Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]([C:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:17]([O:24][C:25]([C:27]1([NH:32][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 2.72 g (10 mmol) of 4-bromomethyl-2'-cyano-biphenyl, 2.63 g (12 mmol) of 1-aminocyclopentane-carboxylic acid benzyl ester, 3.4 ml (20 mmol) of Hunig base and 10 ml of N,N-dimethylformamide is heated to 130°-140° (bath temperature) for 2 hours while stirring. After cooling, the reaction mixture is poured onto 50 ml of ice/water. Extraction using ethyl acetate yields the crude N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine, which forms a hydrochloride melting between 180° and 182° (ethanol/diethyl ether).
Reaction SMILES: [C:1]([O:16][C@H:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:18][C:19](Cl)=[O:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CCCCCCC.[NH2:33][CH2:34][CH2:35][CH2:36][C@@H:37]([NH:41]C(=O)C[C@H](O)CCCCCCCCCCC)[CH:38](N)[OH:39]>>[NH2:33][CH2:34][CH2:35][CH2:36][C@@H:37]([NH:41][C:19](=[O:20])[CH2:18][C@H:17]([O:16][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:38][OH:39]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)N[C@H](CCCN)C(N)O
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)Cl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCN)OCc1ccccc1

Procedure:
D-cysteine is S-alkyl substituted with p-methoxybenzyl bromoacetate in presence of sodium carbonate in a THF-water medium. The S-benzyloxycarbonylmethylcysteine thus obtained is N-acylated with (R)-3-tetradecanoyloxytetradecanoic acid chloride, and the S-alkyl-N-acyl-D-cysteine derivative is then coupled with (2R)-5-amino-2-[(R)-3-hydroxytetradecanoylamino]pentan-1-ol amine {obtained by hydrogenolysis of the (2R)-5-amino-2-[(R)-3-benzyloxy-tetradecanoyl-amino]pentan-1-ol, see 4.1.1.} in presence of IIDQ. The thus obtained product is selectively O-acylated in its primary position with the ester derived from reacting HOBt with 7-(p-methoxybenzyloxy-carbonylamino)heptanoic acid. The two p-methoxybenzyl groups are then removed by treating the ester with aqueous trifluoroacetic acid. C59H112N4O10S. MM 1069.64.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[Cl:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18]>[OH-].[Na+]>[Cl:13][CH2:14][C:15]1[N:1]=[C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]2[C:17](=[O:18])[CH:16]=1
Reactant: Nc1ccn(-c2ccccc2)n1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CCl)nc2ccn(-c3ccccc3)n12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
3-amino-1-phenyl-pyrazole (4 g) was reacted with ethyl 4-chloro-acetoacetate (4.1 g) in polyphosphoric acid (19.8 g; 10.6 g of H3PO4 and 9.2 g of P2O5) under stirring at 100° C. for 30 minutes: after cooling the reaction mixture was diluted with ice water and neutralized with 35% NaOH. The precipitate was filtered and washed with water to give 5-chloromethyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p. 194°-196° C. (5.9 g), which was reacted with triphenylphosphine (6.75 g) in acetonitrile (190 ml) at reflux temperature for 65 hours. After cooling the solution was evaporated in vacuo to dryness and the residue was treated with ethyl acetate: filtration of the crystalline product gave (1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one-5-yl)-methyl-triphenylphosphonium chloride, m.p. 245°-247° C. (10 g), which was dissolved in chloroform (100 ml) and added dropwise to a suspension of 75% NaH (0.74 g) in chloroform (50 ml) and dimethylsulphoxide (5 ml) mantaining the temperature under 20° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.[CH:22]1([CH2:28][CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:34]([O:33][C:31]([C@H:30]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:28][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(=O)CCC1CCCCC1
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
Reaction of 9.5 g of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 26 and ethyl 4-cyclohexyl-2-oxobutyrate is carried out under reductive conditions in a manner similar to that described in Example 16, and the product is purified by silica gel column chromatography (hexane:ethyl acetate=5:1). From the first fraction, 2.3 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18].[Na].[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18])[CH:21]=[CH2:22]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Reactant: C=CCO
Agent: [Na]
Product: C=CCOc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-difluoromethylbenzimidazole is reacted with the sodium salt of allyl alcohol to obtain 4-allyloxy-7-nitro-5-cyano-2-difluoromethylbenzimidazole, m.w., 294.2.
Reaction SMILES: [Cl-].[CH2:2]([O:4][P:5](=O)([OH:9])[O:6][CH2:7][CH3:8])[CH3:3].[CH2:11]([OH:14])[C:12]#[CH:13]>C(Cl)Cl>[CH2:11]([O:14][P:5](=[O:9])([O:6][CH2:7][CH3:8])[O:4][CH2:2][CH3:3])[C:12]#[CH:13]
Reactant: CCOP(=O)(O)OCC
Reactant: C#CCO
Agent: [Cl-]
Solvent: ClCCl
Product: C#CCOP(=O)(OCC)OCC

Procedure:
1 mol of phosphoric acid diethyl ester chloride was added dropwise to 1.2 mols of propargyl alcohol at 20°-30° C., while stirring and passing nitrogen through. The mixture was allowed to react at 20°-30° C. for 2 hours and at 50° C. for 1 hour and was then taken up in 500 ml of methylene chloride and the methylene chloride mixture was washed twice with dilute sodium carbonate solution and once with water. On distillation, 0.76 mol of phosphoric acid diethyl ester chloride (boiling point: 76°-53° C./0.6-0.7 mbar) was recovered and no phosphoric acid diethyl propargyl ester was isolated. If the reaction was carried out at 80° to 100° C. for 6 hours, about 15% of impure diethyl propargyl phosphate was obtained, boiling point: 70°-82° C./0.2 mbar.
Reaction SMILES: [CH2:1]([C:3]1([CH:10]([CH3:12])[CH3:11])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:5]2[C:4](=[O:9])[C:3]([CH2:1][CH3:2])([CH:10]([CH3:11])[CH3:12])[NH:7][C:6]2=[O:8])=[CH:18][CH:19]=1
Reactant: CCC1(C(C)C)NC(=O)NC1=O
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(C(C)C)NC(=O)N(CC(=O)Nc2ccc(Br)cc2)C1=O

Procedure:
A mixture of 5-Ethyl-5-(1-methylethyl)-2,4-imidazolidinedione, (CAS #98492-91-2 (50 mg, 0.29 mmol), N-(4-bromophenyl)-2-chloro-acetamide (CAS #2564-02-5) (80 mg, 0.32 mmol), K2CO3 (48 mg, 0.35 mmol) in acetone was stirred at ambient temperature for 18 h. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and solvent removed. The crude product was purified by preparative TLC. The title compound was isolated as white solid.
Reaction SMILES: C([O:5][C@@H:6]([CH3:35])[C@H:7]([NH:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:32][CH:31]=[CH:30][CH2:29]2)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=2[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C@@H:7]([NH:18][C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:29][CH:30]=[CH:31][CH2:32]4)=[O:27])=[C:22]([CH3:33])[CH:21]=3)[C@@H:6]([OH:5])[CH3:35])=[N:9][C:10]=2[CH:16]=1
Reactant: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@H](C)OC(C)(C)C)ccc1C(=O)N1CC=CC1
Agent: ClCl
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@H](C)O)ccc1C(=O)N1CC=CC1
Yield: 99 %

Procedure:
Prepared analogously to Example 17 from N-[(1R,2S)-2-tert-butoxy-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzamide, and trifluoroacetic acid. Yield: 99%; Rf value: 0.48 (silica gel: dichloromethane/ethanol=9:1); C23H23ClN4O3 (438.913); mass spectrum: (M+H)+=439/441 (chlorine isotope) and (M−H)-=437/439 (chlorine isotope).
Reaction SMILES: [NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O.ClC([O:24][CH2:25][CH:26]1C2C=CC=CC=2C2[C:27]1=CC=CC=2)=O>O1CCOCC1>[NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:25](=[O:24])[CH2:26][CH3:27])[CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(N)Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)Oc1ccc2[nH]cc(CC(C)N)c2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 162.4 %

Procedure:
A 35 mL round bottom flask was charged with 3-(2-aminopropyl)-1H-indol-5-ol (0.20 g, 0.65 mmol) was added NaHCO3 (0.9 g, 11 mmol), water (2 mL) and 1,4-dioxane (8 mL). 9-Fluorenylmethyl chloroformate (0.20 g, 0.82 mmol) was added and the mixture stirred for 16 h at 23° C. TLC analysis indicated that the reaction was complete and the solution decanted into aqueous NaHCO3, then extracted with ether (2×30 mL). The combined organic extracts were washed with water (20 mL), dried over MgSO4 and concentrated. The crude product was purified by chromatography (silica, 65:35 hexanes:ethyl acetate) to furnish the title compound (0.26 g, 97%): 1H NMR (CDCl3) δ 7.88 (bs, 1H), 7.76 (d, J =6 Hz, 2H), 7.57 (d, J=6 Hz, 2H), 7.44-7.19 (m, 6H), 7.07 (s, 1H), 6.94 (s, 1H), 6.77 (dd, J=8, 2 Hz, 1H), 4.8 (m. 1H), 4.45 (m, J=8 Hz, 2H), 4.20 (m, J=8 Hz, 1H), 2.81 (bm, 2H), 1.15 (d, J=8 Hz); MS(ESI) m/z 430 (M+NH4)+, 413 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].[ClH:37]>C(O)C>[ClH:37].[Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Br)sc1Br)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cc(Br)sc1Br)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 7-(2,5-dibromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.07 g) and 1-amino-3-hydroxyguanidine p-toluenesulfonate (58 mg) were added ethanol (1.5 ml) and concentrated hydrochloric acid (0.04 ml), and the mixture was stirred at 90° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added 0.2N sodium hydroxide solution (10 ml). The mixture was extracted with ethyl acetate (30 ml) and tetrahydrofuran (20 ml). The organic layer was washed with water, to which was added concentrated hydrochloric acid (0.02 ml). The mixture was concentrated, and to the residue was added ethanol (1 ml). To the solution was added ether (0.2 ml), and the mixture was stirred for 3 hours. Precipitated crystals were filtered, washed with a mixture of ethanol/ether and dried to give 7-(2,5-dibromothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 126) (0.27 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[C:21]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:24])[CH:22]=[CH2:23]>ClCCl>[CH3:31][O:30][C:28]([CH2:27][CH2:26][NH:25][C:21]([CH:22]=[CH:23][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)=[O:24])=[O:29].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: C=CC(=O)NCCC(=O)OC
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)CCNC(=O)C=Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 11.5 %

Procedure:
This compound is prepared according to synthesis 68, from 70 mg (0.21 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 71) and 36 mg (0.23 mmol) of methyl 3-acryloylamino-propionate. After trituration in dichloromethane, 10 mg (12%) of 8-[2-(2-methoxycarbonyl-ethylcarbamoyl)-vinyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: C([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:5]1)(=O)C.C(=O)(O)[O-].[Na+].O>CO>[CH2:12]([C:7]1[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:53])[CH3:52])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])=[N:5][NH:4][C:8]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccccc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.68 g) in methanol (27 mL) was added sodium bicarbonate (0.596 g) under stirring at room temperature. The reaction mixture was stirred at room temperature for 17 hours. After confirming the completion of the reaction, water was added to the reaction mixture in order to precipitate the crystals. The crystals were collected by filtration, and the obtained crystals were washed with water and dried under reduced pressure to give 4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.45 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:15][NH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1.CCOCC>CO>[ClH:27].[N:11]1([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)[CH2:15][NH2:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: NCC(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (185 mg; 0.5 mmol; 1.0 eq.) and 4M hydrogen chloride in dioxane (1.8 ml; 7.4 mmol; 15 eq.) in Methanol (3.00 ml) was stirred at room temperature overnight. Ether was added to the reaction mixture. The precipitate was filtered, washed with ether and dried to yield 2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylamine hydrochloride salt as off-white solid in 67% yield.
Reaction SMILES: [CH2:1]([N:3]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13](=O)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:42](N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CC1C=CC(OCCN2CCNCC2)=CC=1)C>>[CH2:1]([N:3]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH3:42])[CH2:18][CH2:19]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(Cc1ccc(OCCN2CCNCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: CCN(C(=O)c1ccc(OCC(=O)N2CCNCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-oxo-2-piperazin-1-ylethoxy)benzamide according to an analogous synthetic method to Example 337, ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][4-(2-piperazin-1-ylethoxy)benzyl]amine (650 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{4-[2-(4-methylpiperazin-1-yl)ethoxy]benzyl}amine (490 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (70 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[F:24][C:25]([F:33])([F:32])[CH2:26][NH:27][C:28]([NH:30][NH2:31])=S.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:13][C:28]([NH:27][CH2:26][C:25]([F:33])([F:32])[F:24])=[N:30][N:31]=3)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=2)(=[O:15])=[O:16])[CH:3]=1
Reactant: NNC(=S)NCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.1 %

Procedure:
A solution of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.996 g, 4.52 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarbothioamide (0.783 g, 4.52 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.60 g, 13.57 mmol) (Sigma-Aldrich) in DMF (8.0 mL) was heated at 80° C. for 21.25 h, then at 90° C. for 24 h. The solution was cooled to RT. H2O was added and the solution was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude material. The crude material was purified by flash chromatography (10-60% EtOAc in Hex). The fractions were combined and DCM was added to the residue. A solid was present and was removed by filtration to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (180 mg, 0.320 mmol, 7.08%) as an off white solid. MS (ESI, pos. ion) m/z: 562.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (t, J=6.6 Hz, 1H), 8.21 (s, 1H), 8.10-8.16 (m, 1H), 7.89-7.99 (m, 3H), 7.73 (s, 1H), 7.43 (d, J=8.2 Hz, 2H), 4.06-4.20 (m, 2H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C[CH2:18][O:17][CH2:16]C1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:18][O:17][CH2:16][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Reactant: C1COCCN1
Product: NC(=O)c1cc(N2CCOCC2)ccc1N

Procedure:
According to the preparation of compound 25, morpholine was used to afford 29 (0.8 g) as brown powder; MS m/z 221 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([O:16]C)=[O:15])[NH:11]2)=[CH:7][C:6]=1[O:18][CH3:19].CCO>O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([OH:16])=[O:15])[NH:11]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2[nH]1
Solvent: CCO
Solvent: O
Product: COc1cc2cc(C(=O)O)[nH]c2cc1OCCCl
Yield: 100.1 %

Procedure:
A mixture of the above ester (1.00 g, 3.52 mmol), CsCO3 (1.723 g, 5.29 mmol), 95% EtOH (20 mL), and water (10 mL) was stirred at reflux for 6 h. Water (15 mL) was added and the EtOH was evaporated. The solution was filtered through Celite and acidified with 2 M HCl. The precipitate that formed was collected by filtration, washed with water, and dried to give 6-(2-chloroethoxy)-5-methoxyindole-2-carboxylic acid (0.95 g, 100%) as a white powder, which crystallized from MeOH as white needles, mp 187-189° C. 1H NMR [(CD3)2SO] δ 12.63 (br s, 1 H, CO2 h), 11.47 (s, 1 H, NH), 7.12 (s, 1 H, H-4), 6.97 (d, J=1.6 Hz, 1 H, H-3), 6.91 (s, 1 H, H-7), 4.23 (t, J=5.2 Hz, 2 H, OCH2), 3.97 (t, J=5.2 Hz, 2 H, CH2Cl), 3.78 (s, 3 H, OCH3); 13C NMR 162.5 (CO2), 147.5, 145.6, 132.1, 126.9, 120.4 (C-2,3a,5,6,7a), 107.4 (C-3), 103.1 (C-4), 96.5 (C-7), 68.9 (OCH2), 55.7 (OCH3), 43.0 (CH2Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1.Br[C:19]1[N:23]2[N:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[N:23]3[N:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccc(F)cn2)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: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)cnn34)ccc2F)nc1
Yield: 35.9 %

Procedure:
4-Fluoro-3-(5-fluoropyridin-2-yl)phenylboronic acid (61 mg, 0.25 mmol) was coupled to 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.046 g, 0.17 mmol) as described in Example 37, step e, using 2 M Na2CO3 (0.26 ml) and tetrakis(triphenylphosphine)palladium(0) (0.010 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 2.5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (23 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 7.39 (1H, dd, J 8.8, 10.8 Hz), 7.51-7.56 (1H, m), 8.89-7.94 (1H, m), 8.14-8.17 (1H, m), 8.63 (1H, d, J 2.7 Hz), 8.66 (1H, s), 8.74 (1H, dd, J 7.4, 2.3 Hz), 8.83 (1H, s); MS (ES+) m/z 378 [M+H]+.