-[(5R*,6S*)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl]benzonitrile as a beige solid. 1H NMR (CDCl3): 7.62 (2H, d, J=8.1 Hz), 7.25-7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J1=12.8 Hz, J2=6.4 Hz), 3.16 (3H, s), 2.4-2.7 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].CCCCCCC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: Cc1ccccc1N=C=O
Reactant: NCc1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1ccccc1NC(=O)NCc1ccccc1F

Procedure:
ortho-Tolylisocyanate (4.95 ml) was added to a solution of 2-fluorobenzylamine (4.56 ml) in toluene (50 ml) under an atmosphere of nitrogen at 5° C. to produce rapid formation of a white solid. Heptane was added, the solid broken up and filtered off to afford 1-(2-fluorobenzyl)-3-(2-methylphenyl)urea (9.5 g) as a white solid. The urea (8 g) and cyanoacetic acid (2.9 g) were ground together and heated in acetic anhydride (15 ml) to 80° C. After cooling the reaction mixture to room temperature, diethyl ether was added and washed with water. The separated ether phase was dried over magnesium sulphate, filtered and evaporated in vacuo to give a crude solid residue (8.9 g). This residue was redissolved in dichloromethane (120 ml), triethylamine (5.7 ml) added and the mixture stirred at room temperature for 3 days. Filtration of the precipitate yielded the desired uracil as a white solid (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[O:18][N:17]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole:
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.CCOC(C)=O.[H][H]>CO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:18]=1
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cc(N)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Yield: 81.9 %

Procedure:
To a stirred solution of ethyl 2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-nitrophenylcarbamate (0.15 g, 0.34 mmol) in 10 mL of MeOH: EtOAc was added Pd/C (10 wt. % on activated carbon, 50 mg), followed by charging with hydrogen under 50 psi for 2 hour. The crude was filtered through celite, concentrated, the residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound ethyl 5-amino-2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenylcarbamate as light yellow solid (114 mg). MS calcd for (C16H17BFN3O6S): 409.1. MS found (ESI negative): (M−H)−=408.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 9.30 (s, 1H), 8.49 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.24 (m, 2H), 7.20 (d, J=10 Hz, 1H), 6.18 (dd, J=8.8, 2 Hz, 1H), 6.09 (bs, 2H), 4.89 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40]([NH2:42])=O)[S:39][C:31]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40](=[S:10])[NH2:42])[S:39][C:31]1=2
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Yield: 38.8 %

Procedure:
To a mixture of Lawesson's reagent (26.3 mg, 0.065 mmol) and the compound of Example 127 (50 mg, 0.13 mmol) was added toluene (10 mL) and the reaction heated at 110° for 1 h. A further portion of Lawesson's reagent (52.6 mg, 0.13 mmol) was added and reaction heated for 6.5 h. The reaction was diluted with DCM, washed with water, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 5–10% EtOAc in DCM) to give the title compound as a yellow solid (10 mg, 20%). δH (MeOH-d4) 7.67 (1H, m), 7.58–7.46 (7H, m), 7.40 (3H, m), 6.48 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.41 minutes, 397 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12].[CH:17]1([NH:22][C:23]2[N:31]=[C:30]([N:32]=[N+:33]=[N-:34])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[C@H:35]2[C@H:39]([OH:40])[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.[Cu]I>[OH:40][C@@H:39]1[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36][CH:35]1[N:27]1[CH:26]=[N:25][C:24]2[C:28]1=[N:29][C:30]([N:32]1[CH:12]=[C:11]([C:10]([O:14][CH2:15][CH3:16])=[O:13])[N:34]=[N:33]1)=[N:31][C:23]=2[NH:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=Nc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.470 g of diisopropylethylamine and ethyl prop-2-ynoate (1.9 mmol) were dissolved in 20 mL of THF. To the solution was added (4S,2R,3R,5R)-2-[6-(cyclopentylamino)-2-(azido)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (1.3 mmol) and 350 mg of CuI. The mixture was stirred at room temperature for 24 hours. The solvent was then removed by evaporation and the residue treated with 5 mL of ethanol and ethyl ether. The yellow solid was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.[CH2:16]1[CH:20]2[CH2:21][NH:22][CH2:23][CH:19]2[CH2:18][N:17]1[C:24]1[N:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[N:25]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([N:22]1[CH2:21][CH:20]2[CH2:16][N:17]([C:24]3[N:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[N:25]=3)[CH2:18][CH:19]2[CH2:23]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(C#N)nc(N2CC3CNCC3C2)n1
Product: Cc1cc(C#N)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 12 and Intermediate 49. MS (ESI): mass calculated for C21H19F2N8O, 418.44; m/z found 419.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.91-7.80 (m, 2H), 7.75 (s, 1H), 7.55-7.42 (m, 1H), 7.15 (ddd, J=8.4, 6.6, 4.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.07-3.46 (m, 7H), 3.35-3.20 (m, 1H), 3.19-2.94 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: O=O.[C:3]1([NH:9][C:10](=S)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH3:19].O>CC([O-])=O.CC([O-])=O.[Cu+2].CO>[C:3]1([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Solvent: CO
Product: N=C(Nc1ccccc1)Nc1ccccc1
Yield: 94.2 %

Procedure:
Air is used as the oxygen-containing gas in the following example. 0.1 mol of diphenylthiourea, 1.2 mol of ammonia, and 0.02 mmol of Cu(OAc)2 are reacted with air (pressure of 5 bar) in a solvent mixture of 40 g of water and 40 g of methanol. Diphenylguanidine is obtained in a 94.2% yield at a reaction temperature of 50° C. and a reaction time of 70 min.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:5])C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:21]([O:20][C:18]([CH:17]1[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[CH2:15][C:7]2[N:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[S:10][C:6]=2[C:4]1=[O:5])=[O:19])[CH3:22]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C(C)(C)C)sc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(=O)c2sc(C(C)(C)C)nc2CN1Cc1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-tert-butyl-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (12.8 g, 26.7 mmol) in 350 mL of anhydrous THF was cooled to 0° C. with an external ice bath and 53 mL of 1 N potassium tert-butoxide was added slowly. The reaction was stirred at 0° C. for 2 h and then allowed to warm to room temperature and stirred for 2 h. The reaction was diluted with ethyl acetate and washed with a solution of 200 mL saturated ammonium chloride and 50 mL 1 N HCl. The organic fraction was washed with brine, dried over anhydrous sodium sulfate and concentrated to 11.5 g of product. MS (ESI+): m/z 433.4 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Yield: 42.8 %

Procedure:
2-Fluoronitrobenzene (4.2 ml, 40 mmol), methyl 3 -hydroxyphenylacetate (5 g, 32.5 mmol) and potassium carbonate (6.9 g, 50 mmol) were heated together in DMF (100 ml) at 100° C. for 36 hrs. After evaporation of the solvent, the residue was partitioned between water (100 ml) and dichloromethane (100 ml), and the aqueous phase further extracted with dichloromethane (2×100 ml). The combined organics were dried and evaporated, and the residue chromatographed on silica, eluting with 25% ethyl acetate/60°-80° petrol to yield methyl 3-(2-nitrophenyloxy)phenylacetate (4 g); δH (CDCl3) 3.62 (2H, s, CH2CO2Me), 3.69 (3H, s, CO2Me), 6.94 (1H, d, J 7.2 Hz, ArH), 7.00-7.04 (2H, m, ArH), 7.09 (1H, d, J 8.3 Hz, ArH), 7.19 (1H, t, J 8.3 Hz, ArH), 7.32 (1H, t, J 7.9 Hz, ArH), 7.50 (1H, t, J 7.2 Hz, ArH), 7.94 (1H, d, J 8.2 Hz, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:4].S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[Cl:22][CH2:17][C:16](=[O:18])[C:8](=[N:7][O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)CON=C(C(C)=O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CON=C(C(=O)O)C(=O)CCl

Procedure:
To a solution of tert-butyl 2-methoxycarbonylmethoxyimino-3-oxobutyrate (syn isomer) (51.9 g) in glacial acetic acid (52 ml) was slowly added sulfuryl chloride (72.2 ml) at 40° C. with stirring. The reaction mixture was stirred at the same temperature for an hour. The resultant solution was concentrated under reduced pressure and the residual oil was dissolved in ethyl acetate (300 ml). The ethyl acetate layer was washed with 10% hydrochloric acid once and washed with a saturated aqueous solution of sodium chloride four times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was diluted with n-hexane (100 ml) and evaporated under reduced pressure. The white crystalline precipitates were washed with diisopropyl ether (100 ml). The precipitates were collected by filtration, dried under reduced pressure to give crystalline 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (13.4 g), mp. 127° to 128.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].Cl[CH2:10]CCl.S(=O)(=O)(O)O>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:10])=[O:7]
Reactant: ClCCCl
Reactant: O=C(O)c1cccs1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccs1
Yield: 90 %

Procedure:
The synthesis was carried out according to the method of Example 7-(1). 2-Thiophenecarboxylic acid (25.0 g), : 1,2-dichloroethane (120 ml), methanol (23.7 ml) and concentrated sulfuric acid (0.8 ml) were used as reagents to give 24.9 g of a pale-yellow transparent liquid (yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Bromo-2-chloro-6-methylphenol (50 g, 0.225 mole) and K2CO3 (31.8 g, 0.23 mole) were combined in acetone (300 ml). Dimethyl sulfate (32 ml, 0.34 mole) was added dropwise and the mixture stirred 22 hours at room temperature, filtered and concentrated to an oil in vacuo. The oil was taken up in 250 ml ether, washed 2×2N NaOH, 1×saturated NaHCO3, 2×brine, dried over MgSO4, reconcentrated to an oil and distilled to yield purified title product, 42.9 g, b.p. 122°-124°0.9 mm, pnmr/CDCl3 /delta/TMS: 2.3 (s, 3H), 3.8 (s, 3H), 7.3 (q, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Yield: 65 %

Procedure:
1-[5-(3,5-Dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.122 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.122 mmol, 25.9 mg) were stirred with dimethylformamide (2 mL) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (34.7 mg, yield 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
28.40 g (0.131 mol) of 3-bromo-5-nitroaniline were dissolved in 250 ml of pyridine and treated with 30 ml (0.317 mol) of acetic anhydride. The mixture was stirred at room temperature for 18 hrs. and subsequently at 40° C. for 2 hrs. Then, the residue was digested in water and the precipitate was filtered off. The filter material was rinsed with a large amount of water and dried at 45° C. in a high vacuum. There were obtained 31.0 g (91.5%) of N-(3-bromo-5-nitrophenyl)-acetamide as orange-yellow crystals. MS (ISP): me/e=260, 258 (C8H8BrN2O3+).
Reaction SMILES: OO.C(O)=[O:4].[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH:12]=[CH:13][CH3:14])[O:8][CH2:7]1.S(=O)(=O)(O)O>O.CC(C)=O>[CH2:7]1[O:6][C:17]2[CH:16]=[CH:15][C:11]([CH2:12][C:13](=[O:4])[CH3:14])=[CH:10][C:9]=2[O:8]1
Reactant: O=CO
Reactant: CC=Cc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Cc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Hydrogen peroxide (70 ml, 30%) was added with caution to a solution of formic acid (350 ml, 88%) in a three-necked flask (1 L) cooled with running water. Isosafrole (72 ml) was added drop-wise, by a dropping funnel, to the reaction mixture at a rate to keep the temperature of the reaction mixture below 35° C. After the complete addition of isosafrole, a non-homogeneous solution was obtained. At this point, acetone (200 ml) was added to the reaction mixture at a rate to keep the temperature below 35° C. The reaction was allowed to stand at room temperature overnight. The solvent was removed by a rotary evaporator equipped with a dry-ice acetone cold trap, a high vacuum pump and a water bath with temperature not exceeding 30° C. Ethyl ether (500 ml) was added to the residue. The solution was transferred into a separatory funnel. The organic phase was washed with sodium bicarbonate (0.1 N, 2×500 ml) and water (3×300 ml). The organic phase was transferred into a round bottom flask. The solvent was removed by rotary evaporation. Concentrated sulfuric acid (75 ml) was diluted drop-wise in water (425 ml). Methanol (160 ml) was added to the oily residue, and mixed to obtain a homogeneous solution. The sulfuric acid solution was added to the methanolic reaction mixture. The flask was equipped with a water-cooled reflux condenser and a heating mantel. The reaction mixture was heated to reflux for 4 hours. The heat was removed and crushed ice (150 g) was added to the reaction mixture. The reaction mixture was transferred into a separatory funnel and extracted with ethyl ether (1×350 ml, 1×150 ml and 1×100 ml). The combined organic layers were washed with water (3×150 ml). Sodium hydroxide (40 ml, 0.1 N) was diluted in water (360 ml). The organic phase was washed with diluted sodium hydroxide (2×200 ml, 10 mM) and saturated sodium chloride solution (100 ml). The organic layer was dried with anhydrous sodium sulfate (20 g) overnight. The drying agent was filtered and the cake was washed with ethyl ether (2×10 ml). The solvent was removed by rotary evaporation. The product was distilled at reduced pressure (2-0.5 mmHg). The second fraction distilling at 90-100° C. (˜1 mmHg) contained product. The product was identified by El/MS with the m/z of 182. Infrared spectrum (cm−1) indicated 1714 (C═O) and 2898 (C—H) stretches corresponding to the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)=[CH:19][C:17]4=3)[CH:12]=[CH:11][C:10]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].[Si](I)(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)=[CH:19][C:17]4=3)[CH:12]=[CH:11][C:10]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc3ncc4ccc(=O)n(-c5ccc(F)c(Cl)c5)c4c3c2)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=c1ccc(-c2ccc3ncc4ccc(=O)n(-c5ccc(F)c(Cl)c5)c4c3c2)c[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To a solution of compound 7.0 1-(3-chloro-4-fluorophenyl)-9-(6-methoxypyridin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one (21 mg, 0.05 mmol, 1 equiv.) in CH2Cl2(2 mL) at room temperature was added TMSI (70 μL, 0.5 mmol, 10 equiv.). The resulting solution was stirred at 50° C. for 48 h before being cooled to room temperature and quenched with Na2CO3 (sat. 2 mL). After separation, the organic phase was dried over Na2SO4 and evaporated under vacuum. The residue was diluted with DMF (2 mL) and purified via preparative LC-MS (CH3CN: H2O) to afford the desired product 7.1 1-(3-chloro-4-fluorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one (3 mg). LC-MS (M+H): 417.07
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:25]C(=O)OC(C)(C)C)[CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([OH:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]2[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH2:13][CH3:14])[C:9]([CH3:11])([OH:12])[CH3:10]
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21)C(C)(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cc(F)cc21)C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-6-fluoro-1H-indol-4-ylcarbamate (250 mg, 0.543 mmol) and TFA/DCM (V/V=¼, 10 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in ethyl acetate (20 mL), pH value adjusted to 9˜10 with a saturated sodium bicarbonate solution, dried over sodium sulfate, then filtered. After removing the organic solvent, a crude compound was obtained without purification. LC/MS m/z=361.2 [M+H]+.