Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Cl:24][C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:25]([Cl:24])=[O:27])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCNc1ccc2nc(S)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCN(C(=O)Cl)c1ccc2nc(S)sc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 200.5 %

Procedure:
Into a 250 ml three-neck, round bottomed flask were added 6-(propylamino)-1,3-benzothiazole-2-thiol (500 mg, 2.23 mmol), chloroform (100 ml), and saturated aqueous NaHCO3 (75 ml). The solution was stirred (mechanical stirrer) for 10 min at 0° C. (ice-bath) for 10 min. Stirring was stopped, and a solution of triphosgene (235 mg 0.80 mmol) in CH2Cl2 (2 ml) was added to the lower (organic) phase. Stirring was resumed for 40 min, then the layers were separated, and the aqueous phase was extracted 2× with chloroform. The combined organic fractions were dried (MgSO4), filtered, and concentrated to afford 0.46 g (72%) of the carbamoyl chloride as a waxy solid. IR (neat) 1737 cm−1 (C═O).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:16]([O:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:20][CH2:19]2)=[CH:15][C:14]([CH3:29])=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2>O1CCCC1>[CH3:7][C:8]1[C:16]([O:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)=[CH:15][C:14]([CH3:29])=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2
Reactant: CCC(=O)N[C@H]1CC[C@@H](Oc2cc(C)c3[nH]ncc3c2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN[C@H]1CC[C@@H](Oc2cc(C)c3[nH]ncc3c2C)CC1
Yield: 57.7 %

Procedure:
Lithium aluminum hydride (70 mg, 1.84 mmol) was added to a tetrahydrofuran solution (5 ml) of the cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (116 mg, 0.368 mmol) obtained in Example 668, and the resulting mixture was heated under reflux for 5 hours. After the reaction solution was diluted with 10 ml of tetrahydrofuran, the reaction was terminated by careful addition of water (76 μl), a 4N-aqueous sodium hydroxide solution (76 μl) and water (230 μl) in that order under ice-cooling. The reaction solution thus treated was filtered by the use of Celite and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a preparative thin-layer silica gel chromatography (chloroform/methanol/aqueous ammonia=7:1:0.1) to obtain cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine (64 mg, 58%).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine)palladium (II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid. 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the expected imine (2.72 g, 97%), which was used in next step without further purification. To a solution of the above imine (2.7 g, 9.23 mmol) in anhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol). The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark-colored solid. Purification by column chromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl)[1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl)[1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The compound was purified by column chromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP 219-221° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([F:16])[N:9]=1)(C)(C)C.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]([Si](C(C)C)(C(C)C)C(C)C)[CH:28]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[NH:29][CH:28]=2)=[C:10]([F:16])[N:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Reactant: COc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c2c1

Procedure:
(2-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-2034 was prepared in two steps from (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 48 and 3-iodo-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 5 as shown in Scheme 25.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:18](=[O:20])[CH3:19])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 23.7 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), acetic anhydride (0.042 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 28 mg of N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylacetamide. MS m/z 269; HPLC purity 100% at 210-370 nm, 9.2 min.; 98.7% at 248 nm, 9.2 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C17H20N2O+H+, 269.16484; found (ESI, [M+H]+), 269.1651.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].CN1CCOCC1.[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A stirred solution of methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (0.2 g.) in dichloromethane (5 ml.) under an atmosphere of nitrogen, was treated with N-methylmorpholine (0.25 g.), followed by hexanoyl chloride (0.103 g.). After being stirred for 2 hours, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2x20 ml.). The combined organic extracts were dried (MgSO4) and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (75 ml.), eluting with 6:4 v/v ethyl acetate:hexane, to give the title compound (0.24 g., 92%) as a colorless oil: NMR: 0.83 (t,3 H, CH2.CH3), 1.36 (m,4 H, CH2.CH2.CH3), 1.57 (quintet,2 H, CH2.CH2CON), 2.24 (t, 2 H, CH2.CON), 3.80 (s,3 H, COOCH3), 3.90 (s,3 H, OCH3), 3.99 (s,2 H, CH2.Ar), 7.1 (m, 2 H), 7.21 (m,2 H), 7.44 (m,2 H), 7.69 (s,1 H,H4 -indole), 9.59 (s,1 H, CONH), 10.77 (s,1 H, H1 -indole).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[CH:13][C:12]=1Br)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].O>CN(C=O)C>[CH2:1]([O:8][CH:9]([C:11]1[C:12]([C:20]#[N:21])=[CH:13][N:14]=[CH:15][C:16]=1[Br:17])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: CC(OCc1ccccc1)c1c(Br)cncc1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(OCc1ccccc1)c1c(Br)cncc1C#N
Temperature: 150 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of 4-(1-benzyloxy-ethyl)-3,5-dibromo-pyridine (400 mg, 1.1 mmol) in DMF (5 mL) is added copper cyanide (116 mg, 1.3 mmol). The mixture is heated and stirred at 150° C. for 3 h, then stirred at room temperature for 16 h. H2O is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography provides 225 mg of 4-(1-benzyloxy-ethyl)-5-bromo-nicotinonitrile.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[NH2:13].CCOC(C)=O>OS(O)(=O)=O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[NH2:13]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
Concentrated nitric acid (8.8 g, 91 mmol) was added drop wise over 30 min to a stirred solution of 2-chloro-4-fluoro-phenylamine (12 g, 82.3 mmol) in conc H2SO4 acid (100 mL) at −10° C. The mixture was stirred at that temperature for 10 min. Then the reaction mixture was poured into cooled EtOAc, and ice water was added. The organic layer was separated and washed with brine and saturated NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Recrystallization (ethyl ether) provided 2-chloro-4-fluoro-5-nitroaniline (5.0 g, 32% yield). 1H NMR (400 MHz, DMSO-d6): δ7.59 (d, J=11.2 Hz, 1 H), 7.48 (d, J=7.2 Hz, 1 H), 5.84 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:18]1CCOCC1>O>[NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:9])=[O:18]
Reactant: C1COCCO1
Reactant: COc1ccc(-c2nccc(C#N)c2N)cc1
Solvent: O
Product: COc1ccc(-c2nccc(C(N)=O)c2N)cc1

Procedure:
1 g of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarbonitrile was heated to reflux for 2 hours in 10 ml of water and 10 ml of dioxan in the presence of 4 g of Dowex 1X4-100 (OH form). The resin was removed by filtration and the filtrate was evaporated in order to remove dioxan. The aqueous residue was extracted with ethyl acetate and the organic phase was washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. Recrystallization of the residue from ethyl acetate/hexane yielded 500 mg of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarboxamide as a yellow solid of melting point 179°-181° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.C(OC(=O)C)(=[O:17])C>>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:5]([CH2:9][OH:17])=[N:6][CH:7]=1
Reactant: Cc1cc(OCC(C)C)c(Br)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(C)COc1cc(CO)ncc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-4-isobutoxy-2-methylpyridine 1-oxide (3.40 g) and acetic anhydride (50 mL) was stirred at 80° C. for 1 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in THF (50 mL) and methanol (25 mL). 1N Aqueous sodium hydroxide solution (50 mL) was added to the obtained solution, and the reaction mixture was stirred at room temperature for 15 min. 1N Hydrochloric acid (50 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.20 g) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12](Cl)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O-:24])=[C:20]([CH3:25])[CH:19]=1.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=1[CH3:25])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1cc(Cl)ccc1[O-]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
A mixture of 25.1 g of diethyl-2-chloro-propionyl-malonate, 16.5 g of sodium 4-chloro-2-methyl-phenolate and 100 ml of dimethyl formamide is stirred at 60° C. for 48 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed succesively with 100 ml of a saturated aqueous sodium bicarbonate solution and 100 ml of water. The benzene layer is evaporated to give 28.7 g of the desired compound, yield 82%.
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:31])[CH2:8][C:7]2[C:9]([CH3:30])=[C:10]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[BH4-].[Na+]>O>[CH3:31][C:4]1([CH3:3])[CH2:8][C:7]2[C:9]([CH3:30])=[C:10]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]([OH:29])[CH3:28])=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: CC(=O)c1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C)c(N2CCN(c3ccc(C(C)O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To the methanol (1.0 mL) solution of 1-{4-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]phenyl}ethanone (39 mg, 0.10 mmol) synthesized in Example 95, sodium borohydride (11 mg, 0.30 mmol) was added under ice cooling. The mixture was stirred for 2 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was crystallized from hexane to obtain the title compound 24 mg (yield 60%). Melting point was 133 to 136° C. (hexane-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][C:5]([CH2:14][C:15]([O-:17])=O)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][C:5]([CH2:14][C:15]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:17])=[N:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CC1Cc2ccccc2N1
Reactant: COc1nc(CC(=O)[O-])nc(N2CCOCC2)c1F
Agent: [Na+]
Product: COc1nc(CC(=O)N2c3ccccc3CC2C)nc(N2CCOCC2)c1F

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 600 mg of sodium (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetate obtained in example 1a (step 4a) and 272 mg of 2-methyl-2,3-dihydro-1H-indole. After purification by silica column chromatography (eluent: 97/03 dichloromethane/ethyl acetate), 366 mg of 2-(5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl) ethanone are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(Cl)c1
Reaction time: 16 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.4 g, 2.33 mmol) was diluted with THF (12 mL), treated with 3-chloro-benzoyl chloride (0.330 mL, 2.56 mmol) and stirred for 16 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 70%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[O:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:21][CH2:20]1
Reactant: c1ccc(CN2CCC(OCCN3CCOCC3)C2)cc1
Reactant: [H][H]
Solvent: CCO
Product: C1CC(OCCN2CCOCC2)CN1

Procedure:
A solution of 30.8 g. (0.106 mole) of 1-benzyl-3-(2-morpholinoethoxy)pyrrolidine in 200 ml. of ethanol containing 10% palladium on charcoal was shaken at 60° C. in about three atmospheres of hydrogen until the theoretical amount of hydrogen was used. Concentration of the cooled filtered solution at reduced pressure gave a quantitative yield of oily product. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][S:14]([CH2:17][C:18]2([C:24](O)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[CH:8][CH:7]=1.[Si]([NH:36][OH:37])(C(C)(C)C)(C)C>ClCCl>[OH:37][NH:36][C:24]([C:18]1([CH2:17][S:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:27]=[CH:28][C:6]([Cl:5])=[CH:7][CH:8]=2)(=[O:16])=[O:15])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:25]
Reactant: O=C(O)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Reactant: CC(C)(C)[Si](C)(C)NO
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NO)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
EDC (40 mg) was added to a solution of Example 13 (75 mg) in dichloromethane (20 ml), followed by tert-butyldimethylsilylhydroxylamine (32 mg) and N,N-dimethylaminopyridine (2 mg), and the resulting clear solution was stirred at room temperature for 3 h. The mixture was then washed with water, saturated bicarbonate and brine, dried over MgSO4 and evaporated. The residue was dissolved in a minimum amount of fresh dichloromethane and 1M aqueous hydrochloric acid in ether (2 ml) was added. The solution was stirred for 10 min, then evaporated and the residue purified by chromatography on silica, eluting with ethyl acetate, to give the title compound (30 mg) as a colourless glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[S:13](Cl)(Cl)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2=[N:11][S:13][N:12]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2nsnc2cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution obtained by dissolving 4-chloro-5-nitrobenzene-1,2-diamine (1) (15 g, 0.0799 mol) in 500 mL of dichloromethane (DCM) is cooled down to 0° C., and thionyl chloride (SOCl2, 11.7 mL, 0.159 mol, 2.0 eq) is slowly dripped into the solution. The reactant is agitated and reflowed for 16 hours, cooled down to room temperature, and condensed under a reduced pressure. The condensate is dissolved again in dichloromethane, cleaned with a saturated NaHCO3 aqueous solution, and subfractionated. An organic layer is dried, condensed under a reduced pressure, and passed through a silica column so as to obtain thin brown solid-phase compound (2) (15 g, yield: 87%). 1H NMR (400 MHz, CDCl3): δ ppm 8.49 (s, 1H), 8.26 (s, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:20])[CH:15](Cl)[C:16](=O)[CH3:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[S:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][C:16]=1[CH3:17])=[O:20])[CH3:12]
Reactant: NC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccccc2)nc1C
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of phenylthiourea (5.04 g, 33.1 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.8 mL, 34.8 mmol) in ethanol (50 mL) was refluxed for 19 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (8.18 g): MS: (+) m/z 263.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)C>[CH3:24][C:22]1[CH2:21][C:20](=[O:25])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Yield: 42.8 %

Procedure:
4-Methoxy-phenylhydrazine hydrochloride (5.6 g, 32 mmol; product of Aldrich Chem. Co.), sodium acetate trihydrate (5.45 g, 40 mmol; product of Kishida Chemicals) and ethyl acetoacetate (4.16 g, 32 mmol; product of Kishida Chemicals) were dissolved in 40 ml ethanol, and the solution was heated under reflux for two hours to complete the reaction. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure, 40 ml ethanol was added to the residue, and the insoluble matters were removed by filtration. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in a small volume of a solvent mixture of benzene and ethyl acetate (4:1), and the solution was subjected to silica gel chromatography (150 g of Silica Gel 60; product of Merck) Elution was performed by using a solvent mixture of benzene and ethyl acetate (4:1), the eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized with methanol, giving 2.80 g (yield: 42.9%) of PMPMP. Its structure was confirmed by 1H NMR and 13C NMR. The spectra thus obtained are shown in Table 1 below.