Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:36])[C@@H:25]([NH2:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:36])[CH:25]([NH:35][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: COc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Product: COc1ccc(CC(NC(=O)C(CC(C)C)NC(=O)N2CCCCCC2)C(=O)OC(C)(C)C)cc1
Yield: 86.4 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid tert-butyl ester (Bachem, 0.216 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was purified by crystallization from hexane to give the title compound as a white solid (0.33 g, 87%), mp 105-106° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:12][CH:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:13]([CH3:14])[CH3:12])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.3 %

Procedure:
A mixture of 5-fluoro-4-nitrophenol (314 mg, 2.0 mmol), propan-2-ol (120 mg, 2.0 mmol), diphenyl-2-pyridylphosphine (789 mg, 3.0 mmol) and di-tert-butyl azodicarboxylate (691 mg, 3.0 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature under argon for 22 hrs. The mixture was treated with 1M HCl/diethyl ether (15 ml) and stirred at room temperature for 2 hrs, then concentrated under vacuum and the residue dissolved in diethyl ether (10 ml), treated with 5M HCl acid and stirred for 2 hrs. The organic layer was separated, washed with 5M HCl acid (15 ml), then 10% Na2CO3 solution (2×10 ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 5-70% ethyl acetate/60-80 petrol ether to afford the title compound as a yellow oil (276 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])c1ccc([N+](=O)[O-])o1
Yield: 28.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.56 g of 5-nitro-2-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.25 g of the title compound was obtained as yellow plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(O)(=O)C>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]2[NH:13][CH2:12][C:11]3[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=3)[NH:1]2)[CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1cccc(CN)c1N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1NC(c1cccnc1)NC2
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A mixture of methyl 2-amino-3-(aminomethyl)benzoate (5.0 g, 27.7 mmol), nicotinaldehyde (3.0 g, 27.7 mmol) and acetic acid (2.0 mL) in dioxane (50 mL) was stirred in the microwave for 20 minutes. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (10% methanol in CH2Cl2) to give methyl 2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-8-carboxylate (4.0 g, 53% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([N:9]=[C:10]=[S:11])[CH:8]=1)#[N:2].[NH3:18]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([NH:9][C:10]([NH2:18])=[S:11])[CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1
Reactant: N
Solvent: CCO
Product: N#Cc1ccc(N2CCOCC2)c(NC(N)=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 25% aqueous ammonia solution (1 ml) at room temperature for 3 hours gave 1-(5-cyano-2-morpholinophenyl)thiourea (m.p. 193°-194° C.)
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc2ccccc12
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
40% Methanolic Triton B (0.2 mL, 0.26 mM) was added to a solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.22 mM) in 7 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (40 mg, 0.3 mM) was added and the resultant mixture stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed twice with H2O, and once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 81 mg (85%) of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 8.2 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.85-7.0 (m, 11H), 6.65 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 6.2 (s, 2H), 4.95 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3364, 1739, 1630, 1582, 1500, 1455, 1285, 1232, 1153, and 774. MS (FD) m/e 438.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([Br:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]=[O:2])=[CH:10][CH:9]=1
Reactant: COC(Cl)Cl
Reactant: BrCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of dichloromethyl methyl ether (62 ml) in methylene chloride (40 ml) was added titanium tetrachloride (75 ml) over 10 minutes under a nitrogen atmosphere at 4-5° C. Then, a solution of phenethyl bromide (85 ml) in methylene chloride (50 ml) was added thereto over 50 minutes at 5-7° C. and the mixture was stirred for 5 hours while gradually raising the temperature of the mixture to room temperature. Water (200 ml) was added to the reaction mixture over 1 hour and the mixture was extracted with chloroform (200 ml). The chloroform layer was washed with water, a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (167 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=20:1) to give 4-(2-bromoethyl)benzaldehyde (32.3 g) as a yellow solid, melting point 50-52° C.
Reaction SMILES: [CH3:1][NH2:2].CCO.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]=[C:15]=[O:16]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([NH:2][CH3:1])=[O:16]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 65 °C
Yield: 74 %

Procedure:
A cooled (0° C.) solution of methylamine in EtOH (50 mL, 400 mmol, 8.0 M) in anhydrous THF (300 mL) was treated with 2,4-dichlorophenylisocyanate (25.0 g, 133 mmol). The cooling bath was removed and the mixture was warmed to 65° C. for 20 min. The reaction mixture was then cooled to 0° C. The solid was collected on a Buchner funnel, washed with cold ether, and dried under vacuum to afford N-(2,4-dichlorophenyl)-N′-methyl-urea (21.7 g, 74% yield) as a colorless solid: mp 213.5–214.5° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=9.2 Hz, 1H), 8.11 (s, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.32 (dd, J=8.8, 2.6 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H), 2.65 (d, J=4.4 Hz, 3H); LRMS (APCI) m/e 259.9 [(M+H+CH3CN)+, calcd for C10H12N3OCl2, 260.0].
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)[CH3:7]>>[CH2:6]([C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH:11]([Li:5])[C:10]=2[N:9]=1)[CH3:7]
Reactant: CCc1ccc2c(n1)CCCC2
Reactant: [Li]CCCC
Product: [Li]C1CCCc2ccc(CC)nc21

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 10 ml, 0.014 mol), and 2-ethyl-5,6,7,8-tetrahydroquinoline (2.3 g, 0.014 mol) and title compound is prepared and converted in situ to methyl 2-ethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate which was converted to the corresponding 8-thioamide by the procedure described in U.S. Ser. No. 460,265.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCNCC4)c3F)s2)c1
Reactant: COCCOC(=O)Cl
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccn2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-2-yl)piperidin-4-yl)methyl)picolinamide (compound example 47) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 638. Ret. time: 1.42 min. (Condition I); analytical HPLC Ret. time: 5.63 min (Condition H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](O)=[C:9]2[C:26]([CH:28]2[CH2:30][CH2:29]2)=O)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:26]([CH:28]4[CH2:30][CH2:29]4)=[N:33][NH:32][C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(N2C(=O)C(O)=C(C(=O)C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Reactant: NN
Solvent: O
Product: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 5-(4-chlorophenyl)-4-(cyclopropanecarbonyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 117.1) and hydrazine hydrate. The crude product was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2). tR: 0.83 min (LC-MS 2); ESI-MS: 419 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00-0.11 (m, 1H) 0.44-0.65 (m, 1H) 0.65-0.78 (m, 1H) 0.80-0.90 (m, 1H) 1.68-1.88 (m, 1H) 2.42 (s, 3H) 2.61 (s, 3H) 6.44 (s, 1H) 7.16-7.45 (m, 5H) 8.38 (d, J=0.8 Hz, 1H) 13.55 (br. s., 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#N)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12].C[OH:29].O>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CO
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 M solution (1.2 ml, 1.22 mmol) of diisobutylaluminum hydride in toluene was slowly added to a solution (10 ml) of 4-(4-nitrophenyl)benzonitrile (224 mg, 1 mmol) in toluene at room temperature, and they were stirred for 1 hour. After cooling to 0° C., methanol (0.4 ml) and water (0.4 ml) were slowly added to the obtained mixture, and they were stirred. The reaction mixture was dried over sodium sulfate. After the purification by the silica gel column chromatography (ethyl acetate/hexane), 4-(4-nitrophenyl)benzaldehyde was obtained in the form of a yellow solid (yield: 127 mg, 56%).
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13].Cl>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C#N
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifiuoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6-lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric acid (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=O.CN.CO.CC(O)=O.[C:22]([BH3-])#[N:23].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:23][CH3:22]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) was added a solution of 2.0 M methylamine in methanol (150 mL, 300 mmole) and HOAc (4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr, then was cooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole) was added portionwise over 5 min. The reaction was then allowed to warm to RT. After 16 hr, the reaction was concentrated under vacuum and the residue was taken up in Et2O. The solution was washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Flash chromatography on silica gel (95:5 CHCl3/methanol containing 5% NH4OH) gave the title compound (7.34 g, 52%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 1 H), 7.26 (d, J=7.8 Hz, 1 H), 7.20 (t, 1 H), 7.09 (t, 1 H), 3.88 (s, 2 H), 3.76 (s, 3 H), 2.46 (s, 3 H), 2.32 (s, 3 H), 1.36 (br s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[N:3]1.[Xe](F)[F:20]>C(#N)C.C(=O)([O-])O.[Na+]>[F:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]([C@@H:11]1[CH2:13][C@H:12]1[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:7][CH:6]=[CH:5]2
Reactant: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Reactant: F[Xe]F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)c(F)c12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 5.6 %

Procedure:
To a solution of trans-N-{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (400 mg, 1.644 mmol) in acetonitrile (16 mL) was added xenon difluoride (306 mg, 1.808 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 4.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0), HPLC and TLC to give the title compound (24 mg, yield 6%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[OH:13])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1)c1cccc([N+](=O)[O-])c1O
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 1.7 g (9 mmol) of 3-nitrosalicylic acid and 2.7 g (9 mmol) of 4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenylamine in 20 ml of toluene is heated with stirring to 50° C. 0.5 g of phosphorus trichloride is added, and the mixture is heated at the boil under reflux for a further 4 hours. After cooling, the mixture is concentrated and the residue is extracted with dichloromethane. The organic phase is washed repeatedly with water and dried over sodium sulphate. The solvent is distilled off, giving 1.7 g (41% of theory) of N-[4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenyl]-2-hydroxy-3-nitrobenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].IC.[C:26](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[O:15][CH3:26])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 45 °C
Yield: 52.3 %

Procedure:
A mixture of 1-bromo-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.89 g, 5.07 mmol), iodomethane (632 μL, 10.13 mmol), cesium carbonate (3.3 g, 10.13 mmol) and dimethylformamide (15 mL) was stirred at 45° C. for sixteen hours before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (1.03 g): MS: (+) m/z 387.64, 389.75 (M+1, 79Br/81Br).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][N:6]1[CH:7]=[C:8]([CH3:9])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]1[CH3:10]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cn(C)c1C
Reaction time: 1 h

Procedure:
A solution of 3-acetyl-2,4-dimethylpyrrole (2.0 g) in dry DMF (30 ml) was added dropwise, with stirring, to a suspension of sodium hydride (78% dispersion in oil; 565 mg) in dry DMF (15 ml) at 0° under nitrogen and stirring was continued at room temperature for 1 h. Iodomethane (1.14 ml) was added dropwise at 0° and stirring was continued for 1.5 h. The suspension was evaporated, treated with 8% aqueous sodium bicarbonate (80 ml) and extracted with ethyl acetate (2×80 ml). The combined, dried organic extracts were evaporated to give a solid (2.1 g) which was dissolved in dichloromethane (20 ml) and adsorbed onto silica gel (Merck 7734, 6 g). This was applied to an FCC column and elution with System B (1:3) afforded the title compound (1.89 g) as crystals, m.p. 68°-70°.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]=[O:19].[H-].[Na+].[CH3:22][CH:23]([SH:25])[CH3:24]>CN(C)C=O.O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:25][CH:23]([CH3:24])[CH3:22])=[C:3]([CH:18]=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)c(C=O)sc21
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C=O)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrinidine-6-carboxaldehyde (Example 50 step b; 2 g) in dimethylformamide (20 ml) was added sodium hydride (0.3 g of 60% dispersion) followed by the addition of 2-propanethiol (0.6 g). The mixture was stirred for 24 hours at ambient temperature then the reaction was diluted with water (100 ml) and extracted thrice with ethyl acetate (3×100 ml). The organic phase was washed with water (100 ml), then with brine (100 ml) and then dried, filtered and evaporated to leave the subtitle compound as a pale yellow solid (2.24 g).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([C:8]([OH:20])=[O:13])[S:11][C:1](=[O:3])[C:4]=2[CH:17]=1
Reactant: [OH-]
Reactant: COc1ccc(C=C2SC(=S)NC2=O)c(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(=O)O)sc(=O)c2c1

Procedure:
A solution of the benzylidenerhodanine of Example 7 in 18 ml. of 15% NaOH is refluxed for 0.75 hour and poured into dilute HCl, whereupon a yellow solid forms. The solid is collected and recrystallized from ethanol to give 7-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as pale yellow needles, m.p. 291°-292°.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2.C(N(CC)CC)C>ClCCl>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(O)c(N)cnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2cc(OC)ccc2c1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Butyryl chloride (0.63 mL, 6.1 mmol) was added dropwise to a solution containing 3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.26 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL) and N,N-dimethylfonnamide (10 mL). The reaction mixture was maintained at ambient temperature overnight. The N,N-dimethylformamide was removed under vacuum and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 0.86 g of N-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide as a tan solid.