Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([CH2:19][N:12]2[C:13](=[O:14])[CH:9]([CH2:8][C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][C:11]2=[O:15])[CH:21]=1
Reactant: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Reactant: CNC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(CN2C(=O)NC(Cc3ccc([N+](=O)[O-])cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.2 %

Procedure:
The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[OH:8][CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCCCNCCO
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCCN(CCO)C(=O)OCC
Reaction time: 2 h

Procedure:
117.2 g of 2-(n-butylamino)ethanol and placed in 300 ml of methylene chloride. Then 54.3 g of ethyl chloroformate are allowed to drop in during 1 hour at 30°-35° C. with ice-cooling. After stirring for an additional 2 hours, the methylene chloride is evaporated and the residue is distilled to yield pure ethyl (2-hydroxyethyl)-n-butylcarbamate; b.p. 112° C./0.1 Torr.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1cscn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cscn1
Yield: 44.6 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from thiazole-4-carboxylic acid (50 mg; 0.38 mmol) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg; 0.38 mmol). Crude product was purified by chromatography (CombiFlash, silica C18 column, eluent: 0-100% ACN/water) to obtain 63 mg (44%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 4.30-4.52 (m, 3H), 6.95 (d, 1H), 7.85 (d, 1H), 7.95-8.04 (m, 2H), 8.14 (s, 1H), 8.27 (d, 1H), 8.77 (d, 1H), 9.22 (d, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)([O-])=O.[C:27](=[O:30])([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:30][C:27]3[CH:23]=[CH:18][CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)cc2)c1
Temperature: 65 °C
Yield: 99.4 %

Procedure:
A 3 liter glass reaction vessel was charged with 186 grams (1.0 mol) of 4,4'-dihydroxybiphenyl, 438 grams (2.6 mols) of m-dinitrobenzene, 363 grams of potassium carbonate and 2,000 ml of N,N-dimethylformamide. The mixture was reacted at a temperature of 145°-150° C. for 16 hours. After completing the reaction, the resultant mixture was cooled and filtered to remove potassium nitrite. The solvent was distilled off from the filtrate under reduced pressure. The residue was cooled to 65° C., added with 2,000 ml of methanol and stirred for an hour. The resulted crystals were filtered, washed with water, washed with methanol and dried to obtain 426 grams (99.5% yield) of 4,4'-bis(3-nitrophenoxy)biphenyl as brown crystals.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Cl-:1].[OH:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(O)c(CO)c1
Reactant: Cl
Solvent: CC#N
Product: COc1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Cl-]
Reaction time: 5 h
Yield: 78 %

Procedure:
In the course of 30 minutes, at from 40° to 60°, 18 g of hydrogen chloride are introduced into a solution of 49.8 g of 2-hydroxy-5-methoxy-benzyl alcohol and 115.8 g of triphenylphosphane in 150 ml of acetonitrile. The reaction mixture is then stirred for 5 hours at 75°, the product beginning to crystallise after approx. 30 minutes. The reaction mixture is cooled to 0°, stirred for a further one hour and then at that temperature the crystals are filtered off with suction. [(2-Hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride is thus obtained in the form of colourless crystals [m.p.: 270° (decomposition); IR (KBr): 2990, 1585, 1395, 1295, 1240, 1145, 995 cm-1 ; 1H-NMR (360 MHz, CH3OH-d4 : 3.47 (s, 3H, OCH3), 4.74 (d, 2H, CH2P+), 6.40 (dd, 1H), 6.62 (d, 1H), 6.73 (m, 1H), 7.56 to 7.72 (m, 12H), 7.87 (m, 3H) ppm]; yield 78% of the theoretical yield.
Reaction SMILES: [C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22]Cl)=[O:19])([O:3][CH2:4][CH3:5])=[O:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH2:37][CH2:36]1)=[O:19])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCCl
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCN1CCN(c2ccccc2OC)CC1
Yield: 40.5 %

Procedure:
A solution of Example 5A (462 mg, 1.37 mmol), 1-(2-methoxyphenyl)piperazine (1.7 mmol), diisopropylethylamine (0.29 mL) in acetonitrile (5 mL) was processed as in Example 1B. Purification of the residue on silica gel with ethyl acetate provided 282 mg (41%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:35])([F:34])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]#[N:33])=[CH:27][N:26]=3)=[O:24])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:34])([F:35])[C@:12]([C:15]2[N:16]=[C:17]([NH:22][C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]#[N:33])=[CH:27][N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[F:21])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(NC(=O)OC(C)(C)C)OCC2(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)n1
Yield: 80 %

Procedure:
A solution of ((R)-4-{6-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (26 mg, 0.052 mmol) and TFA (200 μl, 2.6 mmol) in dichloromethane (1.3 ml) was stirred at it for 5 hours. The reaction mixture was evaporated and the residue diluted with aq. ammonia and ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and evaporated. 24 mg yellowish solid. Trituration with cyclohexane afforded the title compound as a slightly yellow solid. 17 mg (80% yield).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[C:11]([C:30]#[CH:31])[C:12]([N:15](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][CH:14]=1.[Cl:32][CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38](Cl)=[N:39][OH:40])=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:40][N:39]=[C:38]([C:37]3[CH:42]=[CH:43][C:34]([CH2:33][Cl:32])=[CH:35][CH:36]=3)[CH:31]=2)[C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (330.3 mg, 455.0 μL, 3.264 mmol) was added to a solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (1000 mg, 2.511 mmol) and 4-(chloromethyl)-N-hydroxy-benzimidoyl chloride 6 (563.6 mg, 2.762 mmol) in DCM (7.092 mL). The mixture was stirred at RT overnight. The reaction mixture was partitioned between DCM and water. The combined organic extract was dried (MgSO4) and concentrated in vacuo yielding an oil that was dissolved in DCM (10 mL). TFA (2 mL) was added and the mixture was stirred at RT for 15 min and was concentrated in vacuo. MS (ES−) 364
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[CH2:55][CH2:54][C@@H:53]([CH3:56])[NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[C@H:53]([CH3:56])[CH2:54][CH2:55][C@H:51]2[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CC[C@@H](C)N1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2R,5R)-2,5-dimethylpyrrolidine and isolated as colorless gum (11.2 mg, 60%). MS (m/e): 399.4 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([N:20]([CH3:21])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: CNc1ccc(OC)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-methoxy-N-methylaniline (933 mg, 6.80 mmol) using method A to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as a yellow solid. Yield: 617 mg (85%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 3.74 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C4CCCCO4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)c(F)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCO)c5)nn34)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(6-Fluoro-1-methyl-1H-indazol-5-yl methyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 281.1, 269 mg, 566 μmol) was dissolved in DCM (5 mL). HCl in dioxane (4 N, 283 μl) was added and the RM was stirred 1 h at rt. The solvent was totally evaporated and the residue was taken up with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and solvent evaporated under vacuo. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The acetonitrile was removed and the aqueous solution was basified with 5% NaHCO3. It was extracted 3 times with EtOAc and then the organics were joined and washed with brine. It was dried over Na2SO4 and the solvent was removed. The residue was triturated with pentane and the precipitate was filtered off to give the title compound a white solid (tR 0.93 min (conditions 2), MH+=392, 1H-NMR in DMSO-d6: 8.42 (s, 1H); 8.1 (s, 1H); 8.02 (d, 1H); 7.97 (s, 1H); 7.75 (d, 1H); 7.52 (t, 3H); 4.95 (m, 1H); 4.40 (s, 2H); 4.21 (t, 2H); 3.96 (s, 3H); 3.77 (m, 2H)).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1)=[O:19].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCl)Nc1ccnc2ccccc12
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCN1CCC(Oc2ccccc2)CC1)Nc1ccnc2ccccc12
Temperature: 70 °C
Reaction time: 144 h

Procedure:
To a solution of 4-phenoxy-piperidine (0.03 mmol) in dry THF (1 mL) is added 1-(2-chloro-ethyl)-3-quinolin-4-yl-urea (0.03 mmol), solid NaHCO3 (2.5 mg), and Nal (1 mg). The flask is tightly sealed, and shaken at 70° C. for 6 days. The reaction mixture is evaporated, taken up in aqueous formic acid, and purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(C(=O)OC)c1csc2ccc(C)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1csc2ccc(CBr)cc12
Temperature: 25 °C

Procedure:
A mixture of 71 g of methyl α-(5-methyl-3-benzo[b]thienyl)-β-methoxyacrylate (see Example 1 ), 57.8 g of N-bromosuccinimide, 1.1 g of azodiisobutyronitrile and 720 ml of carbon tetrachloride is refluxed for 75 minutes. The mixture is cooled to room temperature and filtered, and the filtrate is then concentrated under reduced pressure, and the yellow oil which remains is purified by chromatography on silica gel using diethyl ether/n-hexane (1:1). The crude product is crystallized from methylene chloride/n-hexane, and methyl α-(5-bromomethyl-3-benzo[b]thienyl)-β-methoxyacrylate is obtained in this manner as pale yellow crystals, m.p. 124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[NH3:39].O1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23]([NH2:39])=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(N)=O)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.014 g, 0.031 mmol), DMAP (7.46 mg, 0.061 mmol), EDC (0.023 g, 0.122 mmol), 0.5M ammonia in dioxane (0.092 mL, 0.046 mmol), and DCM (0.3 mL) at 23° C. for 48 h. Reverse-phase HPLC afforded 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, Methanol) δ ppm 8.72 (1H, br. s.), 7.98-8.27 (2H, m), 7.82 (1H, d, J=7.2 Hz), 7.67 (1H, d, J=9.6 Hz), 7.59 (1H, d, J=3.9 Hz), 7.39 (1H, m), 7.08 (1H, br. s.), 6.77 (1H, br. s.), 6.66 (1H, br. s.), 3.70-3.94 (4H, m), 3.03-3.25 (5H, m), 2.01-2.24 (3H, m). Mass Spectrum (ESI) m/e=457.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:26](=[O:50])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:38]5[CH:39]=[CH:40][C:41]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:42][C:37]5=[N:36][CH:35]=4)=[CH:30][C:29]=3[F:49])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.C1COCC1>[F:49][C:29]1[CH:30]=[C:31]([C:34]2[N:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:42][C:37]3=[N:36][CH:35]=2)[CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([NH:25][C:17]1[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:51])[CH:16]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(NC(=O)Cc3ccc(-c4cnc5cc(-c6ccccn6)ccn45)cc3F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cc1ccc(-c2cnc3cc(-c4ccccn4)ccn23)cc1F)Nc1cc(C(=O)N2CCNCC2)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Dissolve 4-(3-{2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetylamino}-5-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (0.76 g, 0.108 mmol) in 1:1 CH2Cl2 MeOH (20 mL) and add 2M HCl in THF (2 mL), then stir 2 hours and concentrate in vacuo. Load onto a Varian MegaElut® SCX cartridge (10 gram cartridge prewashed with methanol), rinse with methanol to remove impurities then elute crude product with 2 M NH3 in methanol. Concentrate this solution in vacuo then purify by silica gel chromatography (0%→10% 2 M NH3 Methanol:DCM) to give a yellow residue (0.400 g, 49% over 2 steps). MS (ES), m/z 603 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[C:23]([Cl:29])[CH:22]=1)(=[O:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O.O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]([C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=2)[C:1](=[O:3])[CH3:2])=[C:23]([Cl:29])[CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Reactant: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(CN(C(C)=O)c2nc(Br)ccc2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a solution of 2-acetamido-6-bromo-3-nitropyridine (203 mg) in N,N-dimethylformamide (2.34 ml) was added sodium hydride (60%, 34.3 mg) under ice-cooling, and the mixture was stirred for 1 hr. 4-Acetoxy-2-chlorobenzylbromide (288 mg) was added, and the mixture was stirred for 30 min under ice-cooling and at room temperature for 1 hr. Ethyl acetate (350 ml) and water (700 ml) were added to the reaction mixture under ice-cooling, and the mixture was partitioned. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography and eluted with hexane/ethyl acetate=4/1-3/1. The eluate was concentrated under reduced pressure to give 2-[N-(4-acetoxy-2-chlorobenzyl)acetamido]-6-bromo-3-nitropyridine as an oil (256 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of 2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.2466 g, 0.51 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.3 mL, 2.5 mmol), and stirred at room temperature for 18 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—MeOH—NH4OH) provided 0.1031 g (58%) of COMPOUND 89 as a pale yellow solid. 1H NMR (CDCl3) δ 1.32-1.43 (m, 5H), 1.60-1.68 (m, 1H), 1.72-1.81 (m, 5H), 1.96-2.02 (m, 1H), 2.08-2.17 (m, 1H), 2.45-2.60 (m, 9H), 2.69-2.71 (m, 1H), 2.76-2.86 (m, 1H), 3.70-3.84 (m, 2H), 3.95-4.01 (m, 1H), 7.05-7.10 (m, 1H), 7.36 (d, 1H, J=7.5 Hz), 8.44 (d, 1H, J=3 Hz). 13C NMR (CDCL3) δ 20.80, 22.38, 22.71, 23.07, 25.37, 28.77, 30.54, 41.23, 48.53, 49.81, 60.54, 121.36, 133.94, 136.52, 146.20, 146.32, 157.37. ES-MS m/z 354.5 (M+H). Anal. Calcd. for (C21H31N5)0.7(H2O)0.1(CH2Cl2): C, 67.65; H, 8.77; N, 18.69. Found: C, 67.46; H, 8.80; N, 18.43.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][NH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H][H]>[Pd].CO>[CH2:14]([NH:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1cccc2ccccc12
Reactant: O=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc(CNCCc2cccc3ccccc23)cc1
Reaction time: 6 h

Procedure:
100 ml of methanol and 350 mmol of 1-naphthylethylamine are initially taken and 350 mmol of benzaldehyde are added dropwise at 24° C. in the course of 15 minutes. Stirring is effected for 6 hours at 24° C., the completeness of the iminization is checked by GC, 0.5 g of Pd/C (10% by weight) is added and the crude mixture is hydrogenated with hydrogen for 5 hours at atmospheric pressure. A sample is taken and the composition is investigated by GC analysis.