Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C.C1COCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Nc1cc(Br)nc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dibromopyridin-4-amine, DMAP (0.048 g, 0.397 mmol) and pyridine (0.48 ml, 5.95 mmol) were taken-up in THF (7.9 ml) under argon. Acetic anhydride (0.41 ml, 4.37 mmol) was slowly added and the mixture was stirred overnight at room temperature. The reaction was then heated to 65° C. for 5 days and cooled to room temperature, diluted with methanol, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc/hexanes) to afford N-(2,6-dibromopyridin-4-yl)acetamide as a light yellow solid. MS ESI calc'd. for C7H6Br2N2O [M+H]+ 294. found 294.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([CH:26]=[O:27])=[C:21]([Cl:28])[N:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([C:23]2[N:24]=[C:19]([Cl:18])[N:20]=[C:21]([Cl:28])[C:22]=2[CH:26]=[O:27])[CH2:7][CH3:8])=[CH:4][CH:3]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
Solutions of 15.56 g (0.1 mole) of 4-chloro-N-ethylaniline (III) and 11.13 g (0.11 mole) of triethylamine, in each case in 50 ml of tetrahydrofuran, were successively added dropwise to a solution of 21.14 g (0.1 mole) of 2,4,6-trichloropyrimidine-5-carbaldehyde (II) in 100 ml of tetrahydrofuran. The solution was then stirred for three hours at room temperature and the triethylammoniumchloride was filtered off. The filtrate was then evaporated in vacuo and stirred with 150 ml of methanol at 0° C. 23.9 g of colorless crystals were obtained.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][S:10][CH2:11][C:7]=2[CH:6]=1)C=C.[BH4-].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:9]1[C:8]2[CH:12]=[CH:13][C:5]([OH:4])=[CH:6][C:7]=2[CH2:11][S:10]1
Reactant: C=CCOc1ccc2c(c1)CSC2
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CSC2
Temperature: 45 °C
Reaction time: 15 h

Procedure:
The allyl ether from stage (ii) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) and treated with palladium tetrakis(triphenylphosphine) (481 mg, 0.42 mmol) followed by sodium borohydride (944 mg, 25 mmol). The mixture was then heated to 45° C. and stirred at this temperature for 15 h. After cooling to room temperature the THF was evaporated and the residue partitioned between 2M NaOH solution (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer re-extracted with 2M NaOH solution (25 mL). The combined aqueous layers were neutralised to pH 7-8 with concentrated hydrochloric acid and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (MgSO4) and evaporated to a clear oil of the title phenol which solidified upon standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H, s), 6.63-6.68 (2H, m), 7.04 (1H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH:15]C(=O)OC(C)(C)C)=[CH:14][N:9]3[N:8]=2)[CH:2]=1.Cl.C(OCC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of tert-butyl 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (1.34 g, 4.3 mmol), dichloromethane (10 ml) and hydrochloric acid (5 molar in diethyl ether (36.0 g, 30 ml, 987 mmol) was stirred for 18 hours at 25° C. The solvents were evaporated under reduced pressure and the residue treated with sodium hydroxide solution (2 molar in water). The mixture was extracted with ethyl acetate, the organic layers were washed with water and brine, dried over magnesium sulfate, filtrated and evaporated to dryness, affording 2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (482 mg, 53%) as light brown solid. Mp.: 230° C. MS: m/z=212.1 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[O:8].CC(C)([O-])C.[K+].O.Cl>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11](=[O:13])[CH2:10][NH:9][C:7]1=[O:8]
Reactant: CCOC(=O)CNC(=O)Cc1cccs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CNC(=O)C1c1cccs1
Yield: 94 %

Procedure:
To a solution of ethyl 2-thiopheneacetylaminoacetate (31.77 g, 140 mmol) in anhydrous toluene (190 mL) was added potassium tert-butoxide (20.95 g, 187 mmol). The mixture was heated to reflux for 2 hours. After cooling, it was poured into water (190 mL) and the water phase was isolated and acidified with dilute HCl to about pH 1 (˜70 mL 10% HCl). The pale brown precipitate was filtered, washed with water and dried. Finally, a pale brown solid with some dark brown chunks was obtained (23.8 g, yield 94%). 1H NMR (d6-DMSO, 500 MHz), δ=7.55 (dd, J=3.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.30 (dd, J=5.0 1.0 Hz, 1H), 7.01 (dd, J=5.0, 4.0 Hz, 1H), 3.88 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(C)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefins): δ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 15 H), 1.90 (tdd, J=7.0, 7.0, 1.0, 2 H), 2.36 (s, 3 H), 3.30-3.50 (m, 21 H), 4.40 (d, J=4.0 Hz, 2 H), 5.20-5.40 (m, 1 H), 5.95 (dt, J=16.0, 1.0 Hz, 1 H), 6.90 (m, 2 H), 7.10-7.30 (m, 2 H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). mp 94-97° C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-:24]#[N:25].[Na+].N([O-])=O.[C-]#N>Cl.O.[Cu](Cl)Cl>[C:24]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1)#[N:25]
Reactant: [C-]#N
Reactant: CCOc1cc(N)ccc1C(=O)O
Agent: Cl[Cu]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOc1cc(C#N)ccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A suspension 4-amino-2-ethoxybenzoic acid (20 g, 110 mmol) in 2N hydrochloric acid (200 mL) was well stirred with ice bath cooling. To this was added sodium nitrite (7.68 g, 111 mmol) in 22 mL of water. After stirring for 5 min, solid sodium carbonate was added to adjust the pH to 9-10. Separately, copper chloride (14.2 g, 143 mmol) in 200 mL water was slowly added to a solution of sodium cyanide ((18.28 g, 371 mmol) in 200 mL water at 0-5° C. and stirred for 2 h. The cold nitrite solution was added slowly to the cyanide solution and stirred at 0-5° C. for 15 min, followed by 25° C. for 2 h. This was filtered and the aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid. This was extracted with ethyl acetate (4 L). The organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 19 g of crude 4-cyano-2-ethoxybenzoic acid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Yield: 52734.1 %

Procedure:
Pyridinium p-toluenesulfonate (22 mg, 0.088 mmol) was added to a solution of (2R)-4-(5-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (197 mg, 0.422 mmol). The solution was heated to reflux in ethanol (10 ml) and stirred at this temperature until complete. The solution was cooled to RT, and the volatiles were removed in vacuo. The solid was triturated in ethanol (5 mL), collected via filtration, then washed with ethanol (3×5 mL), hexanes (10 mL), and ether (3×10 mL). The solid was dried under vacuum to afford a white solid (85.1 g, 76.4%). LC-MS m/z 383.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.11-2.23 (m, 0H) 2.41-2.55 (m, 1H) 3.12 (s, 3H) 3.73-3.84 (m, 1H) 3.99-4.11 (m, 1H) 6.53 (d, J=7.61 Hz, 1H) 7.41-7.73 (m, 5H) 8.04 (d, J=6.44 Hz, 1H) 9.24 (s, 1H) 11.10 (s, 1H).
Reaction SMILES: [Na].[P:2]([O-:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].CO[N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O1CCOCC1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:2]([O:6][CH2:7][CH3:8])(=[O:9])[O:3][CH2:4][CH3:5]
Reactant: CCOP([O-])OCC
Reactant: CO[n+]1ccccc1
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccccn1

Procedure:
To pyridine N-oxide (19 g; 0.2 mole) was added dimethyl sulfate (25.2 g; 0.2 mole) during 30 minutes. The reaction was completed by heating at 100° C. for two hours yielding N-methoxy pyridinium methosulfate. Diethyl sodio phosphonate was prepared by dissolving sodium (4.6 g; 0.2 mole) in a solution of diethyl phosphite (27.6 g; 0.2 mole) in dioxane (100 ml) in an argon atmosphere. The N-methoxy pyridinium quaternary was suspended in toluene by stirring while the diethyl sodio phosphonate solution was added. The reaction flask was cooled to maintain the temperature at 25° - 35° C. After stirring for 11/2 hours, water (100 ml) was added and the organic product isolated by chloroform extraction. Evaporation of the chloroform extract and distillation yielded diethyl pyridine-2-phosphonate with a small amount of diethyl pyridine 4-phosphonate. Yield -- 14g (33%) bp 140° - 8° C./1.5 mm. The presence of the two isomers was established by infrared absorption; 2-isomer 13.3 μ (strong, 4 adjacent hydrogen) and 4 isomer, 12.3 μ (weak, 2 adjacent hydrogen).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10]C.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl.BrC1C(OC)=CC(O)=C(C=1)C(C1C=CC=CC=1F)=O>>[Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[F:12])=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(OC)c1Br
Agent: COc1cc(O)c(C(=O)c2ccccc2F)cc1Br
Agent: Cl
Agent: [Al+3]
Product: COc1ccc(C(=O)c2ccccc2F)c(O)c1Br

Procedure:
2-bromo-1,3-dimethoxybenzene (217 g; 1.0 mole) and 2-fluorobenzoyl chloride (158 g; 1.0 mole) are dissolved in 1,2-dichlorothane and aluminum chloride (133 g; 1.0 mole) is added slowly. The reaction mixture is refluxed for 2 hours and then worked up with 5% hydrochloric acid. In this way a 1:2 mixture of 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone is obtained, as indicated by nuclear magnetic resonance (NMR). A quantity of this mixture is separated by preparative high pressure liquid chromatography into its two components, 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 127°-129° C. and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 137°-139° C.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:10][CH3:11])=[O:9])[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=3)[C:8]([NH:10][CH3:11])=[O:9])\[CH3:4])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CNC(=O)c1cccc(C(C)=CBr)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-(1-Bromoprop-1-en-2-yl)-N-methylbenzamide (202 mg, 0.8 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica (100-200 mesh) using 0-7% MeOH:DCM as eluent. Yield: 101 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.1 (s, 1H), 7.8 (m, 2H), 7.6 (t, 1H), 7.3 (s, 1H), 7.15 (d, 1H), 7.1 (d, 1H), 7.05 (s, 1H), 4.6 (bs, 2H), 3.7 (bs, 2H), 3.1 (bs, 5H), 3.0 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH3:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:14][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: CNS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 85 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and methylamine (10 mL, 33% in ethanol) were stirred together for 16 hours. 4-bromo-3-fluoro-N-methylbenzenesulfonamide (0.33 g, 85%) was provided after purification. HRMS: calcd for C7H7BrFNO2S, 266.93649; found (EI, M+.), 266.9376. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29]O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][Br:32])[CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CCC(CCCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(CN2CCC(CCCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.7 using 4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine (5 mmol), carbon tetrabromide (6.3 mmol), and triphenylphosphine (7.5 mmol). Purify to obtain the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([NH:51][C:52]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:58]([Br:61])[CH:59]=[CH:60][C:52]=3[NH:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetamido-5-bromobenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(Cl)cccc1Cl)/C=C/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(73) To a 0.33 M solution of 2,6-dichlorobenzaldehyde (1.75 g, 10 mmol) and acetone (290 mg, 5 mmol) in 30 ml of ethanol was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for 18 hr at room temperature, a solid precipitated and was filtered. The precipitate was recrystallized from ethanol to afford 1.46 g (78.5%) of pale yellow, cotton-like flakes: mp 154.0-154.4° C. (lit. mp 145-146° C., Unterhalt, Arch. Pharm., 1978, 311, 262-267). 1H NMR (250 MHz) δ 7.85-7.79 (d, 2 H), 7.40-7.36 (d, 4 H), 7.26-7.19 (d, 2 H), 7.24-7.18 (m, 2 H); 13C NMR (62.7 MHz) 189.1, 137.6, 135.4, 133.3, 132.5, 130.2, 129.1 ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([CH2:55][OH:56])[CH:51]=[C:52]([NH2:54])[CH:53]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1>>[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:53]=[C:52]([NH:54][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:51]=[C:50]([CH2:55][OH:56])[CH:49]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 70.2 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: CC[C:3]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]2[C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]3[CH2:13][O:14][C:15]([C@:17]([OH:20])([CH2:18][CH3:19])[C:9]=3[CH:8]=[C:7]12)=[O:16].CS(C)=O.O.[C:34](O)(=O)[CH3:35].C(O)(=[O:40])C.IC1C=CC=CC=1>[Pt].C(O)(=O)C>[CH3:34][CH2:35][C:24]1[CH:25]=[CH:26][C:27](=[O:40])[C:28]2=[CH:3][C:4]3[CH2:5][N:6]4[C:7](=[CH:8][C:9]5[C@@:17]([OH:20])([CH2:18][CH3:19])[C:15](=[O:16])[O:14][CH2:13][C:10]=5[C:11]4=[O:12])[C:21]=3[NH:22][C:23]=12
Reactant: CC(=O)O
Reactant: CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: [Pt]
Solvent: Ic1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(=O)c2cc3c([nH]c1-2)-c1cc2c(c(=O)n1C3)COC(=O)[C@]2(O)CC
Temperature: 25 °C

Procedure:
In a 100 ml beaker, 0.5 g (1.239 mmol) of 7-ethylcamptothecin, 0.32 g of 5% hydrogenation catalyst Pt/C (containing 0.028 mmol of platinum) and 0.025 ml (0.352 mmol) of dimethyl sulfoxide are added to 70 ml of acetic acid. The obtained suspension is quantitatively transferred into a 100 ml autoclave. After closure, the autoclave is flushed three times with nitrogen at the pressure of 0.5 MPa and then three times with hydrogen at the pressure of 0.5 MPa. The temperature is adjusted to 65° C. and the mixture is stirred at 950 r.p.m. The hydrogen pressure is adjusted to 0.5 MPa. After 43.5 hours the consumption of hydrogen stops and the procedure is terminated. After cooling to 25° C., the stirring is stopped and the internal pressure is equilibrated with the ambient atmosphere. The autoclave is flushed three times with nitrogen, the hydrogenation catalyst is removed from the hydrogenation mixture by filtration under pressure of nitrogen and the catalyst cake is washed with 10 ml of acetic acid. The obtained solution (80 ml) of 7-ethyl-1,2,6,7-tetrahydrocamptothecin is immediately added under vigorous stirring into a 250 ml one-necked flask containing 22 ml (1.218 mol) of water and 0.77 g (2.343 mmol) of iodobenzene diacetate. The obtained solution is stirred for 15 minutes at 22° C. Then the solvent is evaporated and the residue is mixed with 10 ml of acetonitrile. The obtained suspension is homogenized by sonication. The solid 7-ethyl-10-hydroxycamptothecin is isolated by filtration, washed on the filter with 10 ml of acetonitrile and dried to the constant weight in a vacuum oven at 60° C. to 65° C. The yield of 7-ethyl-10-hydroxycamptothecin is 0.283 g (58.3%). Its relative purity, determined by high performance liquid chromatography, is 90.2%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:24](=[O:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1c2ccccc2OC12CCNCC2
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Oc3ccccc3C4=O)nn2)n1

Procedure:
The object product (163 mg, 72%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (123 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,4′-piperidin]-3-one hydrochloride (150 mg) and potassium carbonate (173 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](S(C3C=CC=CC=3)(=O)=O)[CH:7]=[CH:6][C:5]=2[C:4]=1[CH:21]=O.[CH3:23][NH:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:24]([CH3:25])[CH3:23])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: CNC
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2[nH]ccc2c1CN(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (366 mg, 1.16 mmol; Intermediate 75) was dissolved in DCE, dimethylamine (3.48 mmol as 2M in MeOH) and sodium triacetoxyborohydride (738 mg, 3.48 mmol) was added in sequence. The reaction mixture was left stirring at r.t. for 23 h, diluted with DCM, NaOH (2M aq) was added until sustained pH at 10. The organic phase was separated, and the water-phase extracted once DCM. The combined organic phases were dried over Na2SO4 and purified by preparative HPLC. Yield: 57 mg residue mauve color