Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](O)=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH2:1]([N:8]1[C:12]([Cl:23])=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1nnn(Cc2ccccc2)c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)CCc1nnn(Cc2ccccc2)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 1.0 g. (4 mmol.) of 1-benzyl-4-(2-carbethoxyethyl)-5-hydroxy-1,2,3-triazole in 2 ml. of phosphorus oxychloride is added 0.5 g. (5 mmol.) of phosphorus pentachloride. The reaction mixture is stirred at 25° for 2 hours, then warmed on a steam bath for 10 minutes and evaporated to dryness. The residue is dissolved in 0.5 ml. of phosphorus oxychloride and the solution is neated to reflux for 30 minutes, cooled and evaporated to dryness to give 1-benzyl-4-(2-carbethoxyethyl)-5-chloro-1,2,3-triazole.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][C:4]1([CH3:10])[CH3:9].[Cl:11]OC(C)(C)C>CO>[Cl:11][N:5]1[C:4]([CH3:10])([CH3:9])[CH:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)NC(=O)OC1CO
Solvent: CO
Product: CC1(C)C(CO)OC(=O)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a 0° C. solution of 5-(hydroxymethyl)-4,4-dimethyloxazolidin-2-one (250 mg, 1.72 mmol) in 2 mL of methanol was added tertbutyl hypochlorite (290 uL, 2.58 mmol). The reaction was stirred at 0° C. for 1 hour, then concentrated to a crude residue under reduced pressure. The crude product was purified by column chromatography (20 to 80% ethyl acetate in hexanes) to give the title compound as a clear liquid (248 mg, 1.38 mmol, 80%). 1H NMR (CDCl3, 400 MHz) δ 1.29 (s, 3H), 1.42 (s, 3H), 2.28-2.31 (dd, J=4.8, 7.7 1H), 3.85-3.88 (m, 1H), 3.91-3.98 (m, 1H), 4.37-4.40 (dd, J=4.7 6.9 Hz, 1H). LRMS (ESI/APCI) m/z 180 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([CH2:12][C:13](OCC1C=CC=CC=1)=[O:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C>CCOCC>[CH2:1]([O:8][C:9]([C@@H:10]1[NH:11][C:13](=[O:14])[CH2:12]1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1C[C@H](C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
In 485 ml of dry ether was dissolved 45 g (143.8 m mol) of D-aspartic acid dibenzyl ester (42) and after cooling the solution to 0° C. under an argon atmosphere, 20 ml (143.8 m mol) of triethylamine was added dropwise to the solution. Then, 15.6 g (143.9 m mol) of trimethylsilyl chloride was further added dropwise to the mixture at the same temperature as above and the resultant mixture was stirred for one hour. Precipitates thus formed were filtered off under an argon atmosphere and the filtrate was cooled to 0° C. to -5° C. and then 134.8×1.01 m mol of an ether solution of t-butyl magnesium chloride was added dropwise to the mixture with stirring. After further stirring the mixture for 2 hours at 0° C. and then for 3 hours at room temperature, the mixture was cooled to 0° C., 100 ml of 2N HCl (saturated with NH4Cl) was added to the mixture and after stirring the mixture for 30 minutes, 100 ml of a saturated aqueous ammonium chloride solution was added to the mixture. The ether layer thus formed was separated and the aqueous layer was extracted twice each time with 200 ml of ethyl acetate. The ether layer was combined with the ethyl acetate extract, and after washing the mixture with 300 ml of a saturated aqueous ammonium chloride solution and drying with anhydrous magnesium sulfate, ether and ethyl acetate were distilled off under reduced pressure. To the residue was added 10 ml of ethyl acetate to form crystals, which were collected by filtration to provide 13.7 g of (R)-4-benzyloxycarbonyl-2-azetidinone (43). In addition, the mother liquor was concentrated and purified by silica gel column chromatography (eluant:ethyl acetate-n-hexane (2:1)) to provide 5.1 g of the desired product. M.p. 136°-138° C.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([Pb+3])=[C:31]([CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH3:37])[CH:30]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: Cc1cc(Br)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 7.6 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 0.039 mol) and 4-dimethylaminopyridine (24 g, 0.196 mol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-dimethylphenyllead triacetate (24 g, 0.042 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-dimethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (1 g).
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][O:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25]C(OC(C)(C)C)=O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])=[O:36]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(N)C(C)C)N2C(=O)C(N)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. 2,236,620, are mixed in 100 ml of dimethyl formamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness to give 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by standard procedures to give the title product.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11].[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[C:1]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Yield: 92 %

Procedure:
Preparation D10, Step 1: Butyryl chloride (0.68 mL, 6.5 mmol, 1 eq) was slowly dripped into a mixture of 2-amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq), 1.000N NaOH (6.50 mL, 6.5 mmol, 1 eq) and THF (enough to dissolve) at 0° C. More acid chloride and base were added to drive the reaction to completion. After 4 days ethyl acetate was added followed by 1N HCl. The layers were separated and the organic layer washed with 1N HCl (2×), saturated sodium bicarbonate (1×), and brine (1×). The organic layer was dried (MgSO4) and stripped to yield 2-butyramido-5-chlorobenzamide (1.44 g) as a white powder. Mass Spec (ESI) (M+H)+=241.0.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:13]3[C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=3[CH3:33])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]3[C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=3[CH3:33])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccn(-c2ccc(-n3ccnc3)cc2)c1-c1ccc(C(N)=O)cc1C
Solvent: O
Solvent: CO
Product: Cc1cc(C(N)=O)ccc1-c1c(CCC(=O)O)ccn1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of ethyl 3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoate (25 mg, 0.057 mmol) and LiOH monohydrate (42 mg, 1 mmol) in a mixture of methanol (1.5 mL) and water (0.5 mL), and the reaction mixture was stirred at room temperature overnight. Methanol was removed under reduced pressure, and the residue was diluted with water (5 mL), and the aqueous layer was washed with ethyl acetate (5 mL×3). The aqueous layer was adjusted to PH=6˜7 with 1N HCl, and the resulting mixture was extracted with a mixture of dichloromethane and isopropanol (3:1, 5 mL×3). The combined organic layer was dried, and evaporated to give 3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoic acid, (5-4, R1=1H-imidazol-1-yl) (12 mg, yield: 51%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24].O>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:25][CH2:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Solvent: CCO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (8.9 g; 27.7258 mmole) and ethylamine in ethanol (33% w/w; 24 ml) was heated at 100° C. under pressure (autoclaved) for 28 hours. The mixture was cooled, treated with water and concentrated, followed by extraction with chloroform. The organic extract was washed with water, dried and evaporated to give a red solid (8.1 g; 81%).
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[H][H]>C(O)C.[Pt]=O>[CH3:1][NH:2][CH:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CN=C1CCCc2scnc21
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCCc2scnc21
Yield: 80 %

Procedure:
Catalytic hydrogenation of the 4-methylimino derivative obtained in step (e) in ethanol containing excess methylamine, in the presence of platinum oxide, proceeds slowly at 50° C. under ordinary pressure. After the theoretical amount of hydrogen has been taken up, the solution is filtered, evaporated, and the residue is distilled: B.p.0.4 =86°-88° C.; Yield; 80%.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CN([CH:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])C.CO>C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][C:16]1[C:17](=[O:21])[N:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]2=[N:11][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CN(C)C=C1CCOC1=O
Reactant: Nc1nccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c(CCO)cnc2c3ccccc3ccn12
Temperature: 200 °C
Yield: 75 %

Procedure:
A heterogenous mixture containing 14.4 g of 1-isoquinolinamine (0.1 m) and 14.12 g of dihydro-3-[(dimethylamino)methylene]-2(3H)-furanone was heated to 200° C. for 4 hours to yield a homogenous yellow orange solution which solidified upon cooling to ambient temperature. The solidified reaction mixture was titurated with methanol and ethyl acetate to yield 3-(2-hydroxyethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one as a tan solid (18.0 g; 75% yield) of the formula ##STR26## having a melting point of 185.2°-187.0° C. and the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[CH3:54][C:55]1([CH3:62])[CH2:60][CH2:59][CH2:58][CH:57]([NH2:61])[CH2:56]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:61][CH:57]3[CH2:58][CH2:59][CH2:60][C:55]([CH3:62])([CH3:54])[CH2:56]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: CC1(C)CCCC(N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CCCC(NC(=O)c2cc3nc(Nc4c(Cl)cncc4Cl)[nH]c3c3c2OC(C)(C)C3)C1
Yield: 11.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.070 g, 0.178 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.114 g, 0.355 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 3,3-dimethylcyclohexanamine (0.100 g, 0.787 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 0.93 (s, 6H), 1.07-1.11 (m, 2H), 1.23-1.29 (m, 2H), 1.33 (s, 6H), 1.49-1.54 (m, 2H), 1.80 (s, 2H), 3.00 (s, 2H), 3.80 (m, 1H), 7.20 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 8.43 (s, 2H), 10.89 (s, 1H), 11.41 (s, 1H); MS [M+H]+: 502.31.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[C:33]([Cl:38])=[C:32]([Cl:39])[CH:31]=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[CH:31][C:32]([Cl:39])=[C:33]([Cl:38])[C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 24 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc and yielded 0.16 g of impure product. Then, crystallization from EtOAc/heptane gave 90 mg (37%) of a white solid; mp 208.5-210.0° C.; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (m, 3H), 7.07 (m, 1H), 5.08 (br s, 2H), 3.63 (m, 4H), 3.40 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 3275, 1693, 1671, 1602, 1554, 1449, 1409, 1365, 1319, 1312, 1302, 1254, 1166, 1113, 762 cm−1; MS (EI) m/z 487 (M+), 346, 345, 105, 94, 92, 76, 65, 62, 56, 52; MS (FAB) m/z 488 (M+H+), 488, 487, 434, 433, 432, 431, 388, 57, 42, 41; HRMS (EI) calcd for C25H27Cl2N3O3 487 1429, found 487.1441; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.41; H, 5.70; N, 8.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:31]I.O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:31])[C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.25 mmol) of N-(2-fluoro-4-nitrophenyl)-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 0.75 ml of DMA is added dropwise to a suspension of 30 mg (0.75 mmol) of sodium hydride in 0.75 ml of DMA, and the mixture is stirred at RT for 30 min. 77 μl (1.24 mmol) of methyl iodide are then slowly added dropwise, and the mixture is stirred for a further 30 min. Water is then added, and the mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:27]1CCCC1>O.C(OCC)(=O)C>[OH:27][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O)ccnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.3 mmol) in tetrahydrofuran (1.8 mL) was added sodium hydride as a 60% dispersion in mineral oil (22 mg, 0.56 mmol) followed by a few drops of water. The reaction mixture was stirred at ambient temperature for 5 minutes and then at 40° C. for 2 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 5-100% ethyl acetate in heptane) to afford the title compound as a pale yellow oil, which was used in the next step without any further purification (70 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCCNC(=O)OC(C)(C)C)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)CCNC(=O)OC(C)(C)C)c1C
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a stirred solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-chloro-2-methylbenzoate (0.5 g, 1.46 mmol) in acetonitrile (10 mL), cesium carbonate (0.95 g, 2.92 mmol) and methyl iodide (1 g, 7.3 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue washed with ethyl acetate and the filtrate concentrated before purification by column chromatography to afford desired product (0.325 g, 62%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)[C:11]([Cl:13])=O>ClCCl.CN(C=O)C>[Cl:13][CH2:11][C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCl)C1CCCCO1
Temperature: 2.5 °C

Procedure:
Tetrahydropyran-2-carboxylic acid (3.3g) in dry dichloromethane (60ml) was treated with oxalyl chloride (4.8g, 3.3ml) and DMF (2-3 drops). After the initial effervescence had ceased the mixture was left for a further 1h at ambient temperature. The solvent and excess oxalyl chloride were removed in vacuo and the resultant oil [vmax (CH2Cl2)1830cm-1 ] was dissolved in dichloromethane (20ml). This acid chloride solution was then added dropwise to a freshly prepared ethereal solution of diazomethane (ca 2 fold excess) cooled to 0-5° C., t.l.c. analysis (60% ethyl acetate in hexane) showed a single mobile spot, i.r. spectrum of a sample showed clean conversion to the diazoketone [vmax (CH2Cl2) 2100cm-1 ]. Hydrogen chloride gas was bubbled through the solution until no further starting material was observed by t.l.c. The mixture was washed with brine, dried and the solvent removed in vacuo and the residue purified by flash chromatography on silica gel. The title compound was obtained as a pale yellow oil, (2.8g, 68%); vmax (CH2Cl2) 1740cm-1 ; δH (CDCl3) 1.4-1.7 (4H, m), 1.91-1.98 (2H, m), 3.42-3.53 (1H, m), 3.95-4.07 (2H, m) and 4.48 (2H, s) [Mass spectrum: +ve ion (NH3), MH+ (163), MNH4+ (180)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccccc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), phenylboronic acid (65 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-phenyl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[S:12](=[O:16])(=[O:15])([OH:14])N>>[NH2:1][C:2]1[C:7]([S:12]([OH:16])(=[O:15])=[O:14])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Product: Cc1cc(N)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
1 mol of 1-amino-3-methyl-4-nitrobenzene, 1,000 ml of one of the solvents indicated below, 198 g of sulphamic acid and the % by volume of catalyst indicated below are reacted analogously to Example 2. The yields of 1-amino-3-methyl-4-nitrobenzene-6-sulphonic acid obtained, and the reaction temperatures are indicated in the table which follows: