Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[SH:12])([O-:3])=[O:2].[CH3:13][O:14][C:15](=[O:23])[CH:16]=[CH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19](=[O:20])[CH2:18][CH:17]([S:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:16][C:15]([O:14][CH3:13])=[O:23]
Reactant: COc1ccc([N+](=O)[O-])c(S)c1
Reactant: COC(=O)C=CCC(=O)OC
Product: COC(=O)CC(CC(=O)OC)Sc1cc(OC)ccc1[N+](=O)[O-]

Procedure:
The starting material can be obtained by reaction of 2-nitro-5-methoxyphenol with N,N-dimethyl-thiocarbamoyl chloride in DMF in the presence of NaH to give 1-dimethylamino-thiocarbonyloxy-2-nitro-5-methoxyphenol (m.p. 125°), rearrangement, by heating for half an hour at 210°, to give 1-dimethylaminocarbonylmercapto-2-nitro-5-methoxyphenol (m.p. 101°), saponification with aqueous-ethanolic sodium hydroxide solution at 20° to give 2-nitro-5-methoxy-thiophenol (m.p. 87°), addition reaction with glutaconic acid dimethyl ester to give 3-(2-nitro-5-methoxy-phenylmercapto)-glutaric acid dimethyl ester (m.p. 91°), saponification to give the free acid (m.p. 165°-166°), cyclization to give 5-methoxy-8-nitro-thiochroman-4-one-2-acetic acid (m.p. 182°-183°), conversion into the amide (m.p. 228°-230°), and the nitrile (m.p. 164°-165°), ether cleavage to yield 5-hydroxy-8-nitro-thiochroman-4-on-2-acetonitrile (m.p. 187°-188°), hydrogenation on 5% Pd-C in methanol at 20° and normal pressure to give 5-hydroxy-8-amino-thiochroman- 4-one-2-acetonitrile (hydrochloride, m.p. 240° with decomposition), acetylation with ketene in dichloromethane/methanol to give 5-hydroxy-8-acetamidothiochroman-4-one-2-acetonitrile (m.p. 142°), reaction to give the aldehyde (m.p. 142°-144°) and condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(5-hydroxy-8-acetamidothiochroman-4-on-2-yl)-ethylidene]-2-thiazolin-5-one (m.p. 222°-224°), condensation with acetonedicarboxylic acid monomethyl ester-monoamide to give a mixture of stereoisomeric 4-thiobenzamido-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12-trihydroxy-7-acetamido-1,11-dioxo-6-thianaphthacene-2-carboxamides (m.p. 238°-240° with decomposition), epimerization with pyridine at 40° to give a mixture (m.p. 228°-230° with decomposition) of 4-de-dimethylamino-4-thiobenzamido-7-acetamido-12a-de- hydroxy-6-thiatetracycline and its 5a-epimer, hydroxylation of the mixture and separation of the isomers via the imino ethers.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)(C)C.O>[OH:18][N:17]=[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH2:4]1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1=C([N+](=O)[O-])CC(=NO)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of methyl 4-formyl-2-nitrobenzoate (2.0 g, 9.4 mmol) in isopropanol (50 ml) and water (25 ml) was treated with hydroxylamine hydrochloride (0.7 g) and sodium acetate (0.72 g) and stirred for 2 hours at room temperature. The solvent was then evaporated and the residue was treated with water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 4-hydroxylimino-2-nitrobenzoate (1.8 g). 1H-NMR (400 MHz, CDCl3): 11.90 (1H, s), 8.20 (1H, d), 8.00 (1H, d), 7.89 (1H, d), 3.85 (3H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8]/[C:9](/[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[N:10]\[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>ClCCl>[CH3:44][S:41]([NH:1][C:2]1[N:7]=[C:6]([NH:8]/[C:9](/[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])=[N:10]\[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1)(=[O:43])=[O:42]
Reactant: Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
(Z)-N-(((6-Aminopyridin-2-yl)amino)((2-(trifluoromethyl)benzyl)amino) methylene)-4-(trifluoromethyl)benzamide (200 mg, 0.42 mmol) was dissolved in dichloromethane (3.8 mL) and pyridine (0.4 mL) was added followed by mesyl chloride (32 μL, 0.42 mmol). The reaction was stirred at room temperature for 3 days, and another equivalent of mesyl chloride (32 μL, 0.42 mmol) was added, and stirring continued for another 24 h. The crude material then was concentrated, and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine, then dried over sodium sulfate, and concentrated in vacuo to provide the crude product. The crude product was purified by chromatography (gradient: 8:2 hexanes:EtOAc to 2:8 hexanes:EtOAc) to provide the title compound (95 mg, 41% yield).
Reaction SMILES: I.[F:2][CH:3]([F:22])[C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](SC)=[NH:17])=[CH:11][C:10]=2[O:20][CH3:21])[CH:8]=1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:29](O)=O.[NH2:39][NH2:40]>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([C:29]1[NH:40][N:39]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:7]3[CH:8]=[C:4]([CH:3]([F:22])[F:2])[N:5]=[CH:6]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:17]=1)[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C(F)F)c1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)ccc1-n1cnc(C(F)F)c1
Yield: 101.6 %

Procedure:
Methyl 4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate hydroiodide (500 mg, 1.601 mmol, from preparation N) and 6-chloro-2-(4-fluorophenyl)hexanoic acid (392 mg, 1.601 mmol, from preparation AH) were coupled and then reacted with hydrazine (0.201 mL, 6.40 mmol) using a procedure analogous to Step A of Example 13 to afford 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (821 mg, 100% yield). LC-MS (M+H)+ 505.3. The crude products were used in the subsequent step without purification.
Reaction SMILES: COC([C:5]1[CH:6]=[N:7][N:8]([CH3:14])[C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])=O.[O-:15][C:16]#N.[Na+].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([CH3:28])[N:21]=1>C(#N)C.N1C=CC=CC=1>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([CH3:28])[N:21]=[C:20]([NH:19][C:16]([NH:13][S:10]([C:9]2[N:8]([CH3:14])[N:7]=[CH:6][CH:5]=2)(=[O:11])=[O:12])=[O:15])[N:25]=1
Reactant: COC(=O)c1cnn(C)c1S(N)(=O)=O
Reactant: COc1cc(C)nc(N)n1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccnn2C)n1
Temperature: 40 °C
Yield: 108.3 %

Procedure:
23.8 g of 4-methoxycarbonyl-1-methylpyrazole-5-sulfonamide was dissolved in 100 g of acetonitrile and 8.0 g of sodium cyanate and 13.9 g of 2-amino-4-methoxy-6-methylpyrimidine were added thereto with stirring. The reaction mixture was maintained at 40° C. for about 10 minutes. To this mixture was added dropwise 0.3 g of pyridine over 5 minutes. The whole mixture was vigorously and continuously stirred for 2 hours while maintaining the temperature of 40° to 45° C. to complete the reaction. The mixture was then treated according to the same procedure as Example 7 to obtain 35.3 g (Yield 92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]2)[CH:25]=1)[C:20](O)=[O: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>CN(C)C=O.C(OCC)(=O)C>[C:14]([CH2:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]3)[CH:25]=[C:17]([F:16])[CH:18]=2)=[CH:3][CH:4]=1)#[N:15]
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Reactant: N#CCOc1ccc(N)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC#N)c4ccccc34)c2)CC1
Yield: 13.4 %

Procedure:
(4-Aminonaphthalen-1-yloxy)-acetonitrile (1.068 g, 5.4 mmol), 3-fluoro-5-(4-methylpiperidin-1-yl)-benzoic acid (1.27 g, 5.4 mmol), diisopropylethylamine (3 ml) and HBTU (2.45 g, 6.5 mmol) are stirred at room temperature in anhydrous dimethylformamide (20 ml) for 1 day. The mixture is then poured into ethyl acetate (200 ml) and washed with water (2×200 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 25-30% ethyl acetate in hexanes to give a pale purple solid. This is then recrystallized from ethyl acetate/methanol to give N-(4-cyanomethoxynaphthalen-1-yl)-3-fluoro-5-(4-methylpiperidin-1-yl)-benzamide as a pale purple solid (303 mg). 1H NMR 300 MHz (CDCl3) 8.27 (d, 1H, J=7.5 Hz), 7.94 (s, 1H), 7.86 (t, 2H, J=9.6 Hz), 7.6 (m, 2H), 7.3 (s, 1H), 6.97 (m, 2H), 6.77 (d, 1H, J=11.4 Hz), 5.0 (s, 1H), 3.77 (m, 2H), 2.83 (m, 2H), 1.75 (m, 2H), 1.25-1.4 (m, 3H), 1.0 (d, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C(OC(=O)C)(=O)C.I.[PH2](O)=O.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]>O>[CH3:21][C:22]1[NH:23][C:24]([CH:1]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(=O)c1ccccc1
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C(C)c2ccccc2)c1C
Reaction time: 48 h

Procedure:
A solution of 0.6 ml of acetophenone of 5 ml of acetic anhydride was slowly added to a stirred mixture of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid containing 548 mg of 2,4-dimethyl-3-acetyl pyrrole. The mixture was allowed to stand for two days at room temperature then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless rhombic plates (75%), mp. 146°-148.5° C. Anal. Calc. For C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.47: H, 7.78; N, 5.79.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccc(F)c(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3,4-difluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 26 ml DMF were added 1.172 ml benzyl bromoacetate and 4.607 g cesium carbonate. After stirring at RT for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1Br)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(COC(C)=O)c1
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: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 3-[(acetyloxy)methyl]-4-bromobenzoate (4.7 g; 16.4 mmol; 1 eq.), o-tolylboronic acid (2.45 g; 18 mmol; 1.1 eq.), potassium carbonate (11.3 g; 82 mmol; 5 eq.) and Pd(PPh3)4 (1.89 g; 1.64 mmol; 0.1 eq.) in toluene (23.5 mL) and water (23.5 mL) was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® which was further washed with toluene (50 mL). The filtrate was concentrated in vacuo, the residue taken up in ethyl acetate (250 mL) and washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (4.9 g, 100%) as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:24][C:8]2[N:9]=[C:10]([NH2:23])[N:11]=[C:12]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:7]=2[CH:6]=1)=O.[NH3:25]>>[NH2:23][C:10]1[N:11]=[C:12]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[C:7]2[CH:6]=[C:5]([C:3]([NH2:25])=[O:2])[S:24][C:8]=2[N:9]=1
Reactant: N
Reactant: COC(=O)c1cc2c(Nc3ccc4[nH]ncc4c3)nc(N)nc2s1
Product: NC(=O)c1cc2c(Nc3ccc4[nH]ncc4c3)nc(N)nc2s1
Temperature: 60 °C
Yield: 31 %

Procedure:
A mixture of 2-amino-4-(1H-indazol-5-ylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (Example #N.7.1, 0.050 g, 0.15 mmol) and ammonia (ca. 7N in methanol, 1.0 mL) was heated at about 60° C. in a sealed vessel for about 1.5 hours. The mixture was allowed to cool to ambient temperature and additional ammonia (ca. 7N in methanol, 5.0 mL) was added. The reaction mixture was then heated at about 75° C. for about 18 hours, cooled to ambient temperature, additional ammonia (ca. 7N in methanol, 2.0 mL) was added, and heating at about 75° C. was continued for about another 3 days. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min, 5-100% CH3CN/50 mM aqueous ammonium acetate over 30 min, hold at 100% CH3CN for 5 minutes, 21 mL/min) to give 2-amino-4-(1H-indazol-5-ylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (0.015 g, 31%) as a beige solid; RP-HPLC (Table 1, Method a) Rt 0.68 min, m/z (ESI+) 325.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(I)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(I)cc2c1O

Procedure:
Analogously to Example D-43 d), 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester was allowed to react with 5 ml of POCl3 to afford 0.057 g of a pale white solid: Proton NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), 7.97 (m, 1H), 4.5 (t, J=7Hz, 2H), 2.0-1.8 (m, 2H), (t, J=7Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[N:14][C:13]3[C:12](=O)[N:11]=[CH:10][NH:9][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:12]1[C:13]2[N:14]=[CH:15][C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:7][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2cc(OCC3CC3)cnc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(OCC3CC3)cnc12
Temperature: 130 °C

Procedure:
To a mixture of 7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg, 0.230 mmol) in Toluene (1.6 ml) were added diisopropylethylamine (122 μl, 0.702 mmol) and phosphorus oxychloride (65.3 μl, 0.714 mmol). The resulting reaction mixture was refluxed at 130° C. for 15 min. It was concentrated and the residue was dissolved in DCM and neutralized with sat. NaHCO3 until PH=6-7. The mixture was passed through silica plug. The filtrate was diluted with water and extracted with DCM for three times. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a dark brown solid. It was used for next step directly. MS m/z=236.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[C:5]([OH:7])=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:19][C:18]=1[NH:17][C:5](=[O:7])[C:4]1[C:8]([CH3:16])=[C:9]([O:14][CH3:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c(C)c(OC)c(C(=O)O)c1C
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Product: COC(=O)Cc1ccc(O)c(NC(=O)c2c(C)c(OC)c(C)c(C)c2OC)c1

Procedure:
2,5-Dimethoxy-3,4,6-trimethylbenzoic acid (m.p. 98°-100° C.) was reacted with methyl 3-amino-4-hydroxyphenylacetate to give methyl 4-hydroxy-3-(2,5-dimethoxy-3,4,6-trimethylbenzoylamino)phenylacetate [m.p. 159°-160° C., δ 2.14 (3H), 2.20 (3H), 2.32 (3H), 3.48 (2H), 3.65 (6H), 3.70 (3H), 7.02 (3H), 8.30 (1H), 8.87 (1H)] (11.0 g, 28.4 mmol), which was dehydrated with phosphorus oxychloride (13.1 g) to give methyl 2-[6-(2,5-dimethoxy-3,4,6-trimethylphenyl)benzoxazol-6-yl]acetate m.p. 68°-69° C., δ 2.22 (3H), 2.27 (3H), 3.58 (3H), 3.70 (3H), 3.72 (3H), 3.76 (2H), 7.32 (1H), 7.55 (1H), 7.76 (1H)] .
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:30]([Cl:33])(=[O:32])=[O:31])[CH2:29][CH2:28]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:33].[NH2:16][C@H:15]([C:24](=[O:26])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:14][CH2:13][CH2:12][NH:11][S:30]([CH:27]1[CH2:29][CH2:28]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cl
Product: N[C@@H](CCCNS(=O)(=O)C1CC1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclopropanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CCCNCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
A suspension of 5-nitro-isophthalic acid monomethyl ester (D77) (1.0 g, 4.44 mmol, 1 equiv) in CH2Cl2 (40 ml) was treated with (COCl)2 (655 mg, 5.2 mmol, 1.2 equiv) followed by a few drops of DMF. The resulting mixture was stirred for 1 h at room temperature and then dipropylamine (1.65 g, 15 mmol, 3.4 equiv) was added and the resulting solution stirred for a further 30 min. The solution was then washed with 2N aqueous HCl solution (50 ml), saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo to give 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (D87) (1.5 g, 110%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[CH:14][NH:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[K+]>CO>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]=[C:26]([C:13]2[C:10]3[CH:11]=[N:12][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:8][C:9]=3[NH:15][CH:14]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1cc2cnc(N3CCOCC3)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(N4CCOCC4)ncc23)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine (197 mg, 0.97 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (387 mg, 1.94 mmol) and potassium hydroxide (218 mg, 3.88 mmol) were added in MeOH (10 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (50 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×20 mL). The organic extracts was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to obtain 337 mg (91%) of the desired product. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.50. MS (electrospray): exact mass calculated for C21H28N4O3, 384.22; m/z found, 749.3 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.24 (br s, 1H), 8.77 (s, 1H), 6.95 (d, J=2.15 Hz, 1H), 6.45 (s, 1H), 6.09 (br s, 1H), 4.09-4.04 (m, 2H), 3.66 (t, J=6.06 Hz, 4H), 3.60 (t, J=5.28 Hz, 2H), 3.25 (t, J=5.09 Hz, 4H), 2.38 (d, J=6.26 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[CH:12]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1>[Br:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=2)[CH:17]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2cc(-c3ccccc3)ccc2c1
Temperature: 78 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Under an argon gas atmosphere, 128.0 g (1.049 mol) of phenylboronic acid, 300.0 g (1.163 mol) of 2.6-dibromonaphthalene, 24.2 g (21.0 mmol) of tetrakis(triphenylphosphine)palladium(0), 4.3 L of dimethoxyethane and 1.60 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture was further added with toluene and water, and then aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by hexane, 108 g of 2-bromo-6-phenyl naphthalene was obtained with an yield of 36%.