Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1.C(O)(=O)C.Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[CH3:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:33])[NH:20][C:19](=[O:34])[C:18]=2[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:10]=2)=[CH:24]1
Reactant: Clc1ncccn1
Reactant: Cn1cc(C2=C(c3cn(CCCN)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cn1cc(C2=C(c3cn(CCCNc4ncccn4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A mixture of 100 mg of 3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate, containing an extra equivalent of acetic acid, 75 mg of 2-chloropyrimidine and 100 mg of sodium carbonate in 100 ml of DMSO was heated at 80° C. for 2 hours. 50 ml of water were added to the cooled solution and the precipitate was filtered off and chromatographed on silica gel with 5% methanol in dichloromethane to give 60 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 214°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:30]([F:33])([F:32])[F:31])=[N:20][N:21]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:30]([F:32])([F:31])[F:33])=[N:20][N:21]([CH:24]([CH2:28][CH3:29])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)c(Cl)c1C
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C)n1nc(C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]butanoic acid (0.037 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.042 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.04 (s, 1H), 7.35-7.24 (m, 2H), 7.21-7.11 (m, 2H), 4.80 (dd, J=8.7, 6.5 Hz, 1H), 2.98 (m, 1H), 2.42-2.29 (m, 5H), 1.26 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H); MS: (ES) m/z calculated for C21H22ClF4N5O [M+H]+ 472.1, found 471.9.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[C:7]([O:19][CH2:20][CH3:21])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18]1)[CH3:21]
Reactant: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h, the excess hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL) and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CS(C)=O.[OH-].[K+].[CH2:24](OS(OCC)(=O)=O)[CH3:25]>C1(C)C=CC=CC=1>[CH2:24]([N:9]([CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH3:25]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(NCCc2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCN(CCc1ccccn1)c1ccc(OC)cc1
Temperature: 40 °C
Yield: 48.8 %

Procedure:
With stirring 10.6 g (0.044 mole) of N-[2-(2-pyridyl)ethyl]-4-methoxy-aniline, prepared in a manner similar to that described in Example 1, part A, was added to 25.0 ml of dimethylsulfoxide. After the solution was complete, 4.9 g of ground potassium hydroxide was added slowly to the solution maintaining a temperature under 40° C. After approximately one hour 13.6 g (0.088 mole) of diethylsulfate was added dropwise to the reaction mixture while maintaining a temperature in the range of 25°-40° C., and the resultant mixture was stirred for approximately eighteen hours at ambient temperature. To the reaction mixture there was added 50.0 ml of toluene with stirring. The insoluble potassium sulfate was collected by filtration and discarded. The toluene solution was washed several times with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The toluene was removed under reduced pressure to obtain 5.5 g of N-ethyl-N-[2-(2-pyridyl)ethyl]-4-methoxyaniline (Formula VI: R1 =C2H5 ; R2 =R9 =H; R11 =CH3O) a brown-colored oil. A significant infrared maximum appeared at 1592 cm-1 (C=C;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[C:8]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:20].CI>CCCCCC>[CH3:3][O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: CCCCCCC(CC=CCCCCCCCC(=O)OCC)OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a 1-l flask equipped with a stirrer, a dropping funnel and a condenser, 24 g (0.6 mol) of 60% sodium hydride, 500 ml of dimethylformamide were charged, followed by the dropwise addition of a solution of 163.3 g (0.5 mol) of ethyl ricinoleate in 142 g (1.0 mol) of methyl iodide over one hour while stirring at 40° C. under an N2 atmosphere. After the completion of the dropwise addition, stirring was conducted at 40° for further 6 hours. To the reaction mixture so obtained, hexane was added. The resulting mixture was then washed with an aqueous solution of ammonium chloride and an aqueous solution of sodium thiosulfate, followed by concentration under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 155.8 g of ethyl 12-methoxy-9-octadecenoate were obtained (yield: 92%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>O.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([NH:10][S:25]([CH3:24])(=[O:27])=[O:26])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 32.5 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product of step (vii) (471 g, 2.099 mol), toluene (1880 mL) and pyridine (471 mL), then methanesulfonyl chloride (179 mL) was added dropwise over 1 h while maintaining the temperature below 35° C. The reaction was stirred at 30-35° C. overnight, before being cooled to below 20° C., then water (1880 mL) and 2 M HCl (1880 mL) were charged (pH 3 achieved). The layers were separated and the organic phase was washed with 2.5% brine (1880 mL). Heptane (3760 mL) was then charged to the organic layer over 0.5 h to isolate a precipitate. The mixture was cooled to 0° C. and stirred for 1 h. The solid was collected via vacuum filtration and washed with heptane (1880 mL), before being dried, under vacuum, at 40° C. overnight. Yield=551 g (87%). HPLC purity 98.5%. Purity >97% by 1H NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.CN([CH:38]=[O:39])C.[BH4-].[Na+]>C1COCC1.CO.C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[CH2:38][OH:39]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 100 mg, 0.210 mmol) in THF (2 ml) at −78° C. under argon was treated drop wise with n-BuLi (1.5 M in hexane, 0.309 ml, 0.463 mmol). The resulting brown solution was stirred for 2 min and then DMF (0.1 ml, 1.29 mmol) was added. The resulting yellow solution was stirred at −78° C. for 15 min. The reaction mixture was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the 7-(dimethoxymethyl)-6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated to give a white solid. This material was dissolved in MeOH (2 ml) and DCM (1 ml), treated at room temperature with NaBH4 (6.36 mg, 0.168 mmol) and stirred for 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.10 min; ESI-MS 421.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:20](N)[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([NH:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
1-Nitroanthraquinone was reacted in DMF at 20° C. with 5 moles n-butylamine for 5 hours. The reaction produced 1-butylamino anthraquinone which was a deep red solid having a melting point of 78° to 79° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C@H:29]([CH:33]([CH3:35])[CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C@H:29]([OH:28])[CH:33]([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)[C@@H](O)C(=O)O
Agent: Cl
Product: CC(C)[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.1 mg, 34.4%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (R)-2-hydroxy-3-methylbutanoic acid.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[N:13]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:11][C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=2)=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[K+].Cl.[O:33]([NH2:35])[CH3:34]>CCO.CCOC(C)=O.O>[CH:1]1([C:4](=[N:35][O:33][CH3:34])[C:6]2[C:14]3[N:13]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:11][C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CON
Reactant: CCNC(=O)Nc1nc2c(C(=O)C3CC3)cc(-c3cccnc3)cc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2c(C(=NOC)C3CC3)cc(-c3cccnc3)cc2[nH]1
Temperature: 50 °C
Reaction time: 36 h
Yield: 27.4 %

Procedure:
To a solution of 1-(4-cyclopropanecarbonyl-6-pyridin-3-yl-1H-benzoimidazol-2-yl)-3-ethyl-urea (37.2 g, 0.106 mmol) in dry EtOH (3 mL) were added potassium acetate (84 mg, 0.848 mmol, 8 eq.), methoxylamine hydrochloride (70.8 mg, 0.848 mmol, 8 eq.), molecular sieves (4 Å, powdered) in succession. The resulting suspension was stirred at 50° C. for 36 hours. The reaction mixture was then cooled to ambient temperature, diluted with EtOAc and water. The phases were separated, the aqueous layer was extracted with EtOAc (1×) and the combined organic extracts were dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC, converted to the bis-HCl salt to afford the title compound as a tan solid (11.0 mg): HPLC (10 to 90% CH3CN, 8 min.): tR=4.05 minutes; 1H NMR (CD3OD, 500 MHz) δ 9.30 (s, 1H), 8.99 (d, 1H), 8.90 (d, 1H), 8.22 (dd, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 4.14 (s, 3H), 3.36 (q, 2H), 2.04 (m, 1H), 1.23 (t, 3H), 1.15 (m, 2H), 0.92 (m, 2H); MS (ES+) m/z (M++1) 379.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]2[C:17]([O:19][C:20](=O)[C:5]=12)=[O:18])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.O>C(O)(=O)C>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:18])[N:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=3)[C:20](=[O:19])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:16]
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Temperature: 25 °C

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic anhydride (23.3 g, 81.5 mmol) and ethyl (4-aminophenyl)acetate (14.8 g, 82 mmol) were refluxed under nitrogen in acetic acid (160 ml) overnight. The mixture was cooled to room temperature and poured into water (1 L). The white solid was filtered, washed with water and dissolved in dichloromethane (800 ml). The solution was washed with water, brine and dried (MgSO4) and the solvent evaporated under vacuum to give ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as an off-white solid, 33 g, 96%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:15](=[O:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)COc1ccc(CO)cc1
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(COC(C)=O)cc1
Temperature: 0 °C
Yield: 61.7 %

Procedure:
A solution of (4-hydroxymethyl-phenoxy)-acetic acid methyl ester 69 (100 grams, 509 mmol), acetic anhydride (250 mL) and pyridine (20 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (1000 mL) and crude 70 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 70 (75 grams, 61.7%) as a light yellow syrup, Bp15 206-210° C. The structure was confirmed with NMR. IHNMR (CDCl3) δ 2.05 (s, 3H, O═C—CH3), 3.78 (s, 3H, ester), 4.62 (s, 2H, OCH2), 5.02 (s, 2H, CH2), 6.88 (d, 2H, Ar), 7.33 (d, 2H, Ar).
Reaction SMILES: [F:1][CH2:2][C:3]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])([CH2:6][CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)[C:4]#[N:5].C[Si](I)(C)C.C(N(CC)CC)C.Cl>ClCCl.C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CC(CF)(CCCCO)N1C(=O)c2ccccc2C1=O
Yield: 76 %

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-6-benzyloxyhexanenitrile (15.5 g, 40.8 mmol) and trimethylsilyliodide (13 ml, 2.2 equivalents) in dry dichloromethane (100 ml) is stirred at room temperature under nitrogen overnight. After removing the solvent under vacuum, the residue is dissolved in dry chloroform, triethylamine (17 ml, 3 equivalents) is added, and the mixture is refluxed for 30 minutes. Upon cooling, the solution is stirred with 2N HCl (250 ml) for 15 minutes, the phases are separated, and the organic layer is washed with sodium bicarbonate and with water. After evaporation, the residue is dissolved in THF and water (20 ml). Drops of 6N HCl are added, and the resulting mixture is stirred for several minutes. The solvent is removed by evaporation, and the residue obtained in dissolved in chloroform, washed with water, and dried. Removal of solvent gives the crude title compound as an oil (12 g). Chromatography on silica (300 g, eluant: ethylacetate) gives 2-fluoromethyl-2-phthalimido-6-hydroxyhexanenitrile (9.0 g).
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)([CH3:46])[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 165 mg (0.27 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide, prepared as in Example 49, in 5 mL of DMF at 0° C. is added 0.82 mL (0.82 mmol, 3.0 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 51 μL (0.82 mmol, 3.0 equiv) of methyl iodide is added. The resulting solution is stirred for 4 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC on an Si60 column using hexane/EtOAc 4/3 as eluent followed by lyophilization in acetonitrile/H2O afforded 124 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.48-6.95 (m, 16H), 6.71 (d, 1H, J=7.3), 4.78 (m, 1H), 4.21 (s, br, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 2.79 (d, 2H, J=5.9), 1.20 (s, 3H), 0.93 (m, 6H); low resolution MS (FAB)m/e 616 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([OH:23])[CH:11]=1.CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([O:23][CH3:33])[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cc(O)cc(Oc3ccccc3)c2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)cc(Oc3ccccc3)c2)c(F)c1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxy-5-phenoxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.73 mmol) and methyl iodide (2.2 mL, 14.6 mmol) in acetone (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was heated under reflux and stirred for 4 hours. The reaction solution was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (0.31 g, yield 99%) as an oily matter.