Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[CH3:42][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])[CH:38]=[C:37]([CH3:39])[C:36]=1[C:40]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(F)(F)F)nc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 9.09 (d, 1H), 8.57 (dd, 1H), 8.34 (dd, 1H), 8.00 (dd, 1H), 7.87 (d, 1H), 7.76 (dd, 1H), 7.09 (s, 2H), 2.76 (t, 2H), 2.16 (s, 6H), 2.00 (m, 2H), 1.71 (m, 2H). MS (m/z) 533.1 (M+1); Retention time: 1.13 min (Method 10).
Reaction SMILES: I[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23].C(N(CC)CC)C.O>O1CCCC1.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.[Cu](I)I>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[C:27][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8])[CH3:23]
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C#CC(OCC)OCC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O)OCC
Yield: 1079.3 %

Procedure:
A solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (20.0 mg), propargylaldehyde diethyl acetal (62.5 mg), tetrakis(triphenylphosphine)palladium (5.6 mg), copper iodide (1.0 mg) and triethylamine (68 μL) in tetrahydrofuran (1.0 ml) was stirred at room temperature under nitrogen atmosphere for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (216.0 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([CH:14]=O)[C:8]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>COCCOC>[C:1]([O:5][C:6]([C:7]1[C:8]([Br:16])=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:20][N:19]=[CH:14]2)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1Br
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc2[nH]ncc2c1Br
Yield: 100 %

Procedure:
A bi-phasic solution of 2-bromo-4-fluoro-3-formyl-benzoic acid tert-butyl ester (4.25 g, 14 mmol), DME (25 mL) and hydrazine hydrate (15 mL) was heated at 90° C. for 1 hour. After cooling, the products were partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a tan solid (4.1 g, 100%). LCMS (method B) RT=3.63 min, [M+CH3CN+H]+=338/340, [M−H]−=295/297.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@H:20]2[O:77][C@H:76]([CH2:78][O:79][C:80](=[O:82])[CH3:81])[C@@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C@H:53]4[O:70][C@H:69]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[C@@H:64]([O:65][C:66](=[O:68])[CH3:67])[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]4[O:55][C:56](=[O:58])[CH3:57])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[SH:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@H:20]2[O:77][C@H:76]([CH2:78][O:79][C:80](=[O:82])[CH3:81])[C@@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C@H:53]4[O:70][C@H:69]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[C@@H:64]([O:65][C:66](=[O:68])[CH3:67])[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]4[O:55][C:56](=[O:58])[CH3:57])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][S:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92])(=[O:3])[CH3:2]
Reactant: COC(=O)CCS
Reactant: CC(=O)OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O[C@H]4[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]4COC(C)=O)O[C@@H]3COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 79 %

Procedure:
Compound 93 (4.00 g, 3.0 mmol), methyl 3-mercaptopropionate (0.546 g, 0.49 ml, 4.5 mmol) cesium carbonate (1.17 g, 3.6 mmol) and N,N-dimethylformamide (25 ml), were stirred at room temperature until 93 had been consumed (7 h; TLC; SiO2, ethyl acetate:isooctane 4:1). The solvent was removed and the residue was chromatographed (SiO2, ethyl acetate:isooctane 3:1) to give 94 (3.22 g, 78%). [α]D25 +102° (c 1.0, chloroform). 1H-NMR (CDCl3, Me4Si) δ 5.36, 5.28, 5.19 (3d, each 1H, J=3.8, 4.1 and 3.7 Hz, H1', H1", H1"'), 4.57 (d, 1H, J=7.9 Hz, H1), 3.71 (s, 3H, MeO), 2.81, 2.71, 2.61 (3t, each 2H, J=6.7 Hz, CH2 --S--CH2 and CH2 --CO). 13C-NMR (CDCl3, Me4Si) δ 100.2 (Cl), 95.8, 95.6, 95.2 (Cl', Cl", Cl"'), 75.1, 73.7, 72.6, 72.0 71.9, 71.7, 70.7, 70.3, 70.0, 69.8, 69.6, 69.3, 69.2, 68.8, 68.4, 67.3, 65.2, 63.0, 62.9, 61.7, 60.3, 51.7, 34.6, 31.3, 27.2, 20.8-20.5.
Reaction SMILES: CS([O:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH:27]([CH3:34])[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:24][CH:23]=1.Cl>C(C(C)=O)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[O:5][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH:27]([CH3:34])[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Reactant: CCCOC(=O)C(C)Oc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOC(=O)C(C)Oc1ccc(OC2Cc3ccccc3C2)cc1
Reaction time: 8 h
Yield: 12.2 %

Procedure:
2-Methylsulphonyloxyindane (15.9 g) in methyl ethyl ketone (80 ml) was treated with potassium carbonate (15.53 g). The mixture was stirred and then n-propyl 2-(4-hydroxyphenoxy)propionate (16.8 g) in methyl ethyl ketone (20 ml) was added dropwise. The mixture was stirred at 90°-100° for 2.5 hours and was then poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed thoroughly with water, dried and concentrated to an oil which semi-solidified on standing overnight. The oil was triturated with diethyl ether and petroleum ether. The mixture was filtered, and the filtrate concentrated to give an oil which was subjected to preparative thin layer chromatography on silica gel, eluting with chloroform/acetone/acetic acid (90:10:5), to give, as an oil, n-propyl 2-[4-(indan-2-yl-oxy)phenoxy]propionate (3.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 20 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoro-ethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (22 mg, 20%) which was obtained as an off white solid. MS: m/e=412.4 [M+H]+.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:18]([N:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=[O:19])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)C.CC(OC(=O)N[C@@H](C(N1CCC2(C3C(=CC=CC=3)CC2)CC1)=O)COCC1C=CC=CC=1)(C)C>>[NH2:7][CH:8]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]([N:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=[O:19]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccccc1)C(=O)N1CCC2(CCc3ccccc32)CC1
Agent: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CCc3ccccc32)CC1
Product: NC(CCOc1ccccc1)C(=O)N1CCC2(CCc3ccccc32)CC1

Procedure:
Substituting the compound from Step B above for the compound from Example 63, Step A in Step B, Example 78, the title compound was obtained. Calc. for C23H28N2O2 :MW=364.5; found m/e 32 (m+1) 365.2.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8]([OH:10])=O)[CH:7]=1.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]3[N:4]([CH:20]=[N:21][CH:22]=3)[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:10])[CH2:26][O:25]1
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (235 mg, 0.57 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (92 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and DIPEA (0.1 mL, 0.62 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 72 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (298 mg, 97%). LCMS (Method B): RT=3.34 min, [M+H]+=545.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[O:14]=[C:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)CC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CC
Reaction time: 0.17 h
Yield: 13.3 %

Procedure:
Jones Reagent (2.67 M, 7.51 mL, 20.05 mmol) was added dropwise to ethyl 2-hydroxybutanoate (2.65 g, 20.05 mmol) in acetone (67 mL) at 0° C., then the reaction mixture was stirred for 10 minutes. Any excess Jones reagent was quenched by the addition of iso-propanol, then the reaction mixture was neutralized with saturated sodium bicarbonate, and the acetone was removed by evaporation. Water was added and the solution was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 diethyl ether:hexanes to give 346.7 mg (13%) of ethyl 2-oxobutanoate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 4.19 (q, J=7 Hz, 2H), 2.80 (q, J=7 Hz, 2H), 1.24 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: COc1ccccc1[C@H](C)N
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1ccccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]1[C:8]=2[CH:9]=[N:10][NH:11]1)=[O:4]>[OH-].[Na+].CO>[CH3:17][N:6]1[C:7]2[C:15](=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)[CH:16]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2ccc3[nH]ncc3c2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)cc2ccc3[nH]ncc3c21
Yield: 97 %

Procedure:
1-Methyl-1,6-dihydro-1,6,7-triaza-as-indacene-2-carboxylic acid methyl ester D1 (0.67 mmol) was dissolved in 2N sodium hydroxide in MeOH and refluxed for 2.5 h. After solvent removal the slurry was treated with excess 2N hydrochloric acid under vigorous stirring. The precipitate was filtered, washed with water and dried. Obtained the title compound (97%). ESI (+) MS: m/z 216 (MH+); MS (ES−) 214. 1H NMR: 4.35 (s, 3H), 7.30 (d, J=9.75, 1H), 7.34 (s, 1H), 7.58 (d, J=8.90, 1H), 8.49 (s, 1H), 12.61 (bs, 1H), 13.36 (bs, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[O:3].[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21]2)[NH:18][CH:19]=1)[CH3:14]>C1COCC1>[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]2[C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[O:3])[NH:18][CH:19]=1)[CH3:14]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCc1c[nH]c(C2Cc3ccccc3N2)n1
Solvent: C1CCOC1
Product: CCc1c[nH]c(C2Cc3ccccc3N2C(=O)Nc2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1-Isocyanato-2-nitro-benzene (0.002 mol) was added to a solution of intermediate (15) (0.016 mol) in THF (10 ml). The mixture was stirred at room temperature under argon for 5 hours. The mixture was diluted with hexanes, filtered, and allowed to dry, yielding 0.34 g of 2-(4-ethyl-1H-imidazol-2-yl)-2,3-dihydro-N-(2-nitrophenyl)-1H-indole-1-carboxamide (compound 77, mp. 208-209° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:2]1.[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]>N1C=CC=CC=1>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:8]3[CH2:9][CH2:10][NH:11][CH:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH2:7]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: c1cc(C2CNCCN2)co1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccoc4)C3)cc21
Yield: 32 %

Procedure:
A mixture of 592 mg of 3-(3-furanyl)piperazine, 329 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 8 ml of pyridine was heated in a pressure bottle at 95°-100° C. for 18 hours and then purified as described in Example 65, giving 160 mg of the desired product, mp 202°-204° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH2:10].O([C:18]1[C:19]2[C:24]([N:25]=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)=[CH:23][CH:22]=[CH:21][CH:20]=2)C1C=CC=CC=1>>[CH:20]1[C:19]2[C:24](=[N:25][C:26]3[C:31]([CH:18]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1.[CH:20]1[C:19]2[C:24](=[N:25][C:26]3[C:31]([CH:18]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1.[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Agent: NCCCCNCCCN
Product: c1ccc2nc3ccccc3cc2c1
Yield: 30 %

Procedure:
The scheme for directing nucleic acids to certain sites of the body is based upon the intercalation of a ligand which interacts with a cell surface component into the double stranded DNA. A procedure for selective N4 -acylation of spermidine, using N1,N8 -bis(t-butoxycarbonyl) spermidine as starting material, has been reported. R. J. Bergeron et al., Synthesis (1982) 689-692. We have used this procedure (FIG. 8) to link the acid functionalized galactosyl derivatives 9 (n=1) and 9' (n=4) to the secondary amino group of N1,N8 -tBOC-protected spermidine (15) and the resulting galactosylated spermidines 17 and 17' were, after deprotection, further alkylated with 9-phenoxyacridine by a standard chemical procedure to transform them into bis-intercalator compounds 21 and 21'. The synthesis of the carboxylic acid functionalized galactosyl derivatives is detailed (J. Haensler et al., Biochim Biophys Acta (1988) 946:95-105) and is easily applicable to a wide range of carbohydrate ligands (M. M. Ponpipom et al., J Med Chem (1981) 24:1388-1395). The title compounds were obtained in an overall yield of 30% and the NMR and mass spectrometry data are consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)CCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46a (4.00 g, 22.0 mmol) and CH2Cl2 (80 mL). To the resultant solution was added iPr2NEt (7.10 g, 55.0 mmol) followed by acid chloride 74 (4.27 g, 25.3 mmol) in CH2Cl2 (40 mL) over 15 min. The mixture stirred at rt overnight. Another 0.75 g of acid chloride 74 was added, and the mixture stirred 2 hr to completion as monitored by HPLC. The solution was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (125 mL) and brine (100 mL). The solution was filtered through phase separation paper and concentrated in vacuo to an oil/solid mix. The solid was collected with hexanes:EtOAc 4:1 (30 mL) and rinsed with hexanes:EtOAc 4:1 (2×10 mL). The material was dried to give 4.85 g of 75 as an orange solid (70%). 1H NMR (60 MHz, CDCl3): δ 9.8 (bs, 1H), 8.8 (d, 1H), 7.9 (d, 1H), 7.6 (s, 5H), 7.4 (d, 1H), 4.2 (qt, 2H), 3.1 (m, 4H), 1.5 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 98% with a retention time of 6.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:27][C@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:18]1[NH:17][C:12]1[C:11]([CH2:28][CH3:29])=[N:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (214 mg, 0.5 mmol) and pyridine (44 μL, 0.55 mmol) in dichloromethane (5 mL) was purged with nitrogen and cooled to 0° C. The light yellow homogenous solution was treated with acetyl chloride (34 μL, 0.48 mmol) with no visible change. The reaction mixture was gradually warmed to RT. After 16 hrs, the volatiles were removed under reduced pressure and the resulting residue was absorbed on 4 g silica gel and purified by Biotage MPLC (40 g column, 15% ethyl acetate/heptane) to afford the title compound as an off-white solid. IR (diffuse reflectance) 2971, 2934, 1743, 1568, 1550, 1498, 1467, 1393, 1372, 1238, 1207, 1177, 1101, 1036, 751 cm−1; OAMS supporting ions at: ESI+ 470.1; MS (EI) m/z 469 (M+); HRMS (FAB) calcd for C25H25CL2N3O2+H1 470.1402, found 470.1404. [α]25D=73 (c 0.60, methylene chloride); Anal. Calcd for C25H25Cl2N3O2: C, 63.83; H, 5.36; N, 8.93. Found: C, 63.45; H, 5.40; N, 8.79.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([N:16](CC)CC)C.ClC(OCCC)=O.N>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([NH2:16])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCC2(CC1)OCCO2
Reactant: CCN(CC)CC
Agent: CCCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (823 mg, 4.42 mmol) in tetrahydrofuran (22 mL), triethylamine (5.87 mL, 42.1 mmol) and n-propyl chloroformate were added at 0° C., and the obtained solution was stirred at the same temperature for 1 hour. After adding dropwise, the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, 28% aqueous ammonia (1.5 mL) was added, and the obtained solution was stirred at room temperature for 1 hour. The organic layer was separated from the reaction solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (694 mg, 3.75 mmol, 85%) as a colorless amorphous product.