Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][O:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]1=O.Cl.[C:12]([C:15]1[C:16]([CH3:26])=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])(=[NH:14])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:4]1([CH3:9])[C:3]2[N:14]=[C:12]([C:15]3[C:16]([CH3:26])=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[NH:13][C:2]=2[CH2:7][O:6][CH2:5]1
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Reactant: CC1(C)COCC(Br)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2nc3c([nH]2)COCC3(C)C)c(C)cc1C
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.2, 150 mg, 0.72 mmol), methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 135 mg, 0.55 mmol), and potassium carbonate (228 mg, 1.65 mmol) in acetonitrile (8 mL) was heated at 100° C. for 48 hrs. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (10 mL) and washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to yield the title compound as a white solid (27 mg, 15%).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
A mixture of 3-pyrroline (9.1 g), N,N-diisopropylethylamine (28 mL), and chloroform (46 mL) was ice-cooled, benzyl chloroformate (26 g) was added dropwise, and then the mixture was stirred at room temperature for 15 h. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, and then dried with anhydrous sodium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain benzyl 2,5-dihydropyrrole-1-carboxylate (26 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3I)=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[NH:39][CH3:38])=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Reactant: CN
Product: CNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Yield: 85.5 %

Procedure:
A methanolic solution of methylamine (10 mL) was added to 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(2-acetylamino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-amide (90 mg, 0.145 mmol) and the resultant mixture was stirred at 80° C. for 3 h. The mixture was concentrated to dryness and the crude product was recrystallized from MeOH to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide (65 mg, 85.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1 H), 10.57 (s, 1 H), 10.34 (m, 1 H), 8.47 (dd, J=13.0, 7.2 Hz, 1 H), 8.17 (d, J=5.8 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 7.65 (s, 1 H), 7.55-7.42 (m, 3 H), 7.33 (m, 2 H), 6.69 (d, J=5.9 Hz, 1 H), 6.24 (d, J=7.9 Hz, 1 H), 3.01 (d, J=5.0 Hz, 3 H), 2.02 (s, 3 H); MS (ESI) m/z: 524.01 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=3[CH3:21])=[CH:7][C:5]=2[N:6]=1.[H][H]>C(O)C.[Pd]>[CH3:21][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: [H][H]
Reactant: Cc1nc2cc(Oc3ccc([N+](=O)[O-])cc3C)ccc2o1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2cc(Oc3ccc(N)cc3C)ccc2o1
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (671 mg, 2.36 mmol) in ethanol (10 mL) was added 10% palladium on carbon (50 mg, 0.047 mmol). The reaction mixture was subjected to 40 psi of hydrogen for 2.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed to provide the product (0.411 g, 69%) as yellow oil.
Reaction SMILES: C(Cl)[Cl:2].O[CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[Cl:2][CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(O)c2ccccc2)S1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(Cl)c2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of methylene chloride, there were dissolved 150 mg of 5-[1-(2-hydroxy-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 323 and 45 mg of triethylamine under an argon gas atmosphere and then 51 mg of methanesulfonyl chloride was added to the solution under ice-cooling. After stirring at room temperature for 30 minutes, 30 ml of ethyl acetate was added to the solution, the mixture was in order washed with a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in 10 ml of dimethylformamide, followed by addition of 21 mg of lithium chloride and heating to 70° C. with stirring for 20 hours. The solution was poured into a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (20 ml×3). The resulting extract was in order washed with a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give a crude product. The product was purified by preparatory silica gel thin layer chromatography (hexane:ethyl acetate=10:1) to give 35 mg of 5-[1-(2-chloro-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione as a yellow amorphous substance. The yield thereof was found to be 22%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.O[NH:35][C:36](=[NH:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1COCC1>[NH2:48][C:36](=[N:35][O:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)=[O:18])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=N)NO
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCC(N)=NOC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
At 0° C., to a solution of boc-(4-aminomethyl)-benzoic acid (5.000 g, 19.9 mmol), NMM (2.214 g, 21.89 mmol) in anhydrous THF (50 mL) was added dropwise isobutyl chloroformate (2.853 g, 20.89 mmol). The resulting mixture was stirred for 10 min, then N-hydroxydodecanimidamide (Example 23, step a) (6.398 g, 29.85 mmol) was added at once. After 1 h the ice-water bath was removed and the mixture was stirred for 14 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the mixture was extracted with AcOEt (3×70 mL). The combined organic layers were washed with water (150 mL), dried over MgSO4 and evaporated to give a white solid (9.2 g). This crude product was purified by flash chromatography over silica gel (c-Hex/AcOEt 4/1) to give the title compound as a white solid (7.91 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, 2H, J=8.0 Hz), 7.50 (t, 1H, J=5.7 Hz) 7.32 (d, 2H, J=8.0 Hz), 6.42 (br s, 1H), 6.27 (br s, 1H), 4.20 (s, 1H), 4.18 (s, 1H), 1.91-2.15 (m, 2H), 1.08-1.66 (m, 27H), 0.86 (t, 3H, J=6.9 Hz). M+(LC/MS(ESI)): 448.4; M−(LC/MS(ESI)): 446.3. HPLC (Condition A), Rt: 5.74 min (HPLC purity: 96.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12](Cl)[N:11]=1>C(O)CCCC.C(O)(C)C>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCCO
Solvent: CC(C)O
Product: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.4 ml (13 mmol) of 3-chloro-aniline are added to a suspension of 650 mg (3.44 mmol) of 2,6-dichloro-purine in 5 ml of 1-pentanol. The reaction mixture is stirred at 100° C. (oil bath temperature) for 3 hours. After cooling to room temperature, the mixture is diluted with isopropanol and stirred at 10° C. for 90 minutes. The precipitate is filtered off and rinsed with isopropanol and diethyl ether. The crystals are partitioned between 50 ml of 2 N (two normal) sodium hydroxide solution, 100 ml of water and 700 ml of ethyl acetate. The aqueous phase is subsequently extracted twice with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The crude product is stirred with diethyl ether and the crystals are dried at 50° C. under an HV. 2-Chloro-6-(3-chloro-phenyl-amino)-purine is obtained; Rf=0.47 (ethyl acetate:hexane=3:1); APCI-MS: (M+H)+=280; HPLC: tret(grad 20/1)=10.26 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[N:3]=[N:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Brc1ccc(Oc2ccc(-n3ccnc3)nn2)cc1

Procedure:
A mixture of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine, 3.2 parts of 4-bromophenol, 4.2 parts of sodium carbonate and 80 parts of 2-propanone was stirred and refluxed over weekend. The reaction mixture was evaporated and the residue was taken up in water and 2,2'-oxybispropane. The layers were separated. The organic phase was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 3.5 parts of 3-(4-bromophenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 168.4° C. (compound 6).
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16](=[O:19])[CH:15]=[C:14]2[CH3:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:24]([C:23]1[O:21][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([O:17][C:16](=[O:19])[CH:15]=[C:14]3[CH3:20])=[C:9]2[C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1cc(=O)oc2c(C(=O)c3ccccc3)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(=O)oc2c1ccc1oc(C(=O)c3ccccc3)c(-c3ccccc3)c12

Procedure:
The route shown in Scheme 1 exemplifies synthesis of the coumarin compounds of the present invention. Triethylamine is added to a solution of 7-hydroxy-4-methyl-chromen-2-one (i) and a benzoyl chloride (ii) in THF at room temperature. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is concentrated to afford a 7-benzoyloxy-4-methyl-coumarin (iii). A mixture of compound (iii) and finely powdered aluminum chloride is heated at 170° C. for 2 hours to afford an 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (iv). A mixture of compound (iv), 2-bromoacetophenone (v), and K2CO3 in CH3CN is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography to afford a pure 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one (vi).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (7.7 g, 21 mmol, HPLC=75%) and DMAP (1.27 g, 10 mmol, 0.5 eq) in dry CH2Cl2 (120 mL), Et3N (6.38 g, 8.45 mL, 63 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (8.1 mL, 104.5 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water (80 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (4.4 g, HPLC≧98%, the total yield for five steps is 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])[CH3:30]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:32][C:29](=[O:31])[CH3:30])[CH:38]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 54 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-acetamidophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.P(Cl)(Cl)([Cl:16])=O>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:16])[C:8]([CH3:13])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2cccc(Br)c2nc1Cl
Temperature: 0 °C
Yield: 74.9 %

Procedure:
A slurry of 8-bromo-3-methylquinoxalin-2(1H)-one (6.33 g, 26.5 mmol) in phosphorus oxychloride (20 mL, 219 mmol) was heated at reflux for 1.5 h in a round-bottomed flask fitted with a water-cooled reflux condenser and drying tube. Excess POCl3 was removed in vacuo (16 Torr, 36° C.), and the residue was taken up in DCM (50 mL), transferred to an Erlenmeyer flask, cooled to 0° C., and saturated aq. NaHCO3 (ca. 80 mL) was added (cautiously, with rapid stirring). The resulting biphasic mixture was stirred rapidly for 5 min. Upon cessation of gas evolution, the mixture was extracted with DCM (3×200 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification of the residue (silica gel, 0-30% EtOAc/hexanes) furnished 5-bromo-3-chloro-2-methylquinoxaline (126e; 5.12 g, 19.85 mmol, 75% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (1H, d, J=7.6 Hz), 8.00 (1H, dd, J=8.4, 1.2 Hz), 7.60 (1H, t, J=7.9 Hz), 2.87 (3H, s). m/z (ESI, +ve) 256.9 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][N:9]([CH3:11])[N:8]=[C:7]1[C:12]([F:15])([F:14])[F:13])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:11][N:9]1[CH2:10][CH:6]([C:4]([OH:5])=[O:3])[C:7]([C:12]([F:13])([F:14])[F:15])=[N:8]1
Reactant: CCOC(=O)C1CN(C)N=C1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CC(C(=O)O)C(C(F)(F)F)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (20 g, 90 mmol) was dissolved in 400 ml of dioxan. 400 ml of a 1 N aqueous sodium hydroxide solution (0.4 mol) were added and the reaction mixture was stirred for 2 h at room temperature. Subsequently the mixture was acidified with concentrated hydrochloric acid (pH 2). The dioxan was removed in vacuo, the residue was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering 15 g of 1-methyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid, which could be directly used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[N:10][CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>>[Br:20][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[N:6]=[CH:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:8]=3[N:9]=[N:10][CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1
Product: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1Br
Yield: 25 %

Procedure:
This was prepared by a Method analogous to that as described above for Preparation 87 using 7-cyclopropyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 93, 450 mg, 1.77 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (253.3 mg, 0.885 mmol) to afford the title compound as a white solid in 25% yield, 500 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:9])=[CH:4][C:3]=1[CH3:15].[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:18][C:17]([NH:9][N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)=[O:16]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(F)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl [1-(4-fluoro-3-methylphenyl)hydrazino]acetate (Intermediate 64, 0.8, 38 mml), sodium cyanate (0.84 g, 0.0129 mol) and trifluoroacetic acid (0.95 ml, 0.0114 mol) in toluene (15 ml) was stirred under nitrogen at room temperature for 24 hours. The mixture was poured into 8% sodium bicarbonate solution (40 ml) and extracted with ethyl acetate (2×30 ml). The organic extract was dried (MgSO4) and evaporated to give a red oil. This was crystallised by trituration with ether to give a white solid (Intermediate 65, 228 mg; 24%), m.p. 132°-133° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Add benzaldehyde (7.5 mL, 74 mmol) to a stirred solution of tyramine (10.00 g, 73 mmol) and anhydrous methanol (90 mL). Heat reaction to reflux for 1 h under nitrogen. Cool reaction to 0° C. and slowly add sodium borohydride (2.84 g, 75 mmol). Stir for 1 h at room temperature and then concentrate on a rotary evaporator. Add water (100 mL) and stir for 1.5 h at room temperature. Filter and wash with water to yield 10.11 g (61%) of 4-(2-benzylamino-ethyl)-phenol: mass spectrum (ion spray): m/z=228.1 (M+1); 1H NMR (DMSO-d6): 9.14 (br s, 1H), 7.29-7.18 (m, 5H), 6.96 (d, 2H), 6.65 (d, 2H), 3.69 (s, 2H), 2.67-2.60 (m, 4H), 2.02 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1COCC1.[Cl-].[Na+].O>[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[C:4]#[C:3][CH:2]([CH3:5])[CH3:1]
Reactant: C#CC(C)C
Reactant: O=C=Nc1ccccc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C#CC(=O)Nc1ccccc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0° C. The resulting mixture was stirred for 30 minutes. Then a solution of 1-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was dropped into the mixture. After stirring for 2 hours at 0° C., the mixture was treated with brine (100 ml) and extracted with ether (200 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as a yellow oil which was used in next step without purification. MS calcd. for C12H12INO 313.1, obsd. (ESI+) [(M+H)+] 314.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[N+:9]([C:12]1[CH:31]=[CH:30][C:15]([C:16]2[O:17][C:18]3[C:23]([C:24](=[O:26])[CH:25]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[C:27](Cl)=[O:28])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:27]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16]([C:15]1[CH:30]=[CH:31][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1)=[CH:25][C:24]2=[O:26])=[O:28])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)c1cccc2c(=O)cc(-c3ccc([N+](=O)[O-])cc3)oc12
Solvent: c1ccccc1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)cc(-c3ccc([N+](=O)[O-])cc3)oc12
Yield: 65.1 %

Procedure:
The same procedure as in Example 31 was performed employing 0.34 g of N,N-diethylethylenediamine and 4'-nitroflavone-8-carboxylic acid chloride (prepared from 1.00 g of 4'-nitroflavone-8-carboxylic acid and 1.40 ml of thionyl chloride) in 30 ml of benzene to give 0.78 g of yellow crystals, which were recrystallized from methanol as yellowish brown crystals, m.p. 207°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(CC3C=CC=CC=3)(=O)=O)[C@@H:16]([CH3:30])[CH2:15]2)[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C@@H:16]([CH3:30])[CH2:15]2)[CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Product: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccc(Cl)cc1

Procedure:
Prepared by the method of example 62 part (e) using the product from example 62 part (d) and 4-chlorobenzeneacetyl chloride to give the title compound.