Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)=[CH2:19])[CH2:17][O:16]1>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([OH:16])([C:18]([C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[CH2:19])[CH2:17][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C=C(c1ccc(I)cc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 5 h
Yield: 59 %

Procedure:
Sodium 1,2,4-triazole (12.15 g, 133 mmol) was added to a solution of (2,4-difluorophenyl)-2-[1-(4-iodophenyl)ethenyl]oxirane [34.3 g, 89 mmol, from step (e)] in dry DMF (350 ml) under nitrogen at 70° C. The mixture was stirred for 5 hours, cooled, and the solvent removed under reduced pressure. The residue was partitioned between ether (800 ml) and water (2×500 ml). The organic solution was dried (MgSO4), filtered, and silica gel (60-200μ, 75 g) was added. The ether was removed under reduced pressure and the residual solid was applied to the top of a silica gel column (40-60%, 300 g) and the product was eluted using hexane and increasing amounts of ethyl acetate (0-75%). The product was obtained as a white foam (23.8 g, 61%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]2[CH2:6][CH2:7][C:4]=2[CH:3]=1.C([Li])(C)(C)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][C:2]1[CH:9]=[CH:8][C:5]2[CH2:6][CH2:7][C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: Brc1ccc2c(c1)CC2
Agent: [Li]C(C)(C)C
Product: BrCCCCc1ccc2c(c1)CC2
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a clean and dry 1000 ml round bottom flask equipped with a 250 ml addition funnel, low temperature thermometer and magnetic stir bar was transferred anhydrous tetrahydrofuran (500.0 ml) under nitrogen. 4-bromobenzocyclobutane (25.0 g, 0.1370 mol) was added to this flask by syringe. The reaction vessel was placed into a dry ice/acetone bath until a temperature of <−70° C. was achieved. The reaction mixture was then allowed to stir for 45 minutes at a stirring speed of 550 rpm in order to verify the integrity of the stirring apparatus at this temperature. Tert-butyllithium solution (161 ml, 0.2730 mol) was transferred to the addition funnel by cannula, then added dropwise to the reaction never allowing the temperature to rise above −65° C. Following addition, the reaction was allowed to stir for a period of 30 minutes. The vessel was then removed from the dry ice/acetone bath and allowed to warm to a temperature of −20° C. The vessel was then again placed into the dry ice/acetone bath until a temperature of <−70° was achieved. 1,4-dibromobutane (64.7 ml, 0.5460 mol) was added to the reaction dropwise via syringe, maintaining the current temperature. The reaction was allowed to stir for 30 minutes at this temperature following addition. The reaction was slowly warmed to room temperature over the following 12 hours. Reaction completion was confirmed by GC-MS. After warming, the reaction was quenched by the addition of isopropanol (25.0 ml) via syringe.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1I.C([Mg]Cl)(C)C.[CH:32]([N:45]1[CH2:48][C:47](=[O:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:32]([N:45]1[CH2:48][C:47]([C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH2:13][C:12]([C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=4)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=3)=[CH:3][C:2]=2[Br:1])([OH:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(I)c(Br)c2)=NO1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
In an oven-dried flask containing 3-(3-bromo-4-iodophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 27, 1000 mg, 1.67 mmol) in THF (25 mL) at −40° C. was slowly added isopropyl magnesium chloride (1.7 mL of 2.0M solution). The reaction was stirred at approx. −40° C. for 1.5 under nitrogen. 1-benzhydrylazetidin-3-one (520 mg in 4 mL THF) was slowly added. The reaction was stirred at −40° C. for an additional 30 minutes and allowed to warm to room temperature. Stirring was continued for 2 hours at room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×75 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 60:40 EtOAc:heptane, collecting the intermediate (615 mg, 52%) as a glass. 1HNMR (CDCl3): 7.87 (1H), 7.66-7.63 (3H), 7.45 (4H), 7.36-7.21 (7H), 4.39 (1H), 4.07 (1H), 3.73-3.58 (5H), 3.06 (1H); m/z (Cl) 711 ([M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCc1ccccc1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzyloxyethylamine (25 g) and potassium carbonate (50 g) in dichloromethane (500 ml) was treated dropwise with methyl chlorooxoacetate (25 g) at 0° C. After stirring for 3 h at room temperature, the mixture was washed with aq. sodium bicarbonate and dried over magnesium sulfate. Removal of solvent in vacuo gave methyl (2-benzyloxyethyl)aminooxoacetate as an oil. Yield: 40 g. The oil was dissolved in tetrahydrofuran, conc. aq. ammonia (500 ml) was added followed by reflux for 1/2 h. After cooling, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate. Removal of the solvent gave 4a as a crystalline material. Yield: 32 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.CON(C)[C:20](=[O:22])[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:20](=[O:22])[CH3:21])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccnc(Br)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 66.6 %

Procedure:
To a stirred solution of 2-bromo-4-methylpyridine (Compound 15) (20.20 g, 117.4 mmol) in THF (250 mL) at −78° C. was added LDA (2.0 M THF/Hex, 70.5 mL, 141 mmol) dropwise over 10 min. The solution was stirred at −78° C. for 35 min. Then a solution of N-methoxy-N-methyl acetamide (14.5 g, 141 mmol) in THF (30 mL) was added dropwise over 10 min. After 15 min. at −78° C., the solution was warmed to 0° C. and stirred for 1 h. The solution was poured into H2O (250 mL), extracted with Et2O (3×250 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (16.75 g, 78.2 mmol, 67%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>CN(C)C=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
4-(2-Morpholinoethoxy)benzoic acid 194 (330 mg, 1.31 mmol) was dissolved in thionyl chloride (4 mL) and a few drops of dimethylformamide were added. The reaction mixture was allowed to stir at 80° C. in a sealed tube for 1.5 hrs then opened to leave evaporate overnight. The residue was placed on a vacuum pump overnight and used as is in the next reaction (0.30 g, 100%). MS: 269.08 (calc, COCl), 265.13 (calc, Me ester), 266.2 (obs, Me ester)
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2N)=[CH:11][CH:10]=1>C(O)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:7]=[C:2]2[CH3:3])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Nc1ccc(I)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetimidate hydrochloride (6.757 g, 54.9 mmol) was added to a suspension of N-(4-iodophenyl)-1,2-diaminobenzene (6.812 g, 22.0 mmol) in absolute ethanol (30 ml) at room temperature. After 2 hours, 50 ml of ice cold 2N aqueous sodium hydroxide was added and the product was extracted into ethyl acetate (2×100 ml). The extracts were washed with.water (3×100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1-(4-iodophenyl)-2-methylbenzimidazole, 6.695 g as a white solid, m.p. 136°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].I(C1C=CC=C(C[C:22]([O-])=[O:23])C=1CC([O-])=O)=O.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:23][CH3:22])=[CH:5][NH:6][C:7]2=[O:12]
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Reactant: O=c1[nH]ccc2c(Cl)cccc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1c[nH]c(=O)c2cccc(Cl)c12
Yield: 87.8 %

Procedure:
To a solution of 5-chloroisoquinolin-1(2H)-one (3.8 g, 21.2 mmol) in methanol (70 ml) was added iodosobenzenediacetate (7.5 g, 23.4 mmol) followed by methane sulphonic acid (2.45 g, 25.5 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (3.9 g, 88%) as a light red colored solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.06-8.03 (d, J=12 Hz, 1H), 7.60-7.57 (d, J=12 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.01-6.99 (br s, 1H), 3.51 (s, 3H); MS: MS m/z 209.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.[NH2:38][CH2:39][C:40]#[N:41]>>[C:39]([CH2:40][NH:41][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:38]
Reactant: N#CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCC#N)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with amino acetonitrile hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]([CH2:21][CH2:22][NH2:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][CH2:22][NH:23][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-phenoxyethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. δH (CD3OD): 3.79 (2H, t), 4.17 (2H, t), 6.88–6.97 (3H, m), 7.08 (1H, s), 7.16 (2H, t), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=316 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CO
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1COS(C)(=O)=O
Yield: 99 %

Procedure:
The product of Example 54B (4.2 g, 12 mmol) was treated with methanesulfonyl chloride according to the procedure described in Example 38G. The title compound was obtained as a brown oil (5.10, 99% yield). 1H NMR (MeOH-D4, 300 MHz) δ 1.46 (s, 9H), 2.80 (m, 1H), 3.08 (s, 3H), 3.40 (m, 2H), 3.70 (m, 2H), 4.16 (m, 1H), 4.35 (m, 2H), 5.16 (s, 2H), 7.30 (m, 5H); MS (DCI/NH3) m/z 446 (M+NH4)+, 429 (M+H)+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][O:35]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25]C(=O)C1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][OH:35])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of nucleoside 61 (0.80 g, 1.42 mmol) in anhydrous dichloromethane (30 cm3) at −78° C. was dropwise during 30 min added BCl3 (1 M solution in hexane; 11.36 cm3, 11.36 mmol). The mixture was stirred for 4 h at −78° C., additional BCl3 (1M solution in hexane, 16.0 cm3, 16.0 mmol) was added drop-wise, and the mixture was stirred at −78° C. for 3 h. Then the temperature of the reaction mixture was raised slowly to room temperature and stirring was continued for 30 min. Methanol (25.0 cm3) was added at −78° C., and the mixture was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92:8, v/v) as eluent to give nucleoside 61A as a white solid material (0.332 g, 84%). δH ((CD3)2SO) 8.22 (1H, s, 8-H), 8.15 (1H, s, 2-H), 7.33 (2H, s, NH2), 5.89 (1H, s, 1′-H), 5.83 (1H, d, J 4.2, 3′-OH), 5.14 (1H, t, J 5.9, 5′-OH), 4.14 (1H, s, 2′-H), 4.25 (1H, d, J 4.2, 3′-H), 3.92 (1H, d, J 7.8, 1″-Ha), 3.81-3.41 (3H, m, 5′-Ha, 1″-Hb). Oc ((CD3)2SO) 155.90 (C-6), 152.64 (C-2), 148.35 (C-4), 137.72 (C-8), 118.94 (C-5), 88.48, 85.17 (C-1′, C-4′), 79.09, 71.34, 69.83, 56.51 (C-2′, C-3′, C-1″, C-5′). FAB-MS m/z 280 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:39])[N:24]([CH:35]2[CH2:38][CH2:37][CH2:36]2)[CH2:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:19]([Cl:40])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:40][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:35]1[CH2:36][CH2:37][CH2:38]1)[CH2:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:39]
Reactant: CC(C)(C)CNC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCC1
Reaction time: 64 h

Procedure:
A solution of [2-(3-chloro-5-{cyclobutyl-[2-(2,2-dimethyl-propylcarbamoyl)-ethyl]-carbamoyl}-phenoxy)-ethyl]-pyridin-4-yl carbamic acid tert-butyl ester (0.016 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.012 g) as a colourless gum.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:38]=[CH:37][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:37][CH:38]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (2.42 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (3.40 g), potassium carbonate (2.51 g) and N,N-dimethylformamide (50 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (1.78 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 1-[4-(5-methyl-2 phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-carboxylic acid (3.66 g, yield: 75%). This was recrystallized from acetone-hexane. Melting point: 165–166° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].F[C:6]1[C:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]=2[C:9](F)=[CH:8][CH:7]=1>C1COCC1>[NH2:3][CH2:2][CH2:1][NH:4][C:6]1[C:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]=2[C:9]([NH:3][CH2:2][CH2:1][NH2:4])=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Solvent: C1CCOC1
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O
Reaction time: 3 h

Procedure:
To a warm solution (55° C.) of ethylenediamine (154.4 mL, 2.29 mol) in THF (1400 mL), 6,9-difluorobenzo[g]isoquinoline-5,10-dione (70.1 g, 0.29 mol) was portionwise added over a period of 2.5 hours (about 4.6 g/10' each portion). The mixture was stirred for 3 hours at the same temperature and a blue precipitate was gradually formed. After one night stirring at 25° C., the suspension was filtered under nitrogen blanket, washed with THF (200 mL) and dried under vacuum (15 torr, 60° C., 3 h) to yield crude 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione as dihydrofluoride salt (117 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:20])[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[N+:17]([O-:19])=[O:18])[C@@H:4]([C:21]([OH:23])=O)[CH2:3]1.C([N:26](CC)CC)C.ClC(OCC)=O>C(#N)C>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:20])[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[N+:17]([O-:19])=[O:18])[CH:4]([C:21]([NH2:26])=[O:23])[CH2:3]1
Reactant: O=C(O)[C@H]1C[C@H](O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CC#N
Product: NC(=O)C1CC(O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5 g (0.015 mole) of trans-4-hydroxy-1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 1 are suspended in 130 ml of acetonitrile at room temperature and then 2.25 ml (0.015 mole) of triethylamine are added. After 30 minutes of stirring starting from the end of the addition, 1.5 ml (0.015 mol) of ethyl chloroformate are added into the suspension previously cooled at 5° C. The reaction mixture is again stirred for 30 minutes. Ammonia is bubbled through this solution, the temperature of which is maintained between 0° C. and 5° C. A precipitate appears. It is spun, washed with ether and recrystallized in acetonitrile.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C>CN(C)C=O.[Pd]>[CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][C:9]=2[NH2:12])[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cccc2ccncc12
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A suspension of 5-bromo-8-nitro-isoquinoline (2.0 g, 7.93 mmol), triethylamine (1.2 g, 11.90 mmol) and Pd/C (10%; 200 mg) in dimethylformamide (10 mL) was hydrogenated at atmospheric pressure for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford isoquinolin-8-amine (700 mg, 66%) as a pale yellow solid.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CO.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO.O1CCOCC1>[O:27]=[C:26]1[NH:4][CH:2]=[N:3][C:30]([CH2:31][CH2:32][CH3:33])=[C:25]1[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:23][CH:22]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To an ice-cooled mixture of formamidine hydrochloride (3.73 g) and methanol (25 mL) was added dropwise 28% sodium methoxide-methanol solution (13.7 mL), and a mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (5.90 g), 1,4-dioxane (18 mL) and methanol (25 mL) was added dropwise. The mixture was stirred at room temperature for 12 hr. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the diluted solution was washed with 0.1 M aqueous hydrochloric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude crystals. The crude crystals were washed with diisopropyl ether to give the title compound as a colorless solid (3.40 g, 61%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: OCCOCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOCCO)cccc2c1Nc1ccccc1C
Yield: 57.8 %

Procedure:
3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (2.40 g, 7.5 mmol) and potassium t-butoxide (1.22 g, 10 mmol) were dissolved in tetrahydrofuran (40 ml), 2-(2-chloroethoxy)ethanol (1.58 ml, 15 mmol) added, and the mixture heated at reflux for 18 hours. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 3-5% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-hydroxyethoxy)ethoxy)quinoline (1.77 g, 60%), m.p. 144°-146°.