Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[CH2:26][CH2:25][O:24][CH:23]([CH2:27]Cl)[CH2:22]1)([CH3:20])[CH3:19].O>C1C=CC=CC=1>[CH:18]([N:21]1[CH2:26][CH2:25][O:24][CH:23]([CH2:27][N:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]2=3)[CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCOC(CCl)C1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
To a suspension of sodium amide (0.5 g) in benzene was added a solution of 10,11-dihydro-5H-dibenz[b,f]azepine (1.0 g) in benzene at room temperature, and the resulting mixture was stirred under reflux for 1 hour. After cooling, a solution of 4-isopropyl-2-chloromethylmorpholine (1.0 g) in benzene was added to the reaction mixture at room temperature, and the resulting mixture was stirred at room temperature for 1 hour and refluxed for 20 hours with stirring. The reaction mixture was cooled and admixed with water. The benzene layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to afford 5-(4-isopropyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 203.5° -- 204.5° C (oxalate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCC(=O)CC1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
10% palladium on carbon (350 mg) was added to an ethanol solution (50 ml) of 4-(3,4-dichlorophenoxy)piperidine (7.1 g) and 1,4-cyclohexanedione (6.47 g), and the mixture was stirred at 50 to 60° C. for 5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to afford the title compound as a pale brown powder (5.2 g).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][S:5][CH:4]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:3]=12.O.[CH2:16](O)[CH2:17][OH:18]>Cl>[OH:18][CH2:17][CH2:16][O:1][C:2]1[CH2:7][CH2:6][S:5][CH:4]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:3]=12
Reactant: NS(=O)(=O)C1=CC2=C(O)CCSC2S1
Reactant: OCCO
Agent: Cl
Solvent: O
Product: NS(=O)(=O)C1=CC2=C(OCCO)CCSC2S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
5,6-Dihydro-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide, (2.0 g, 0.008 mole) was dissolved in ethylene glycol (20 ml), treated with concentrated hydrochloric acid (10 drops), and stirred at room temperature for 24 hours. The mixture was poured into water (100 ml) and extracted repeatedly with ethyl acetate. Evaporation of the washed and dried ethyl acetate extract left the crude product as an oily solid. Trituration with 10% ethanol in ether followed by recrystallization of the obtained solid (1.35 g) from ethyl acetate gave 885 mg (37%) of product, m.p. 110°-113° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:13][C:12]([CH3:25])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+].CS(C)=O>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:26])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH3:25])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(OCc2c(F)cccc2Cl)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 198 mg (0.62 mmol) of 7-(2-chloro-6-fluorobenzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 136A) in 6.7 ml of 1,4-dioxane was admixed with 2 M sodium hydroxide solution (2.5 ml). The mixture was stirred at 90° C. for a further 18 hours. The reaction mixture was admixed with 0.8 ml of dimethyl sulphoxide and stirred at 90° C. for a further 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was admixed with acetonitrile (5 ml) and trifluoroacetic acid (0.8 ml), and then with water and dichloromethane. The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: dichloromethane/methanol, gradient 80% to 100%), which gave 105 mg (27% yield, 56% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>O>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:12][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:3])[CH:11]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=Cc1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)Oc1ccc(C=O)c(O)c1
Yield: 29.7 %

Procedure:
To a suspension of sodium hydride (5.74 g, 239 mmol), which was prepared free from mineral oil by washing with hexane, in dimethylformamide (100 ml) was added 2,4-dihydroxybenzaldehyde (15.0 g, 109 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere. Subsequently, N,N-dimethylcarbamoyl chloride (10.1 ml, 110 mmol) was added at 0° C., and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. After stirring, water (300 ml) was added to the reaction mixture, and the resulting mixture was washed with ethyl acetate (200 ml×1). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml×3). The extract was washed successively with water (300 ml×3) and saturated aqueous sodium chloride solution (200 ml×2), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:2) as the eluent to afford the title compound (6.78 g, yield: 30%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].I[CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:15]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60 percent in mineral oil, 1.44 g, 36 mmol) in anhydrous DMF (30 mL) was added dropwise a solution of 4-hydroxy-3-methylacetophenone (4.5 g, 30 mmol) in dry DMF (20 mL) at 0° C. over a period of 20 minutes. After addition, the mixture was stirred at 0° C. for 30 minutes and iodomethane (2.2 mL, 36 mmol) was added in one portion. The mixture was then stirred at approximately 25° C. overnight. Water was added (10 mL) and the mixture was extracted with ether three times. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum to give crude product as a colorless oil.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26]([O:28]CC)=O)=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26](=[O:28])[N:8]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH3:7])=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CCCNCCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 45 h
Yield: 31 %

Procedure:
To a solution of trimethylaluminum in toluene (4.68 mL, 9.38 mmol) was added dipropylamine (1.29 mL, 9.38 mmol) and the solution was stirred for 45 hours. A portion (1.9 mL) of this solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.56 mmol) in toluene (2 mL). Additional toluene (7 mL) was added. The solution was stirred for 70 minutes at room temperature and then quenched with 1N hydrochloric acid (9.3 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with 1N hydrochloric acid and water (25 mL) and concentrated by rotary evaporation. The crude residue was purified by chromatography eluting with hexanes:ethyl acetate (95:5-50:50) to give the title compound (31% yield, m.p. 270° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: Nc1nccs1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
A mixture of 7.85 g of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine, 3.12 g of 2-aminothiazole, 1.50 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 1.35 g of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 13.8 g of potassium phosphate and 80 ml of 1,4-dioxane was stirred at 100° C. for 4.5 hours, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:14](O)[CH3:15]>>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-bromo-4-methoxyphenylacetic acid and ethanol.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reaction time: 24 h
Yield: 71.1 %

Procedure:
Combine 6-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 ml), and TFA (25 ml) at room temperature. After the reaction stirred for 24 hours followed by the addition of 11K2CO3 (aq), extract the product out of the aqueous layer with several washings of ethyl acetate/THF. Concentrate the organic phase under reduced pressure and add to 2, 10 g SCX Columns pre-treated with 5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, the elute the product using 1N NH3-MeOH solution to afford 2.00 g, 7.7 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:33]([OH:35])=O)[CH2:19][C:20]3[CH:31]=[C:30]([CH3:32])[C:23]4[NH:24][C:25]([N:27]([CH3:29])[CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[NH:3]1.[O:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:31]=[C:30]([CH3:32])[C:23]4[NH:24][C:25]([N:27]([CH3:28])[CH3:29])=[N:26][C:22]=4[CH:21]=3)[C:33](=[O:35])[N:49]3[CH2:48][CH2:47][N:46]([CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)[CH2:51][CH2:50]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc(N(C)C)[nH]c12
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2nc(N(C)C)[nH]c12

Procedure:
Prepared analogously to Example 1h from 90 mg (0.14 mmol, purity 85%) (R)-1-carboxy-2-(2-dimethylamino-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 35 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:70])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:70][C:40]([F:39])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:52][CH2:53][N:54]([C:5](=[O:7])[C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][OH:4])[CH2:55][CH2:56]2)=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of Boc-Ser-OH (162 mg, 0.79 mmol, 2 equiv.) in DMF (2 mL) were added HATU (300 mg, 0.79 mmol, 2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (200 mg, 0.39 mmol, 1 equiv.) and DIEA (140 μL, 0.79 mmol, 2 equiv.). The reaction mixture was stirred overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-(1-(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 56%). LRMS (M+H+-Boc) m/z 557.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under a stream of nitrogen, 30.2 g (82.0 mmol) of 4,4′-dibromobenzil, 9.31 g (86.1 mmol) of 1,2-phenylenediamine, and 300 mL of chloroform were put into a 500-mL three-neck flask and a reflux thereof was performed at 80° C. for 5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water. An aqueous layer was extracted with chloroform and dried with magnesium sulfate together with an organic layer. After the drying, the mixture was suctioned and filtrated, and the filtrate was enriched. The obtained solid was dissolved in toluene, and the resulting solution was subjected to suction filtration with florisil, celite, and alumina. The filtrate was enriched, whereby 30.0 g of a white powder solid of 2,3-bis(4-bromophenyl)quinoxaline that was a subject matter was obtained at a yield of 99%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([N:21]=[C:22]=[S:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:13]([NH:21][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C=NCCc1ccccc1
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: S=C(NCCc1ccccc1)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 30 ml. of anhydrous ether is added dropwise a solution of 4.89 g. of phenethyl isothiocyanate in 30 ml. of anhydrous ether over 10 minutes. An additional30 ml. of anhydrous ether is required to maintain stirring over 30 minutes.The resulting solid is collected, dissolved in 100 ml. of benzene and 25 ml. of ethanol and cooled. The resulting solid is collected, giving 5.68 g. of the desired product as a white solid, m.p. 162°-163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.[Li]CCCC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=2)=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)[OH:32])[CH:3]=2)[N:8]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: Clc1nc2ccc(Br)cc2cc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)cc2c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a 50-mL round-bottom flask containing a solution of 6-bromo-2-chloro-3-phenylquinoline (210 mg, 0.66 mmol, Intermediate 31: step b) in tetrahydrofuran (10 mL) was added 2.5 M n-BuLi in hexanes (0.29 mL, 0.72 mmol) dropwise with stirring at −78° C. After 45 minutes at −78° C., a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (132 mg, 0.60 mmol, Intermediate 8: step b) in tetrahydrofuran (2 mL) was added dropwise. The resulting solution was stirred at −78° C. for an additional 2 hours, then quenched with 30 mL of aqueous NH4Cl and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by FCC (20:1 DCM/MeOH) to provide the title compound as a white solid. MS (ES): mass calcd. for C26H19Cl2N3O, 459.1; m/z found, 460.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J=3.9 Hz, 1H), 8.33 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.42-7.56 (m, 9H), 6.93 (s, 1H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4]Cl.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>O1CCOCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)=CCCC(C)=CCn1ccnc1
Yield: 88 %

Procedure:
72.3 parts by weight of 3,7,11-trimethyldodeca-2,6,10-trienyl chloride and 40.8 parts by weight of imidazole are dissolved in 500 parts by weight of dioxane. The reaction mixture is then refluxed for 6 hours. After the mixture has cooled it is filtered and the filtrate is concentrated in vacuo. Distillation of the residue from the filtrate under an oil pump vacuum gives 72 parts by weight (88% of theory) of 1-(3,7,11-trimethyldodeca-2,6,10-trienyl)-imidazole; b.p. (0.01 mm Hg): 155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccncc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6-chloro-4-(3-iodobenzylamino)nicotinamide (200 mg, 0.50 mmol) in Dioxane (2 mL) was added pyridine-4-boronic acid (92 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (56 mg, 0.08 mmol), followed by a solution of Na2CO3 (173 mg, 1.63 mmol) in H2O (1 mL). After stirring at 100° C. for 2 h, it was concentrated and purified by preparative HPLC to give 6-chloro-4-(3-(pyridine-4-yl)benzylamino)nicotinamide (56 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:37])(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N)c3)cs2)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC(C)=O)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution (4 mL) of the crude compound (310 mg, 0.88 mmol) obtained in Example 26a in tetrahydrofuran were added triethylamine (0.16 mL, 1.1 mmol) and acetoxyacetylchloride (145 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=7/3) to give the title compound (270 mg, 72% in 2 steps) as a colorless oil.