Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1OC1C.COC1C(OCCCCCCCC2C=CC=CC=2)=C2C(=C([N+]([O-])=O)C=1)N=CC=C2C>CCOCC.CCN(CC)CC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCc1ccccc1
Agent: CC1CO1
Agent: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCc1ccccc1
Reaction time: 5 h

Procedure:
To a stirred mixture of 5-hydroxy-6methoxy-4-methyl-8-nitroquinoline (5.9 g, 0.025 mol), 1-bromo-4-phenylbutane (4.3 g, 0.02 mol) and HMPA (15 ml), at 110°-115° C., was added dropwise, during 1 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 5 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1.1 g of insoluble starting material, 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline. The pet ether and Et2O fractions were worked up as described above for 6-methoxy-4-methyl-8-nitro-5-(7-phenylheptoxy)quinoline (see example 1, part b) to give crude 6-methoxy-4-methyl-8-nitro-5(4-phenylbutoxy) quinoline as an oil. This material was dissolved in CHCl3, placed on a silica gel column and eluted with CHCl3. The eluates were concentrated to an oil which on trituration with pet ether gave 3.2 g (43%) of 6-methoxy-4-methyl-8-nitro-5-(4-phenylbutoxy) quinoline as yellow-green crystals, mp 88°-89° C. Recrystallization from hexane provided the analytical sample, mp 90°-91° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[H-].[Na+].Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:13])[C:19]=2[CH:26]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (0.3 g, 1.72 mmol) in DMF (5 mL) was added 60% NaH (0.1 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 15 min and added 3-(Bromomethyl)-5-chlorobenzo[b]thiophene (0.54 g, 2.07 mmol). The reaction mixture was heated to 65° C. and stirred at that temperature for 2 h. When the reaction was complete, the mixture was treated with water. The mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC to afford 0.53 g (87%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 62.1 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and toluene (50 g) was heated under reflux for 12 hours. Analysis by high speed liquid chromatography revealed the presence of 20% of the compound (II) as unreacted. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the compound (I) (10.9 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH:11]=[C:12](O)[CH3:13])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH3:13])[NH:18][N:17]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(=O)C=C(C)O)cc1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Cc2cc(C)[nH]n2)cc1
Temperature: 100 °C

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification. (2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4). (3) A solution of the above t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H). (4) A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[Se:42][C:41]([CH:43]=O)=[CH:40][CH:39]=3)=[C:34]([F:45])[C:33]=2[F:46])=[CH:28][CH:27]=1)[CH3:25].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[CH:43]([C:41]1[Se:42][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:30]=[CH:31][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=3)=[C:33]([F:46])[C:34]=2[F:45])=[CH:39][CH:40]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)c(F)c2F)[se]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.8 g (12.0 mmol) of propyltriphenylphosphonium bromide are initially introduced together with 3.60 g (9.56 mmol) of 5-(4′-ethyl-2,3-difluoro-biphenyl-4-yl)selenophene-2-carbaldehyde in 180 ml of THF, and a solution of 1.30 g (11.6 mmol) of potassium tert-butoxide in 20 ml of THF is added with ice-cooling. The mixture is stirred at RT for 1 h. Water and 2 N hydrochloric acid are added, and the batch is extracted with MTBE. The organic phase is washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=95:5). 2-But-1-enyl-5-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene is obtained as a yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][N:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:34]O>>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][N:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:17]([O:19][CH3:34])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(N[C@@H](CN(c1ccccc1)c1ccccc1)C(=O)O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at −5° C., to 75 ml of methanol, and the mixture was stirred for 15 min. 3.6 g (9.22 mmol) of 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (9), dissolved in 75 ml of methanol, were then added and the mixture was stirred at room temperature for a further 3 hours (h). After the solvents had been evaporated, the residue was taken up in ethyl acetate and the whole was extracted with sodium carbonate solution. Purification by means of flash chromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g (50% yield) of methyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate (10).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.C([O:20][B:21](C(C)C)[O:22]C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([O:10][CH3:11])=[C:2]([B:21]([OH:22])[OH:20])[CH:7]=1
Reactant: COc1cc(F)c(Cl)cc1Br
Reactant: CC(C)OB(OC(C)C)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(Cl)cc1B(O)O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
2-Bromo-4-chloro-5-fluoroanisole (Reference Compound No. 16-1, 239 mg, 1.00 mmol) was dissolved in mixed solvent of anhydrous toluene (2 mL) and anhydrous tetrahydrofuran (0.5 mL), 1.6M hexane solution of n-butyl lithium (750 μL, 1.20 mmol) was added thereto at −40° C., and then the reaction mixture was stirred at the same temperature for 30 minutes. Triisopropyl boronic acid (277 μL, 1.20 mmol) was added dropwise to the reaction mixture, warmed to −20° C. over 10 minutes, and then 2N aqueous HCl solution (1 mL) was added. After the reaction mixture was stirred at room temperature for 20 minutes, ethyl acetate (20 mL) and water (20 mL) were added and partitioned. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (181 mg) as a colorless solid. (Yield 89%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid tert-butyl ester (0.45 g, 1.49 mmol ) in dioxane (3.0 mL) at room temperature was added 4M HCl in dioxane (8 mL). The reaction mixture was stirred at room temperature 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue treated with ether. The titled compound was collected by filtration. MS (CI) m/z 203 (M+1)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:24])[F:25])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CN)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylamine hydrochloride obtained by Example 57 (100 mg) and triethylamine (0.073 ml) in chloroform (10 ml) was added dropwise methanesulfonyl chloride (0.04 ml) at room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:47][C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: COc1ccc(NC(=O)c2ccc(Oc3ccc(OCc4ccccc4)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1

Procedure:
A solution of the product from Example 43D and 4-Methoxy-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-(4-methoxy-phenyl)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (27 mg, 52%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 3.74 (s, 3 H) 6.77 (m, 2 H) 6.92 (m, 5 H) 7.64 (m, 2 H) 7.87 (d, J=8.82 Hz, 1 H) 7.96 (dd, J=8.64, 2.02 Hz, 1 H) 8.12 (d, J=2.21 Hz, 1 H) 8.89 (s, 1 H) 8.99 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.12 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=3[C:13]=2[O:14][CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=3[C:13]=2[O:14][CH3:15])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(O)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)methanone (2.0 g) synthesized in the above-mentioned (2) was dissolved in tetrahydrofuran (15 mL) and methanol (3 mL), and sodium borohydride (90%, 0.59 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (2 mL) and 1N hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (1.9 g, quantitative) of the title object compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH3:29]>CN(C=O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:28][CH3:29])[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCBr
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CC)C3=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.15 g, 0.52 mmol) in DMF (10 mL) at 0° C. was added anhydrous K2CO3 (0.14 g, 1.04 mmol) followed by ethyl bromide (0.06 mL, 0.79 mmol). The reaction was stirred at 0° C. for 2 hr then allowed to warm to r.t. Continued stirring overnight then quenched with H2O. The solution was extracted with CH2Cl2 and the organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was further concentrated on the high vac to remove any excess DMF and the resulting greenish solid was purified using silica gel, eluting with 3:1 hexane/acetone to give 95 as an off-white solid. The solid was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 95 as a white solid (m.p. 225-230° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[P:11]([Cl:15])(Cl)(Cl)=[O:12].[Cl-].[NH4+]>>[P:11]([Cl:15])(=[O:12])([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)c1ccc(OP(=O)(Cl)Oc2ccc(C(C)C)cc2)cc1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
Following the procedure of U.S. Patent No. 3,773,866, 54.0 g (0.4 mole) of 4-isopropylphenol was added to 73.4 g (0.47 moles) of phosphorus oxychloride and 0.6 g of ammonium chloride at 105° C. over a 1.5 hour period. After heating an additional 1.5 hour the temperature was raised to 135° C. and a second 54 g portion of 4-isopropylphenol was added. The mixture was stirred at 168° C. overnight, and purified by fractional distillation. The fraction which distilled at 258° C. (0.5 torr) was identified as 97% pure by glc.
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:28]1(=[O:33])[N:27]([N:13]([C:11](=[O:12])[CH2:10][S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[O:16])[C:31](=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)CSC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)CNC(=O)CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 50 ml round bottom flask, 0.37 g (1 mmole) of benzoylmercaptoacetylglycylglycylglycine and 0.126 g (1.1 mmole) of N-hydroxy succinimide are dissolved in approximately 25 mL of tetrahydrofuran and cooled to 5°-10° C. in an ice bath. To this solution, 0.23 g (1.1 mmole) of N,N'-dicyclohexylcarbodiimide is added. The solution is allowed to warm to room temperature and is stirred for 48 hours and the course of the reaction followed by TLC. The precipitate is removed by filtering; the filtered solution is evaporated to dryness under vacuum. The residue is redissolved in 50-60 mL of dichloromethane; this solution is filtered and evaporated to dryness under vacuum. The residue is redissolved in 5-6 mL ethanol with warming and allowed to crystallize for 3-4 hours. The crystals of product succinimidyl-MAGGG are recovered by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:7]2[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)[CH2:24][CH2:23]1
Reactant: ClCC1CC1
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC2CC2)c1=O
Yield: 61.5 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 61.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O1CCOCC1>[Ni].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 55.5 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidin-4-one (2.8 g, 12.7 mmol) in a mixture of 1:4 dioxane: methanol (100 mL) was hydrogenated over Raney nickel (1 g) under balloon pressure at ambient temperature overnight. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The resulting solid was washed with petroleum ether (2×10 mL) and dried to afford 1-(4-amino-phenyl)-piperidin-4-one (1.34 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](O)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[O:34][CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](=[O:24])[NH:31][C:30]1[CH:32]=[CH:33][C:27]([Cl:26])=[C:28]([O:34][CH3:35])[CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(N)ccc1Cl
Reactant: COc1ccc([C@H]2CC[C@@H](C(=O)O)N2C(=O)OC(C)(C)C)cc1OC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.50 g, 7.11 mmol, 1.0 equivalent), 4-chloro-3-methoxyaniline (1.12 g, 7.11 mmol, 1.0 equivalent), PyBrop coupling reagent (3.98 g, 8.54 mmol, 1.2 equivalents), and DIEA (1.86 ml, 10.7 mmol, 1.5 equivalents) in dichloromethane (35 ml) was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with 1N NaOH (3×100 ml). The organic extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil was filtered through a layer of silica and eluted with ethyl acetate:hexanes (1:1). The filtrate was concentrated in vacuo to afford (2S,5R)2-(4-chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.48 g, 7.09 mmol, 100% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.59 (1H, broad s), 7.23 (1H, m), 6.85–6.60 (4H, m) 4.64 (2H, m), 3.00 (3H, s), 3.83 (3H, s), 3.56 (3H, broad s), 2.62 (1H, broad m), 2.36 (1H, m), 2.11–1.89 (2H, m), 1.22 (9H, broad s). MS (LC-MS): Calculated for C25H31ClN2O6 490.19, found 491.15 (M+H)+.