Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=3.CN(C(ON1N=[N:33][C:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=C(N)C=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:32]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:33][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[C:7]4[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][N:6]43)=[CH:10][CH:11]=2)=[O:17])[CH:27]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCC3=O
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1ccc2cc3n(c2c1)CCCC3=O
Temperature: 65 °C
Reaction time: 36 h
Yield: 19.5 %

Procedure:
To a solution of 9-oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid (983 mg, 4.29 mmol) in anhydrous DMF (5 mL) was added HATU (4.00 g, 10.5 mmol), DMAP (3.00 g, 25.0 mmol) and pyridine-3-ylamine (1.00 g, 10.6 mmol). The reaction was stirred at 65° C. for 36 h. The reaction was poured into water and the resulting precipitate was filtered, washed with water and triturated with cold MeCN to give the title compound (256 mg, 20%) as an analytically pure as a brown powder; ESI-MS m/z 306 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:26](O)(=[O:29])[CH:27]=[CH2:28].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CO.C(Cl)(Cl)Cl>[O:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:26](=[O:29])[CH:27]=[CH2:28])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:18][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c2c1
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
3,N-(N,N-Dimethylaminopropyl)-1,N-ethylcarbodiimide hydrochloride (EDAC.HCl) (385 mg, 2.0 mmol) was added in one portion to a solution of 6-amino-4-(4-phenoxyanilino)quinazoline (328 mg, 1.0 mmol), acrylic acid (148 mg, 2.04 mmol), and pyridine (165 mg, 2.1 mmol) in THF (10 mL) stirred under nitrogen at 0° C. After 4 hours at 0° C. tlc (10% MeOH/CHCl3) showed considerable SM, so the reaction mixture was stirred at 25° C. for 2 hours. The mixture was recooled to 0° C., and water (2 mL) was added dropwise. This solution was poured onto rapidly stirred ice-water (40 mL), the pH was raised to 7 with saturated Na2CO3 solution, and the very fine ppt was allowed to settle, collected by Buchner filtration, rinsed with water (2×10 mL), and dried in a vacuum oven at 65° C. for 4 hours. The pale yellow solid was refluxed and sonicated in EtOAc (10 mL), filtered, and the filtrate was eluted through a small silica gel plug with EtOAc. The combined washings were stripped rigourously at 25° C. under vacuum to give N-(4-[4-phenoxyanilino]quinazolin-6yl)acrylamide (162 mg, 41%) as a pale yellow glass; mp 185-191° C. Calculated for C23H18N4O2C20H16N4O.0.25 HCl.0.06 C4H8O2 : C, 70.34; H, 4.76; N, 14.12%. Found: C, 70.42; H, 4.80: N, 13.90%. 1H NMR (DMSO-d6): δ10.50 (1 H, sl brs), 9.86 (1 H, sl brs), 8.80 (1 H, d, J=2.0 Hz), 8.50 (1 H, s), 7.89 (1 H, dd, J=2.2, 9.0 Hz), 7.81 (2 H, d, J=8.9 Hz), 7.77 (1 H, d, J=9.0 Hz), 7.39 (2 H, dd, J=7.6, 8.6 Hz), 7.12 (1 H, t, J=7.4 Hz), 7.06 (2 H, d, J=8.8 Hz), 7.02 (2 H, d, J=7.8 Hz), 6.53 (1 H, dd, J=1.01, 17.0 Hz), 6.34 (1 H, dd, J=1.8, 17.0 Hz), 5.84 (1 H, dd, J=1.8 10.1 Hz). Mass spectrum (APCI) 383.1 (100 MH+).
Reaction SMILES: Br.[CH3:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:12]=1.[Li+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([O-])=[O:35])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([N:9]2[CH2:10][CH2:11][C:5]3[S:4][C:3]([CH3:2])=[N:12][C:6]=3[CH2:7][CH2:8]2)=[O:35])=[CH:19][CH:20]=1
Reactant: O=C([O-])Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Reactant: Cc1nc2c(s1)CCNCC2
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)CCN(C(=O)Cc1nc(-c3ccc(F)cc3)cn1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Yield: 44.8 %

Procedure:
38 mg 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrobromide was added to 40 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid lithium salt, 45 mg TBTU, 0.06 mL DIPEA in 0.75 mL DMF. The reaction was stirred over night at RT. Water was added to the reaction and the mixture was stirred 1 h. The precipitate was filltered and dried to give 26 mg desired product. Rt: 4.59 (method E), (M+H)+: 465
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([NH:11]C(OC(C)(C)C)=O)[CH:8]=[CH:7][C:6]=1[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][O:30][C:29]2=[O:38])[CH2:24][CH2:23]1)=[O:21].Cl>CCOC(C)=O>[F:40][C:2]([F:1])([F:39])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][O:30][C:29]2=[O:38])[CH2:24][CH2:23]1)=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(tert-butyloxycarbonylamino)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.23 g, 0.41 mmol) from Step 10 above in EtOAc (75 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. Ether (75 mL) was added and the cold suspension was filtered. The solids were washed with additional ether and dried under reduced pressure for 18 h to give the hydrochloride salt of the title compound as an amorphous white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[NH:7][N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1n[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.1 %

Procedure:
To a suspension of compound 55 (65 mg) in 5 mL of methanol was added catalytic amount of 5% palladium on carbon. The mixture was stirred under a hydrogen atmosphere at room temperature for 4 hrs and filtered through celite. The filtrate was concentrated to afford compound 56 (59 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([Cl:3])=[O:18])[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
20 mL of thionyl chloride was added dropwise to a mixture containing 20.0 g (0.1 mol) of trans-4-pentylcyclohexanecarboxylic acid represented by the following formula (b-i), 0.5 mL of pyridine and 300 mL of toluene in a nitrogen atmosphere, and the mixture was stirred under heating to 80° C. or less for 1 hour. The solvent was distilled off under reduced pressure to provide trans-4-pentylcyclohexanecarboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(F)cc2)sc1C(=O)NCc1ccccc1
Yield: 30 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 30% yield; 1H NMR (CDCl3, 300 MHz) δ 7.99-7.94 (dd, J=5.1, 8.8 Hz, 2H), 7.19-7.16 (m, 7H), 5.96 (s, 1H), 4.59 (d, J=4.6 Hz, 2H), 2.56 (s, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[O:15]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(OCC2CCCNC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCCC(COc4ccccc4)C3)nn12
Yield: 60 %

Procedure:
Obtained in 60% yield by an analogous method to Example 515, starting from 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 3-(phenoxymethyl)piperidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:67][CH3:68])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:47]2[CH:52]=[C:51]([C:53](=[O:66])[NH:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=3)[CH:50]=[CH:49][N:48]=2)[CH:5]=1)[CH3:2].[CH3:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][N:91]1[CH2:96][CH2:95][NH:94][CH2:93][C:92]1=[O:97]>>[CH3:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][N:91]1[CH2:96][CH2:95][N:94]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([S:35]([NH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][CH2:19][C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:67][CH3:68])=[CH:5][C:6]=3[C:47]3[CH:52]=[C:51]([CH:50]=[CH:49][N:48]=3)[C:53]([NH:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=3)=[O:66])=[O:12])(=[O:37])=[O:36])=[CH:39][CH:40]=2)=[O:43])[CH2:93][C:92]1=[O:97]
Reactant: COCCOCCOCCOCCOCCOCCOCCN1CCNCC1=O
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)O)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)N4CCN(CCOCCOCCOCCOCCOCCOCCOC)C(=O)C4)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 4-(N-(15-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-3,6,9,12-tetraoxapentadecyl)sulfamoyl)benzoic acid 272a by following the procedure described in Example 272 using 1-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)piperazin-2-one 135c.5 as the amine component in this coupling. MS (ES, m/z) 1368.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:16][C:11]=3[N:10]=[C:9]2[NH2:24])[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54](O)=[O:55].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][C:11]=3[N:10]=[C:9]2[NH:24][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([C:50]([F:49])([F:60])[F:61])[CH:52]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1nc2cc(CN3CCCCC3)ccc2n1-c1cccc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(CN3CCCCC3)ccc2n1-c1cccc(F)c1)c1cccc(C(F)(F)F)c1
Reaction time: 24 h
Yield: 13 %

Procedure:
N-[1-(3-fluorophenyl)-5-piperidino-1-ylmethyl-1H-benzoimidazol-2-yl]-3-trifluoromethyl-benzamide: 500 mg 1-(3-fluorophenyl)-5-piperidin-1-ylmethyl-1H-benzoimidazol-2-ylamine (1.54 mmol, 1.0 equiv) was combined in a flask with 877 mg O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 2.32 mmol, 1.5 equiv), 440 mg 3-trifluoromethylbenzoic acid (2.32 mmol, 1.5 equiv) and 312 mg 1-hydroxybenzotriazole hydrate (HOBT, 2.32 mmol, 1.5 equiv) followed by the addition of 12 mL DMF and 254 μL N-methylmorpholine (NMM, 2.32 mmol, 1.5 equiv). The solution was allowed to stir for 24 h and then diluted with sat. Na2HCO3. The solution was extracted (2×10% MeOH/CH2Cl2), washed (1×brine), dried (NaSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 5% MeOH/CH2Cl2) gave 0.2 g of the product as a tan solid (0.2 mmol). 1H NMR (DMSO-d6, 400 MHz) 13.0 (s, 1H), 8.35 (s, 1H), 8.30 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.72 (m, 3H), 7.62 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.22 (broad s, 2H), 3.55 (s, 2H), 2.38 (broad s, 4H), 1.5 (m, 6H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=O.O1C2C(=CC=CC=2)C=CC1C(O)=O.C(N1CCNCC1)C1C=CC=CC=1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH2:11][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:18]1
Reactant: O=C(C1C=Cc2ccccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1C=Cc2ccccc2O1
Agent: c1ccc(CN2CCNCC2)cc1
Product: C1=CC(CN2CCN(Cc3ccccc3)CC2)Oc2ccccc21

Procedure:
By carrying out the preparation as in Example 1, but using, at the start, 1-[(chrom-3-en-2-yl)carbonyl]-4-benzylpiperazine resulting from the condensation of chrom-3-ene-2-carboxylic acid with N-benzylpiperazine, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15]OS(C)(=O)=O)([CH3:14])[NH:10][C:9]2=[O:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH2:15][C:11]1([CH3:14])[NH:10][C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)[C:12]1=[O:13])=[N+:27]=[N-:28]
Reactant: CC1(COS(C)(=O)=O)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CN=[N+]=[N-])NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Yield: 65.2 %

Procedure:
Methanesulfonic acid 1-(4-chloro-3-trifluoromethyl-phenyl)-4-methyl-2,5-dioxo-imidazolidin-4-ylmethyl ester (1.0 g, 2.5 mmoL) from Example 11, NaN3 (1.6 g, 25 mmoL) and KI (40 mg, 0.25 mmoL) in DMF (8 mL) was heated at 100° C. for 10 hrs. The crude product was partitioned between ether and water. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated, then purified by silica gel column chromatography using heptane and ethyl acetate as eluent to afford the title compound as a colorless oil (566 mg, yield 65%).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:28]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCBr
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNOCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 11.55 g of benzyloxyamine hydrochloride, 31.0 g of sodium carbonate and 34.8 ml of dodecylbromide in 100 ml of dimethylformamide is heated at 70° C. for 24 hours, and a further 24 hours at 80° C. The solvent is removed under reduced pressure and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, brine, dried (MgSO4) and evaporated to give an oily residue. Liquid chromatography affords the title compound as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: CC(C)N
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The above compound was prepared from the product of step (ii) (0.6 g), carbonyldiimidazole (0.59 g) and isopropylamine (0.51 ml) using the method of example 115 step (i). Yield 0.68 g.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11](=O)[C:10]2=O)[CH3:3].[NH2:22][N:23]1[C:27]([NH2:28])=[N:26][N:25]=[C:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>C(O)CO.O>[ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11]1[C:10]2=[N:22][N:23]2[C:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[N:25][N:26]=[C:27]2[N:28]=1)[CH3:3]
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: CCN(CC)CCc1cc(C)c2c(c1C)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Solvent: OCCO
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(O)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.60 mmol of 5-(2-Diethylamino-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), stirred for 10 min. Allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitated product was collected by filtration, washed with water (3×1 mL) and dried on high vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[S:33])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCCC2=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2CCCCC2=S)CC1

Procedure:
2-Oxo-[1,4′]bipiperidinyl-1′-carboxylic acid benzyl ester (3.1 g) in tetrahydrofuran (10 mL) was added to a suspension of Lawesson's Reagent (1.98 g) in tetrahydrofuran (40 mL). After 20 minutes the reaction was concentrated and the resulting gum was subjected to chromatography with methylene chloride: ether (gradient 10:1, 5:1) as eluent. The title compound was obtained as a white foam (2.9 g). Rf=0.42 in methylene chloride:ether (10:1). MS: m/z=333 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:13])[C:3]=1[NH:14][N:15]=[C:16](Cl)[C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:22]([N:24]([CH2:27][CH3:28])[C:25]#[N:26])[CH3:23].O1CCCC1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:13])[C:3]=1[N:14]1[C:25]([N:24]([CH2:27][CH3:28])[CH2:22][CH3:23])=[N:26][C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15]1
Reactant: CCN(C#N)CC
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(OC(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(Cl)cc(OC(F)(F)F)cc1Cl
Yield: 87 %

Procedure:
7.3 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,6-dichloro-4-trifluoromethoxyphenylhydrazone and 2.0 g (0.02 mol) of N,N-diethylcyanamide were added to 100 ml of tetrahydrofuran, and 2.2 g (0.02 mol) of triethylamine was dropwise added under reflux and stirring. After completion of the dropwise addition, the mixture was stirred at the same temperature for 0.5 hour. After cooling, the reaction solution was poured into water, and the precipitate was extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.4 g (yield: 87.1%) of the desired compound as a pale yellow liquid. Refractive index nD20 : 1.4940.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>C(#N)C.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: OB(O)c1cccnc1
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: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3cccnc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (50 mg, 0.095 mmol) (Example 33), tetrakis(triphenylphosphine)palladium(0) (5.51 mg, 4.77 μmol), sodium carbonate (20.23 mg, 0.191 mmol) and 3-pyridineboronic acid (14.08 mg, 0.115 mmol) in acetonitrile (1 mL) and water (250 μl) was heated at 80° C. under nitrogen for 17 h. The reaction mixture was then cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in DCM, afforded the title compound (20.5 mg). LCMS (A) m/z: 522 [M+1]+, Rt 1.33 min (acidic), Rt 0.89 min (basic).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.[CH:21](OC)=[O:22]>C1COCC1>[Cl:13][C:14]1[C:19]([CH:21]=[O:22])=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1
Reactant: COC=O
Reactant: Clc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of diisopropylamine (2.6 mL, 18.5 mmol) in THF (18.5 mL) was stirred at −78° C. as a 2.5 N solution of n-butyl lithium (7.4 mL, 18.5 mmol) was added. The solution was stirred at 0° C. for 30 minutes, then cooled to −78° C. for 30 minutes before the addition of 2,4-dichloropyridine (2 mL, 18.5 mmol). The solution was stirred at −78° C. for another 30 minutes before the addition of methyl formate (1.14 mL, 18.5 mmol). The solution was stirred for 30 minutes then was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide 2,4-dichloro-3-pyridinecarbaldehyde (2.18 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.54 (d, J=5 Hz, 1H), 7.75 (d, J=5 Hz, 1H).