Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:20][CH2:21][CH2:22][NH2:23].CCN(C(C)C)C(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH:23][CH2:22][CH2:21][F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: NCCF
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FCCNCCN(Cc1ccccc1)Cc1ccccc1
Yield: 27.9 %

Procedure:
N,N-Dibenzyl-N′-(2-fluoro-ethyl)ethane-1,2-diamine (160 mg) was prepared by following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (520 mg), 2-fluoro-ethylamine hydrochloride (250 mg), DIEA (900 uL) and tetrabutylammonium bromide (60 mg) in DMF (2 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nncc3cc(Br)ccc23)CC1
Temperature: 120 °C

Procedure:
6-Bromo-1-chlorophthalazine (18 mg, 74 umol) and 1-(methylsulfonyl)piperazine (91 mg, 554 μmol) were dissolved in dichloromethane/methanol when the reaction mixture was concentrated by evaporation under a nitrogen line. The concentrate was heated to 120° C. for 6 h to give the title compound. MS (ES+): 373 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:26]=[C:25]([CH:27]=[O:28])[CH:24]=[C:23]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1>C1COCC1>[CH:1]1([CH:27]([C:25]2[CH:24]=[C:23]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:35])[F:34])[N:22]=[C:21]([NH:20][C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[N:26]=2)[OH:28])[CH2:3][CH2:2]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)C3CC3)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of cyclopropylmagnesium bromide (1.90 mL, 0.95 mmol) in THF (10 mL), a solution of 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (40 mg, 0.09 mmol) in THF (6 mL) was added over 5 min. The mixture was stirred on ice-bath for 30 minutes before it was quenched with ammonium chloride (aq, sat). The solvent volume was reduced by evaporation. The mixture was extracted with dichloromethane, the organic phase was passed through a phase separator and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a dry film, 7 mg (16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:22]=[CH:21][C:17]([N:18]([CH3:20])[CH3:19])=[CH:16][C:15]=1[O:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:22]=[CH:21][C:17]([N:18]([CH3:19])[CH3:20])=[CH:16][C:15]=1[O:23][CH3:24])[OH:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cc(N(C)C)ccc1Br
Product: COc1cc(N(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 42.1 %

Procedure:
With 1.97 g of 5-chloroisatin and 4.99 g of the compound obtained in Step 194-1 as starting materials, 1.52 g of the title compound (pale yellow amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH:22](O)[C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH:22]([Cl:3])[C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(Cl)c1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.46 cm3 of thionyl chloride was added dropwise to a solution of 1 g of methyl (3R,4R)-1-(3-phenylpropyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)-propyl]piperidine-3-carboxylate in 15 cm3 of chloroform while maintaining the temperature at 0° C. The reaction mixture was allowed to return to a temperature in the region of 20° C. with stirring over 2 hours. The reaction mixture was subsequently concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The residue was dissolved in 30 cm3 of distilled water and the aqueous phase was washed with 15 cm3 of dichloromethane, then basified to pH 9 with solid potassium carbonate and, finally, extracted with 3 times 20 cm3 of dichloromethane. The organic phases were combined, washed with 2 times 20 cm3 of distilled water, and dried over magnesium sulfate. After filtering and then concentrating under reduced pressure (5 kPa) at a temperature in the region of 45° C., 1.16 g of methyl (3R,4R)-1-(3-phenylpropyl)-4-[3-(R,S)-chloro-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate were obtained in the form of a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[C:9]3[CH:27]=[CH:26][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][C:10]=3[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]O>>[CH3:32][S:29]([O:28][C:25]1[CH:26]=[CH:27][C:9]2[C:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)=[CH:34][CH:33]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[S:11][C:10]=2[CH:24]=1)(=[O:31])=[O:30]
Reactant: OCc1ccccn1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(O)cc2)cc1
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The coupling of the product from Step 2, Example 10 (Methanesulfonic acid 4-[3-(4-hydroxy-benzoyl)-6-methanesulfonyloxy-benzo[b]thiophen-2-yl]-phenyl ester) and pyridin-2-yl-methanol was accomplished by using the procedure outlined in Example 10, Step 3 except stirring for 1 hour instead of 16 hours at room temperature. The solvent was evaporated off and the crude product was chromatographed on silica gel using 1% MeOH/methylene chloride to 2% MeOH/methylene chloride as the gradient eluant to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7](OC)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[NH2:13][OH:14]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:13][OH:14])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: NO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NO)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 5-bromosalicylate (5 g, 21.6 mmol) was dissolved in 90 mL 1,4-dioxane and 10 mL water. 10 mL 50% aqueous hydroxylamine solution was added and the mixture was stirred at ambient temperature for 24 hours. After concentrating the mixture under vacuum, water was added. The formed precipitate was filtered, washed with water and dried yielding 5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) as off-white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:12](OCC)=[O:13])C.O.[OH-].[Na+]>O1CCCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH:11]([CH2:12][OH:13])[CH2:10][OH:9])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC(CO)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a stirred slurry of 11.4 g (0.3 mole) of lithium aluminum hydride (LAH) in 200 ml of freshly distilled (from LAH) tetrahydrofuran (THF) was added dropwise a solution of 57.3 g (0.2 mole) of 2-(4-chlorophenoxy)-1,3-propanedioic acid diethyl ester (CA 59:5051f (1963); Mamaev and Mikhaleva, Isv. Sibirsk. Otd. Akad. Nauk. SSSR, 145-8 (1962)) in 150 ml of THF at such a rate that a gentle reflux was maintained. The mixture was stirred at ambient temperature for 5 hr and then the excess LAH was decomposed with successive, cautious, dropwise additions of 11.4 ml of water, 11.4 ml of a 15% sodium hydroxide solution, and 34 ml of water. A gelatinous precipitate developed which was filtered through Celite® with great difficulty. The filtrate was concentrated and the residue was purified by column chromatography on 500 g of silica gel eluted with 0-35% acetone in benzene. The appropriate fractions were combined and concentrated to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 18.2 g (45%) of white solid, mp 62°-64° C. (isopropyl ether).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>[Cu]I.C(#N)C>[F:36][CH:37]([F:45])[O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: [Cu]I
Solvent: CC#N
Product: C[C@@H](COC(F)F)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 19.5 %

Procedure:
In a 25 mL pressure tube, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (60 mg, 0.12 mmol) and copper(I) iodide (14 mg, 0.070 mmol) were combined with acetonitrile (3 mL) to give a light yellow suspension. The mixture was degassed and placed under argon. The reaction mixture was heated to 50° C. in a sand bath. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (12 μL, 0.112 mmol) was added dropwise slowly to give a light yellow solution. The reaction was stirred for an additional 5 min. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were successively washed with water, saturated sodium bicarbonate, and brine then dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography over silica gel (gradient: 0% to 50% EtOAc in hexanes) to afford 12 mg (18%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+H]+=549.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]C(C)=O.C(=O)=O.S(Cl)(Cl)=O>CO>[CH3:10][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: CC(C)=O
Reactant: NCCCCCC(=O)O
Agent: O=C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-aminohexanoic acid (20 g, 0.15 mol) was suspended in methanol (80 mL), the mixture was cooled to −20° C. (acetone/dry ice) and thionyl chloride (14 mL, 0.2 mol) was added dropwise maintaining a temperature below −10° C. After addition of all thionyl chloride the cooling bath was removed and the mixture stirred for 90 minutes at room temperature. The mixture was refluxed shortly (5 minutes) and the solvents removed in vacuum. The residue was redissolved in methanol (60 mL). The product was precipitated by addition of diethyl ether (200 mL) with cooling on an ice bath. The product was collected by filtration as a white solid (22 g, 81%). The product was shown to be pure by TLC. R1(methanol)=0.13. Melting point 123-124° C. Mass spectroscopy (FAB+): 146.1 (MH+). 1H-NMR (DMSO-d6) δ: 8.1 (br. s, 3H), 3.60 (s, 3) 2.75 (t, 2H), 2.30 (t, 2H), 1.50 (qn, 4H), 1.30 (qn, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:16]1([C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A room temperature solution of 1.1180 gms. 4-(4-nitro-phenyl)-butyric acid in tetrahydrofuran (3 mL) is treated with 0.9052 gms. 1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensity of the reaction. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 0.5 mL morpholine. The reaction is heated overnight at 35° C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-morpholin-4-yl-4-(4-nitro-phenyl)-butan-1-one is isolated as a white solid in the amount of 1.3925 gms.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C:3]([NH:6][C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])([CH3:4])[CH3:5])(=[O:24])=[O:23]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-1,1-dimethylethyl)carbamate (5.1 g, 27 mmol, 1 equiv) in CH2Cl2 (100 ml) at room temperature were added NEt3 (11.3 ml, 81 mmol, 3 equiv) and methanesulfonyl chloride (28.3 mmol, 2.2 ml, 1.05 equiv) and the resulting solution was stirred for 2 h then partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo to give 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) (7.8 g, 108%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[N:17]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])[CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(=O)([O-])O.[Na+].O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[N:17]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])[CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Yield: 178.5 %

Procedure:
A mixture of 1-[6-(5-amino-7-chloro[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridin-2-yl]pyrrolidin-2-one (0.50 g, 1.45 mmol) and phenylboronic acid (0.354 g, 2.90 mmol) in saturated aqueous sodium hydrogen carbonate (5 mL) and 1,4-dioxane (20 mL) was degassed with a stream of nitrogen for 10 min then treated with tetrakis(triphenylphosphine)palladium(0) (0.083 g, 0.0725 mmol), refluxed for 2 h then partitioned between EtOAc and water. The organic phase was separated and the aqueous phase re-extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4), concentrated in vacuo to give a yellow solid (1.00 g) which was purified by column chromatography [SiO2; EtOAc-hexane (1:1) then EtOAc]. The resulting yellow solid (0.68 g) was triturated with diethyl ether to give the title compound (0.38 g, 68%) as an off-white solid.
Reaction SMILES: [H-].[Na+].C(OC([NH:10][C@@H:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][OH:13])=O)(C)(C)C.CI.[Cl-].[NH4+].F[C:26](F)(F)C(O)=O>C1COCC1.C(Cl)Cl>[CH2:14]([C@H:11]([NH2:10])[CH2:12][O:13][CH3:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Sodium hydride (60% dispersion in oil: 322 mg, 8.1 mmol) was added to a stirred solution of N-tert-butoxycarbonyl-(S)-1-benzyl-1-aminoethan-2-ol (2.02 g, 8.1 mmol) in dry THF (50 ml) at 0° C. under argon. The mixture was stirred for 10 min. and methyl iodide (3 ml) added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Saturated ammonium chloride (80 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated to give a clear oil. The oil was dissolved in DCM (40 ml) and treated with excess trifluoroacetic acid. (6.2 ml) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 2 h. The mixture was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulphate. Filtration and evaporation gave (S)-1-benzyl-2-methoxyethylamine (620 mg, 47%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([OH:13])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.C[O-].[Na+].CN([CH:26]=[O:27])C>>[CH2:15]([O:27][CH2:26][O:13][C:5]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:14][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCOCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
The temperature is maintained at -20° to -10° C during the addition. When the exotherm subsides, the addition of gas is discontinued and the reaction mixture allowed to warm up to 5°-10° C. The reaction mixture is washed with chilled water (100 ml) and the organic layer separated. The organic layer is filtered through calcium chloride and added to a solution of the sodium salt of 1-methyl-3,5-diphenyl-4-pyrazolol in DMF. The 4-pyrazolol solution is prepared by stirring 1-methyl-3,5-diphenyl-4-pyrazolol (10 g, 0.04 mole) with sodium methoxide (2.16 g, 0.04 mole) and dry DMF (100 ml).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31]>S1(CCCC1)(=O)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cccc2c(=O)[nH]c(-c3ccc(O)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cccc2c(=O)[nH]c(-c3ccc(OCCCCl)cc3)nc12
Temperature: 25 °C

Procedure:
2.7 gm (10 mmols) of 2-(4-hydroxy-phenyl)-8-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 30 ml of sulfolane and reacted with 1.5 gm (10 mmols+10%) of potassium carbonate. The resulting clear solution was admixed with 2.7 ml of 1-bromo-3-chloro-propane, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then poured into ice water, the aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate and evaporated. A colorless oil was obtained, which crystallized upon cooling.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCCCCCBr
Reactant: Cc1cc(=O)[nH][nH]1
Product: CCCCCCCCN1N=C(C)CC1=O
Temperature: 135 °C
Yield: 41.6 %

Procedure:
A mixture of 19.63 g 3-methyl-3-pyrazolin-5-one and 42.30 g 1-bromooctane was stirred and heated at 135° C. for 50 hour. After cooling, the reaction mixture was triturated with 200 ml water, treated with 17.00 g sodium bicarbonate in small portions, and heated to 100° C. for 1 hour. After cooling, the mixture was extracted with chloroform (3×100 ml portions). The combined extracts were dried over anhydrous calcium chloride and the solvent evaporated to give an oily residue crystallized from hexane (at -5° C.) to give 2,4-dihydro-5-methyl-2-octyl-3H-pyrazol-3-one (17.50 g, 42% yield) as white plates, m.p. 59° C.
Reaction SMILES: COC1C=C2C(=CC=1)C(=O)CCC2.C1(NC2N=CC=CC=2C(OC)=O)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=O)[CH:38]([C:44]([C:46]1[C:47]([NH:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:45])[CH2:37][CH2:36]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:42]=[CH:41][C:40]2[C:39]3[N:52]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[C:46]([C:44](=[O:45])[C:38]=3[CH2:37][CH2:36][C:35]=2[CH:34]=1)=[CH:51][CH:50]=[CH:49][N:48]=4
Reactant: COc1ccc2c(c1)CCC(C(=O)c1cccnc1Nc1ccccc1)C2=O
Agent: COC(=O)c1cccnc1Nc1ccccc1
Agent: COc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2ncccc2c1=O
Reaction time: 8 h

Procedure:
For example, with 3,4-dihydro-6-methoxy-1-napthalenone as the ketone and methyl 2-phenylaminonicotinate as the arylaminonicotinate, the 1,3-diketone, 3,4-dihydro-6-methoxy-2-[[2-(phenylamino)-3-pyridinyl]carbonyl]-1(2H)-napthalenone, results from the process of Example 8. To cyclize, reflux 9 g of the diketone in 400 ml of toluene containing a catalytic amount of p-toluenesulfonic acid. Collect the evolved water in a Dean-Stark trap. Remove the heat after 21/2 hours and allow the mixture to stand overnight. Distill the toluene under vacuum on a steam bath and crystallize the residue from acetonitrile, to provide the product 5,6-dihydro-3-methoxy-12-phenylnaphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. 234°-237.5° C., after crystallization from CH3CN.