Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)N.C(OCC)(=O)C.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH2:1][CH2:3][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: [H][H]
Reactant: NNCC1(O)c2ccccc2C=Cc2ccccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NCC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 6 g. of 5-hydrazinomethyl-5H-dibenzo[a,d] cyclohepten-5-ol, 160 mg. of platinum dioxide, 60 ml. of ethyl acetate and 60 ml. glacial acetic acid is hydrogenated at room temperature and about atmospheric pressure for 9 hours during which the uptake of hydrogen is about stoichimetric. The resulting mixture is filtered, evaporated in vacuo and the residue treated with 10% sodium bicarbonate solution and then with methylene chloride. The separated aqueous phase is extracted with methylene chloride and the combined organic phases extracted with water and then with saturated sodium chloride solution, followed by drying and evaporation in vacuo. The residue is crystallized from diethyl ether to obtain 5-aminomethyl-5H-dibenzo[a,d] cyclohepten-5-ol, m.p. 117°-120° C.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](OC(C)C)=[O:18])=[CH:9][C:8]=1[Br:23])=O)(C)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[Br:23][C:8]1[CH:9]=[C:10]([CH2:17][OH:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH2:5][OH:4]
Reactant: CC(C)OC(=O)c1cc(Br)c(C(=O)OC(C)C)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cc(Br)c(CO)c2ccccc12
Yield: 91.9 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-naphthalene-1,4-dicarboxylic acid diisopropyl ester (191.5 mg, 0.505 mmol) in dichloromethane (1.9 mL) was added a solution of diisobutylaluminum hydride in toluene (1.04 M, 4.9 mL, 5.096 mmol) at −78° C. The temperature of the resultant mixture was raised over 2 hours to 0° C., and then to the solution was added saturated aqueous ammonium chloride to stop the reaction. The resultant mixture was twice extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:1)), to thereby obtain the titled compound (124 mg, 87%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:27]4[CH:28]=[CH:29][O:25][CH:26]=4)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(-n3cccc3)c2)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccoc1
Product: O=[N+]([O-])c1cc(-c2ccoc2)ccc1Nc1cccc(-n2cccc2)c1
Yield: 86 %

Procedure:
N-(3-(1-Pyrrolyl)phenyl)-4-(3-furanyl)-2-nitroaniline (7k) was prepared analogously from 6k (Example 9) and 3-furanylboronic acid. Yield: 86%. Mp 129-131° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4].[OH-].[Na+]>CO>[N+:14]([C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2)=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 95.1 %

Procedure:
4.4 g (20 mmol) 6-Nitro-1H-indole-2-carboxylic acid methyl ester (190) was dissolved in 80 mL methanol and was treated with 30 mL 1M NaOH overnight at 55 C°. The methanol was evaporated, the remaining aqueous solution was diluted to 100 mL and was acidified to pH 2 using concentrated HCl. The precipitate was filtered off, washed three times with water then dried to give 3.92 g (95%) 191 as yellow powder. The NMR was consistent with the structure. 191 was used without further purification.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2Cl)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 485.03 [M+H]+; tR=3.08 min (System 3).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]3[O:18][CH2:19][C@@H:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=3)=[C:4]2[CH2:3]1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]3[O:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=3)=[C:4]2[CH2:3]1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2ccccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 31.4 %

Procedure:
A solution of 4.34 g (0.0128 mol) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 160 ml of hot benzene was treated with 2.02 g (0.0141 mol) of copperl bromide and 3.75 ml (0.020 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 1 hr., cooled and treated with 100 ml of water. The mixture was filtered, extracted with benzene and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 1.36 g (32%) of methyl 2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-oxazole-4-carboxylate as a white solid. An analytical sample was recrystallized from hot methanol and gave white crystals; m.p. 264-265°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=2)=[N:10]1
Reactant: ClCC1CO1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 5% acetone/CH2Cl2) to afford 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (141 mg, 59%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.38. MS (electrospray) m/z 347.1 (347.1, calculated for C17H13F3N4O, M++H). 1H NMR (400 MHz, CDCl3): 8.51 (dd, J=2.8,1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17]C(=O)C(F)(F)F)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCCN1CC=C(c2ccc(Cl)cc2)CC1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NCCCN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 64.1 %

Procedure:
N-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-2,2,2-trifluoroacetamide (1.77 g, 5.10 mmol) and 20% aqueous KOH (25 mL) in ethanol (50 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the solids were washed with methylene chloride, dried over magnesium sulfate and concentrated to give 3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propylamine (0.82 g, 64%) as a waxy white solid. Mp. 57-58° C.; NMR CDCl3 δ 7.29-7.20 (m, 4H), 6.03 (s, 1H), 3.12 (d, J=3.3 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.51-2.44 (m, 4H), 1.69 (p, J=7.5 Hz, 2H), 1.63 (s, 2H); 13C NMR CDCl3 δ 139.20, 133.96, 132.61, 128.36, 126.15, 122.41, 56.20, 53.36, 50.30, 40.77, 30.73, 28.01; IR(KBr) 2929, 2861, 2805, 2767, 2734, 1493, 1467, 1379, 1320, 1128, 1095, 845, 825, 800; Analysis calculated for C14H19CIN2.0.25H2O: C, 65.87; H, 7.70; N, 10.97. Found: C, 65.69; H, 7.44; N, 10.91.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.Cl>CO.O>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22](/[CH:20]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
A solution of 1-(2-phenylamino-pyridin-3-yl)-ethanone (2.13 g, 10.0 mmol) in methanol (42 mL, 0.24M) was treated with sodium methoxide (25% wt. solution methanol, 4.6 mL, 20.1 mmol) and methyl 4-formylbenzoate (2.04 g, 12.4 mmol). The reaction was stirred at 25° C. over 3 d. At this time, the reaction was diluted with water (100 mL), acidified with a 1N aqueous hydrochloric acid solution, and extracted with a 10% methanol/methylene chloride solution. The combined organics were dried over magnesium sulfate, filtered, rinsed with methylene chloride, and concentrated onto silica gel in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 80 g silica gel column, 20% ethyl acetate/hexanes) afforded 4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (3.43 g, 95%) as an orange solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N+:51]=1[O-].[CH:57]1([CH2:63][C@@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67]C2SC=CN=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([CH2:63][C@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67][C:52]2[CH:53]=[CH:54][N:49]=[C:50]([CH3:55])[N:51]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1cccc[n+]1[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: Cc1nccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)n1

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-aminopyridine N-Oxide (110 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-( 1-oxo-1, 3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 2% methanol/ethyl acetate) 340 mg (55%)of (S)-N-(pyridin-N-oxide-2-yl)-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as an off white foam. The product did not appear to be pure by NMR and so it was further purified by reverse phase HPLC (Rainin Dynamax SD-1instrument) using a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to provide 188 mg of pure (S-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-(1-oxy-pyridin-2-yl)-propionamide: ES-LRMS m/e calcd for C22H25N3O3 (M++H+) 380, found 380.
Reaction SMILES: CCCCCC.C([Li:11])CCC.CC(C)([O-])C.[K+].[F:18][C:19]1[C:20]([F:28])=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=1>C(OCC)C>[F:18][C:19]1[C:24]([Li:11])=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[C:20]=1[F:28]
Reactant: [Li]CCCC
Reactant: Fc1cc(F)c(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C
Yield: 95.9 %

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 15.5 g (29.8 mmol) hexane solution of 15.5 wt. % butyllithium, 3.3 g (29.8 mmol) potassium tertbutoxide and 15 ml diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 5 g (29.8 mmol) pentafluorobenzene and 15 ml diethyl ether charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:11]=1[NH2:12]>>[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:11]=1[NH:12]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: Nc1c(F)cccc1F
Product: COC(=O)/C=C(/C)Nc1c(F)cccc1F

Procedure:
By the same procedure as a reaction of Example 158, using methyl acetoacetate and using 2,6-difluoroaniline instead of 4-chloro-2,6-dimethylaniline, the title compound having the following physical data was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:13][CH:14]([CH3:16])[CH3:15])[C:9]2[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:19][C:8]=2[C:7]=1[O:24]C(=O)C(C)(C)C)=[O:5])[CH3:2].[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:13][CH:14]([CH3:15])[CH3:16])[C:9]2[N:17]=[C:18]([C:20]([CH3:22])([CH3:21])[CH3:23])[S:19][C:8]=2[C:7]=1[OH:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1O
Yield: 65.8 %

Procedure:
A solution of 2-tert-butyl-7-(2,2-dimethyl-propionyloxy)-4-isopropylsulfanylmethyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (150 mg, 0.33 mmol) and sodium ethoxide (215 mg of 21% sodium ethoxide in ethanol) in 0.6 mL of ethanol was heated at 90° C. for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl and brine. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting the desired product from silica gel with a gradient of 0-40% ethyl acetate in hexanes to give 80 mg of a clear oil. MS (ESI+): m/z 368.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][C:20]1[C:28]([SH:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[CH3:19][C:20]1[C:28]([S:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH3:18])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Cc1c(S)cccc1C(=O)O
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2cccc(C(=O)O)c2C)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 3-mercaptobenzoic acid using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.93 (s, 3H) 6.79 (s, 1H) 7.62-7.73 (m, 3H) 7.76-7.88 (m, 3H) 7.94 (d, J=8.18 Hz, 1H) 8.12 (d, J=8.26 Hz, 1H) 10.30 (s, 1H) 13.11 (bs, 1H); ESI-MS: m/z calc'd for C20H15N3O3S 377.08. found 378.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:28])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:24][C:20]1[CH:19]=[C:18]([CH2:17][C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1cccc(Nc2nc(Cl)ncc2Cl)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(CC(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-2-(3-nitrophenyl)acetamide (0.055 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water added. The aqueous phase was extracted with EtOAc. The organics were combined, died over Na2SO4 and concentrated to give the desired product as a yellow powder (30 mg, 58%). LCMS for C18H15Cl2N5O (M+H)+: m/z=388.0, 390.0.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:39](=[O:38])[CH2:40][OH:41])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:11]2=[N:10]1.P(Cl)(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:21][C:13]1[C:12]2=[CH:18][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[C:11]2[CH:16]=[CH:15][N:14]=1
Reactant: [O-][n+]1ccc2nn(-c3c(Cl)cccc3Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Temperature: 80 °C
Yield: 49 %

Procedure:
2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine 5-oxide (1.12 g, 4 mmol) was slowly added to phosphorous oxychloride (8 mL). Tetrabutylammonium chloride (1.11 g, 4 mmol) was then added. The reaction mixture was heated at 80° C. for 5 hours and then cooled to room temperature. The reaction was poured into a mixture of ethyl acetate and sodium hydrogen carbonate (sat. aq.) and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (590 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J=1.0 Hz, 1H), 8.11 (d, J=6.0 Hz, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.82-7.81 (m, 1H), 7.75-7.71 (m, 1H). LCMS (Method D): RT=3.42 min, m/z: 298 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: Nc1ccccc1
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3ccccc3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 55.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added aniline (0.005 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (15 mg, 56%). LC-MS m/z 544 (M+H)+; 1H-NMR (MeOD) δ 2.43 (s, 6H), 2.70 (m, 2H), 3.48 (m, 2H), 4.52 (s, 2H), 7.17 (m, 3H), 7.39 (m, 2H), 7.52 (m, 1H), 7.69 (m, 3H), 7.79 (d, 1H), 8.08 (d, 1H), 8.15 (s, 1H).