Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][C:14](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]>CCOC(C)=O.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]
Reactant: CCOC(=O)C=C1CCn2c1cc1c(C)c(OC)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Ethyl 2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (351 mg, 1.23 mmol) was dissolved in EtOAc (6 mL) and ethanol (6 mL), 10% Palladium on carbon (120 mg) was added. The reaction was degassed and charged with hydrogen, then stirred at room temperature overnight. The solid was filtered off. The filtrate was concentrated to give the title compound (320 mg) as an oil without further purification. LCMS m/z=288.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0 and 8.6 Hz, 1H), 2.80-2.95 (m, 2H), 3.73-3.80 (m, 1H), 3.85 (s, 3H), 3.95-4.02 (m, 1H), 4.06-4.18 (m, 1H), 4.18-4.26 (m, 2H), 6.11 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])C(Cl)(Cl)Cl)[NH:5][CH:6]=1.[NH3:13]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:13])=[O:12])[NH:5][CH:6]=1
Reactant: N
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Solvent: CC#N
Product: NC(=O)c1cc(Br)c[nH]1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
A mixture of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (CombiBlocks, Inc., San Diego, Calif.; 1.50 g, 5.15 mmol) and ammonia (30 wt. % in water; 4.0 mL, 55.5 mmol) in CH3CN (62.5 mL) was stirred at 23° C. for 45 min. The reaction mixture was then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes) furnished 4-bromo-1H-pyrrole-2-carboxamide (885 mg, 4.68 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (1H, br. s.), 7.55 (1H, br. s.), 7.08 (1H, br. s.), 6.95 (1H, dd, J=2.8, 1.7 Hz), 6.84 (1H, dd, J=2.4, 1.7 Hz). 13C NMR (100 MHz, DMSO-d6) δ ppm 161.1, 126.9, 121.2, 112.0, 94.8. m/z (ESL+ve) 188.9/190.9 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[C:13]([CH3:20])[CH:12]=1>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:19])=[C:13]([CH3:20])[CH:12]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1cc(Cl)ccc1N=C=O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1NC(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS (MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found C, 66.82; H, 5.41; N, 9.92.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:10])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)cc1F
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A solution of 4-cyano-3-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 36%) as a yellow solid. mp: dec. @ 235° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 7.9 (t, 1H, J=7.6 Hz), 7.9 (dd, 1H, J=1.4, 10.2 Hz), 7.3 (td, 2H, J=1.6, 6.5 Hz), 7.6 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
Reaction SMILES: COC1C=CC=CC=1O[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[OH:8].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:6])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(O)COc2ccccc2OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: COc1ccc(C(C)=O)cc1
Temperature: 120 °C

Procedure:
Wet Raney Ni 4200 was dried under vacuum and carefully weight (20 mg (dry weight), 3.5×10−4 mol, 250 mol %). 4 mL degassed heptane was added, followed by 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethan-1-ol (38 mg, 1.4×10−4 mol). The reaction was heated at 120° C. for 24 hours. Workup: The reaction was cooled, opened and 10 mg of NH4COOH was added. 50 mL of Et2O was used to transfer the crude to an erlenmeyer containing MgSO4. After drying the solution was filtered and concentrated. HNMR gave 100% conversion to 1-(4-methoxyphenyl)ethan-1-one, 100% of the β-O-4 bond was broken.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14](O)=[O:15])=[O:10]>C(Cl)Cl>[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14]([Cl:2])=[O:15])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cccs1
Solvent: ClCCl
Product: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1

Procedure:
Phosphorus pentachloride (27.2 g.) was added portionwise during ca. 20 minutes to a stirred and cooled (ice-bath) suspension of 2-dichloroacetoxyimino-2-(thien-2-yl)acetic acid (syn-isomer) (37.0g.) in methylene chloride (370 ml.). The mixture was stirred at 0° for a further 30 minutes during which time all the solid dissolved. After removal of the solvent under reduced pressure, benzene was evaporated from the residue at 20°, and the process repeated to give 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride (syn-isomer) as an oil that was used directly in the next stage.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2].[Cl:13]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.CCCCCC>CN(C=O)C>[Cl:13][C:8]1[C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Cl)c(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
To a stirred solution of 4-ethyl-2-nitroaniline (26.3 g, Example 13a) in DMF (100 ml) at -25° C. was added N-chlorosuccinimide (25.4 g) in portions. The mixture was stirred for 1 h at 0° C. and 30 minutes at ambient temperature before evaporation of the solvent under vacuum. Addition of CHCl3 /hexane (1:1) to the residue followed by filtration removed crystalline succinimide. 6-Chloro-4-ethyl-2-nitroaniline (4.6 g) was isolated from the filtrate after chromatography on silica. δ (360 MHz, CDCl3) 1.22 (3H, t, CH3), 2.56 (2H, q, CH2), 6.38 (2H. s, NH2), 7.4 (1H, d, 5-H) and 7.90 (1H, s, 3-H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24]C)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2O)nc2ncn(Cc3ccccc3)c12
Temperature: 100 °C
Reaction time: 35.5 h
Yield: 67.6 %

Procedure:
1.36 g (4.09 mmol) of 7-benzyl-2-(2-methoxyphenyl) hypoxanthine prepared by the same method as in Example 15 was dissolved in 20 ml of acetic acid. After the addition of 3 ml of hydrobromic acid, the mixture was stirred for 35.5 hours at 100° C. After cooling, the produced crystals were separated by filtration and washed with distilled water and ethanol. The crude crystals were purified by suspension in hot ethanol to obtain 0.88 g of 7-benzyl-2-(2-hydroxyphenyl)hypoxanthine (yield 68%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=O>O1CCCC1>[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CN1CCNC(c2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNC(c2ccccc2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Lithium aluminium hydride (3.04 g, 0.8 moles) was suspended in tetrahydrofuran (60 ml) under nitrogen atmosphere. A solution of 1-methyl-2-oxo-3-phenylpiperazine (10 g in 10 ml of tetrahydrofuran) was added at 10–15° C. Slowly, raised the temperature of reaction mass and refluxed for 2 hours. Cooled the reaction mass to 5° C. and quenched successively with 3 ml of water, 3 ml of 15% aqueous sodium hydroxide solution and 9 ml of water. Reaction mass was stirred for 1 hour at 25–30° C. Filtered the reaction mass and the filtrate was concentrated under reduced pressure. Dissolved the residue in DM water (25 ml) and concentrated hydrochloric acid (8 ml) and the solution was washed with cyclohexane (20 ml). pH was adjusted to 11.0–12.0 with 50% w/w aqueous sodium hydroxide solution and extracted the product with methylene chloride (2×50 ml). Methylene chloride layer was concentrated under reduced pressure and 7.54 g of pure 1-Methyl-3-phenylpiperazine was isolated in cyclohexane having HPLC purity 99.7%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1([C:22]([F:25])([F:24])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1([C:22]([F:24])([F:25])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:36])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(C(F)(F)F)(C(F)(F)F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C(F)(F)F)(C(F)(F)F)O2
Yield: 67.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 200 mg of 2,2-bistrifluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran and 210 mg of m-chloroperbenzoic acid (67%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 14 hours. Potassium carbonate solution was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 140 mg of 2-(2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 208°-210° C.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH3:45])[C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])[CH2:18][C@H:17]2[C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[Cl:44][C:39]1[CH:38]=[C:37]([C@H:17]2[C@H:16]([N:15]([CH3:45])[C:13](=[O:14])[C:5]3[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:46])([F:1])[F:47])[CH:4]=3)[CH2:21][CH2:20][N:19]([C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])[CH2:18]2)[CH:42]=[CH:41][C:40]=1[Cl:43]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 177.2 %

Procedure:
To a solution of tert-butyl 4-{[(3R,4R)-4-[{[3,5-bis(trifluoromethyl)phenyl]carbonyl}(methyl)amino]-3-(3,4-dichlorophenyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylate (0.502 g) obtained in Example 87 in ethyl acetate (5 mL) was added 4N hydrogen chloride/ethyl acetate (4 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This was washed with 1N aqueous sodium hydroxide solution and dried, and the solvent was evaporated under reduced pressure. The obtained residue was treated with 1 equivalent of 4N hydrogen chloride/ethyl acetate to give the title compound (0.405 g, 89%) as a white powder.
Reaction SMILES: [H-].[Na+].CCOCC.[CH3:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=2)[CH:23]=1.[NH4+].[Cl-].[OH-].[K+]>C1COCC1.O>[CH3:8][C:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=2)[CH:23]=1)([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc2cc(CBr)ccc2c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2cc(CC(C)(C(=O)O)C(=O)O)ccc2c1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred suspension of 3.6 g NaH (90 mmol, 60% in mineral oil) in 200 ml Et2O 16.2 ml (94 mmol) of diethyl 2-methylmalonate was added slowly with cooling. After 2 h stirring at 20 C, solution of 21.2 g (90 mmol) of 2-(bromomethyl)-6-methylnaphthalene (prepared according Buu-Hoi L.; J. Chem. Soc.; 1946; 831) in 30 ml of THF was added, resulting mixture was stirred overnight and decomposed by addition of saturated NH4Cl solution. Organic phase was separated, aqueous—extracted twice with 100 ml portions of ether. Combined extracts were evaporated, residue was dissolved in 150 ml methanol and solution of KOH (20 g, 360 mmol) was added slowly. Mixture was refluxed for 5 h, then evaporated to dryness and resulting semisolid was dissolved in warm water (400 ml). Solution was extracted three times with 100 ml portions of ether, then acidified by carefully addition of 10% HCl. Precipitate of acid 2 was collected and dried, yielded 20 g (81%) of white powder.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH2:25][CH3:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:27][CH2:28][CH2:29][CH:30](Br)[CH3:31]>CCCCCC.O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:19]([CH2:25][CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(Br)CCBr
Reactant: CCC(CC(=O)OC)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(CCCCBr)(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
40 ml (0.1 mol) of n-butyl lithium as a 2.5 molar solution in hexane are added dropwise to a solution of 14 ml (0.1 mol) of diisopropylamine in 150 ml of anhydrous tetrahydrofuran at −30° C. and stirred for 10 minutes at −10° C. At −76° C., 16.4 g (0.1 mol) of methyl 2-phenylbutanecarboxylate are added dropwise and the mixture is stirred for 30 minutes at this temperature. Then 12.12 ml (0.101 mol) of 1,3-dibromobutane are added, when the addition has ended the cooling bath is removed and the mixture is stirred for 14 hours at ambient temperature. The reaction solution is poured onto 1.2 l water and extracted with diethylether. The organic phases are extracted with water, dried over sodium sulphate and the solvent is eliminated. The residue is distilled under high vacuum.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=O.[Na+].[Cl-:21].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>Cl.O>[Cl:21][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: [Cl-]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1Cl

Procedure:
A solution of 3-(3-amino-4-methoxybenzoyl) propionic acid (5 g.) in concentrated hydrochloric acid (25 ml.) was diazotised at 0°C by the addition of a solution of sodium nitrite (1.54 g.) in water (5 ml.). This diazo solution was added with stirring to a solution containing hydrated copper sulphate (6.3 g.) and sodium chloride (5.4 g.) in water (20 ml.) to which had been added a solution containing sodium metabisulphite (1.4 g.) and sodium hyroxide (0.9 g.) in water (10 ml.). The mixture was then heated on the steam bath for 30 minutes when a solid separated. The mixture was cooled, the solid collected and washed with cold water. It was crystallised from methanol to yield the product (4.2 g.), m.p. 187°-189°C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>CCCCC>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:7][C:8]1=[O:9]
Reactant: O=C(CCCl)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: O=C1CCc2ccccc2N1
Temperature: 120 °C

Procedure:
To a stirred solution of AlCl3 (116.2 g, 0.87 mol) was added 3-chloro-N-phenylpropanamide (74-1; 40 g, 0.22 mol). Reaction mass was heated at 120° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with ice cold water (500 mL) and washed with 1N aqueous hydrochloric acid solution (500 mL) slowly under cooling condition and extracted with ethyl acetate (4×200 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was stirred with n-pentane (250 mL) for 0.5 h and filtered with n-pentane (50 mL) to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.33 (bs, 1H), 7.26-7.15 (m, 2H), 7.00-6.97 (t, J=7.4 Hz, 1H), 6.79-6.77 (d, J=7.6 Hz, 1H), 2.99-2.95 (t, J=7.6 Hz, 2H), 2.66-2.63 (t, J=7.4 Hz, 2H). MS (M+1): 148.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26]C)=[O:25]>C1COCC1.CO.[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)nc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)O)c4)nc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g dimethyl 3,3′-(1,8-naphthyridine-2,7-diyl)dibenzoate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.73 g, 93%. 1H NMR (300 MHz, DMSO-d6): δ 7.74 (t, 2H), 8.12 (d, 2H), 8.36 (d, 2H), 8.60 (d, 2H), 8.64 (d, 2H), 8.97 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[N:15]1([S:19]([C:22]2[CH:23]=[C:24](Br)[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])[CH:43]=3)[C:32]([NH:34][C:35]3[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=3)=[O:33])=[N:26][CH:27]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16]1.CO>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:15]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:30]=[C:31]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])[CH:43]=3)[C:32]([NH:34][C:35]3[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=3)=[O:33])=[N:26][CH:27]=2)(=[O:21])=[O:20])[CH2:16][CH2:17][CH2:18]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(S(=O)(=O)N3CCC3)cc2Br)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
Triethylamine (0.025 mL, 0.18 mmol) then triethylsilane (0.96 mL, 6.03 mmol) were added to palladium (II)acetate (12 mg) in DCM (2 mL) and stirred under argon for 15 mins. 3-{[5-(Azetidin-1-ylsulfonyl)-3-bromopyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.175 g, 0.3 mmol) in DCM (2 mL) was added dropwise and the reaction stirred at RT for 24 hours. Methanol was added, the reaction filtered through celite and the solvent removed in vacuo. Ethyl acetate (30 mL) was added and the mixture washed with water (30 mL), citric acid (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a white solid. This was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (69 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:47][CH2:48][CH3:49])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:46])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[C:40]([O:41][CH3:42])=[CH:39][C:29]3[C:30](=[O:38])[N:31]4[CH2:37][CH2:36][CH2:35][C@H:32]4[CH2:33][NH:34][C:28]=3[CH:27]=2)=[CH:13][C:12]=1[N+:43]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:47][CH2:48][CH3:49])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:46])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[C:40]([O:41][CH3:42])=[CH:39][C:29]3[C:30](=[O:38])[N:31]4[CH2:37][CH2:36][CH2:35][C@H:32]4[CH2:33][NH:34][C:28]=3[CH:27]=2)=[CH:13][C:12]=1[NH2:43])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (4R)-hydroxy-(2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (704 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV