Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18](Br)[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[OH:7][CH:6]([CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][O:9][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CNC(C)C)cccc32)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) and triethylamine (143 parts) in dichloromethane (1500 parts) is dropwise added a solution of stannic chloride (80 parts) in dichloromethane (500 parts) at -60° C. with stirring. The mixture is warmed to room temperature, stirred for 5 hours, concentrated and shaken with aqueous 5N-sodium hydroxide and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude product (73 parts) in 87.9% yield. This is triturated in ethyl acetate to give pure 4-(2-hydroxy-3-isopropylaminopropoxy)-1-p-toluenesulfonylindole (56.1 parts) as amorphous solid in 67% yield. NMR: δCD 3SOCD 3 0.97d(6.5 Hz)6H, 2.29s3H, 2.56-2.90m3H, 3.76-4.20m3H, 6.71-7.92m9H. (HCl salt of the product) m.p. 225°-226° C. (decomp.). NMR: δCD 3SOCD 3 1.28d(6.5 Hz)6H, 2.29s3H, 2.76-3.58m, 3.93-4.53m3H, 5.92brs1H, 6.73-7.00m2H, 7.15-7.96m7H, 9.09brs2H. (HBr salt of the product) m.p. 235°-238° C. (decomp.). (HI salt of the product) m.p. 227.5° C. (decomp.)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH2:37])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:38](Cl)(=[O:46])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.Cl>ClCCl.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH:37][C:38]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:46])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl]oxyhexadecanamide hydrochloride (2.17 g) in dichloromethane (8 ml) were added phenyl chlorocarbonate (0.65 ml) and triethylamine (1.68 ml). This mixture was stirred at room temperature overnight, and then poured into a mixture of ethyl acetate (80 ml) and 1N hydrochloric acid (80 ml). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine successively. This solution was dried and evaporated to dryness. The residue was chromatographed on silica gel (200 cc) eluting with a mixture of dichloromethane and methanol (20:1) to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(phenoxycarbonylamino)-pentanoyl]oxyhexadecanamide (1.73 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>CCOCC>[CH2:19]([O:18][CH2:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12)[CH3:20]
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOCc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and lithium aluminum hydride in ether is heated at reflux temperature for 8 hours. To the mixture is added (dropwise) ethanol and water. The ethereal layer is separated, then ethanol and anhydrous hydrochloric acid is added to it. The resulting mixture is refluxed for 8 hours and the solvent is removed. The residue is extracted with dichloromethane. The dichloromethane extract is passed through a column of hydrous magnesium silicate. The eluent is concentrated and diluted with hexane to give the product of the example.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])=[CH:18][CH:19]=1)(=[O:37])=[O:36]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (19%); 1H NMR (d6-DMSO) δ 12.56 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.69–7.53 (m, 3H), 7.39–7.08 (m, 13H), 6.85 (d, J=8.1 Hz, 2H), 6.47 (d, J=15.8 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 528 (M+H+).
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.[CH3:28][C:29]1[C:34]([Pb+3])=[C:33]([CH3:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:29]1[CH:30]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:33]([CH3:36])[C:34]=1[CH:4]1[C:5](=[O:10])[C@H:6]2[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]2)[C:3]1=[O:11]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 32 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 3,5-Dimethylbiphen-4-yllead triacetate (0.805 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. 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 (2×5 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-(3,5-dimethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.139 g).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]([N:13]([CH3:45])[CH2:14][CH2:15][CH:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1)=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH:31]1([C:30]2[C:29]3[CH:28]=[CH:27][C:26]([C:37]([O:39][CH3:40])=[O:38])=[CH:25][C:24]=3[N:22]3[C:21]=2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17][CH:16]([CH2:15][CH2:14][N:13]([CH3:45])[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH3:6])[CH2:23]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN(C)C(=O)CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCCC(=O)N(C)CCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 7(R,S)-{2-[[N-(tert-butoxycarbonyl)-N-methyl-β-alanyl](methyl)amino]ethyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.09 M) in DCM was treated with TFA (20 eq) and the resulting mixture was stirred overnight at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with sat. aq. NaHCO3 then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 532 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12]C1.C(N)(=[O:18])C=C>C(O)(=O)C.O>[NH:10]1[C:14](=[O:18])[CH2:13][CH2:12][C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:1][C:2]1=2
Reactant: C=CC(N)=O
Reactant: C1=C(N2CCCC2)Cc2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC2=C(Cc3ccccc32)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1H-inden-2-yl)-pyrrolidine (5.34 g) and acrylamide (6.15 g) is stirred in argon atmosphere at 100° C. for 30 min. The temperature is then raised to 130° C. and stirring continued for another 15 min. After cooling to room temperature, water (50 mL) and acetic acid (5 drops) are added and the mixture is stirred for 30 min. The mixture is filtered and the organic phase of the filtrate is separated and washed with brine. After drying (MgSO4) and evaporating the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give a brown solid that is triturated with ethyl acetate and dried to afford the title compound. Yield: 1.12 g (21% of theory); Mass spectrum (ESI+): m/z=186 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[N:25])=[CH:16]3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[OH-:29].[Na+].OO.O>CCO.CCOCC>[CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH2:25])=[O:29])=[CH:16]3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1
Reactant: [OH-]
Reactant: CC1(C)CC(Nc2nccc(-n3cc(C#N)c4ccccc43)n2)CC(C)(C)N1
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC1(C)CC(Nc2nccc(-n3cc(C(N)=O)c4ccccc43)n2)CC(C)(C)N1
Reaction time: 8 h
Yield: 57 %

Procedure:
1-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-1H-indole-3-carbonitrile (Example 208, 100 mg, 0.27 mmol) was dissolved in EtOH (3 ml), treated with 10N-NaOH (1 ml) and hydrogenperoxide (30%, 1 ml) and the resulting mixture was stirred vigorously overnight. After addition of water (50 ml) the mixture was extracted with ethylacetate. Crystallisation with ether finally gave 60 mg (0.15 mmol, 57%) of the desired compound.
Reaction SMILES: C(OC([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.C(Cl)[Cl:34]>>[ClH:34].[NH2:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Product: CN(C)C(=O)C(N)Cc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
The acid compound 46 (0.9 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 50 as a white amorphous solid (0.64 g, 83%). 1H NMR (DMSO-d6): 12.2 (br, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.58 (m, 1H), 3.02-3.08 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 3H), 2.57 (t, J=7.6 Hz, 2H).LCMS (m/e): Obsd. [MH]+ 341, Calcd. 340.4.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9]C=1C.[C:17]([OH:20])(=[O:19])[CH3:18]>O.[O-2].[O-2].[O-2].[Cr+6]>[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:18]=1[C:17]([OH:20])=[O:19]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (32 ml) was added carefully with stirring to a solution of 2-fluoro-4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid (200 ml). The mixture was warmed up to 95° C., and solution of chromium trioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise with stirring over 2 h. The mixture was heated with stirring for another 30 minutes, allowed to cool down to r.t., and poured into water (1000 ml). The product was extracted with diethyl ether (3×200 ml). Combined ether layers were washed with water and evaporated to dryness. The residue was dissolved in 10% aqueous potassium carbonate and washed with ether. The aqueous layer was acidified with con. HCl, and the resulting white precipitate filtered and dried (16.3 g, 83%), m.p. 174-177° C. 1H NMR.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:32])=[C:14]([C:28]([O:30][CH3:31])=[O:29])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:16]=1[C:17]([O:19]C)=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:32][C:13]1[NH:12][C:11]2[CH2:10][O:19][C:17](=[O:18])[C:16]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
In an operation carried out in a manner similar to that described in the preceding example, 1.52 grams of 80 percent pyridinium bromide perbromide (3.81 millimoles) was added in one portion to a solution of 1.00 gram (3.17 millimoles) of dimethyl 2,6-dimethyl-4-(o-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.40 milliliter of pyridine in 20 milliliters of dry chloroform cooled to 0° C. The mixture was stirred for 30 minutes at 0° C., then at reflux temperature for 1.5 hours. Thereafter, the mixture was cooled, washed successively with hydrochloric acid and brine, dried, subjected to reduced pressure to remove the solvent and to obtain as residue crude methyl 2-methyl-4-(o-tolyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product. The crude product was chromatographed on silica and eluted with 65 percent ethyl acetate--35 percent hexane to obtain 0.58 gram (61 percent yield) of white crystalline material which after recrystallizing from ethyl acetate-hexane and drying at 80° C./0.005 mm Hg for 17 hours had a melting point of 224°-225° C. and the following analyses:
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[C:25]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:34][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCc1cc(OCc2ccc(C(=O)O)cc2)c2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1cc(OCc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
4-[(2-Propylquinolin-4-yloxy)methyl]benzoic acid (240 mg) was added to a mixture of benzene sulphonamide (120 mg), 4-dimethylaminopyridine (90 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (150 mg) in dichloromethane (20 ml) and the mixture stirred overnight. Chloroform (20 ml) was added the mixture was washed successively with 1M citric acid solution (10 ml), water (2×10 ml), saturated sodium chloride solution (5 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue triturated with methanol to give 4-[(2-propylquinolin-4-yloxy)methyl]-N-phenylsulphonylbenzamide as a white powder (160 mg), m.p. 140° C. (dec.); NMR (d6 -DMSO): 0.95(t,3H), 1.79(m,2H), 2.88(t,2H), 5.5(s,2H), 7.14(s,1H), 7.5-7.7(m,6H), 7.78(dt,1H), 7.87-8.02(m,5H), 8.18(dd,1H); mass spectrum (-ve FAB, DMSO/Gly): 495 (M-H)- ; microanalysis found: C,66.1; H,5.4; N,5.8%; C26H24N2O4S.0.5H 2 O requires: C,66.5; H,5.3; N,6.0%.
Reaction SMILES: [CH:1](OCC)=O.[C:6](#[N:8])[CH3:7].[H-].[Na+].[NH:11]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1)[NH2:12].[OH-].[Na+]>CCOCC.C(O)C>[NH2:8][C:6]1[CH:7]=[CH:1][N:11]([C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[N:12]=1
Reactant: CC#N
Reactant: CCOC=O
Reactant: NNc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccn(-c2nc3ccccc3[nH]2)n1
Reaction time: 16 h

Procedure:
A mixture of ethyl formate (5 ml, 62 mmol), acetonitrile (1 g, 25 mmol) and ethanol (0.5 ml) is added dropwise to a suspension of sodium hydride (0.96 g, 40 mmol) in ether at room temperature. After stirring for 16 hours the volatiles are removed under reduced pressure. The residue is diluted with water and the pH is adjusted by addition of AcOH to 7. After addition of 2-hydrazino1-H-benzimidazole (6.6 g, 45 mmol) the mixture is allowed to stand for 5 hours. The pH is adjusted with sodium hydroxide, and the mixture extracted with chloroform. The crude title product is used without further purification. 1H-NMR (400 MHz, d6-DMSO): 12.7 (s, 1H); 7.57 (s, 1H); 7.49 (m, 2H); 7.40 (m, 2H); 7.19 (s, 2H); 6.9 (s, 2H); 5.44 (d, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@@H:38]([C:52]4[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:66]([C@:73](N)([C:79]([O:81][CH:82]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:80])[CH2:74][O:75][C:76](Cl)=[O:77])([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67].[N:96]1C=CC=CC=1>O1CCCC1>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@@H:38]([C:52]4[CH:57]=[CH:56][C:55]([N:58]([NH2:96])[C:76]([O:75][CH2:74][C@@H:73]([C:66]([O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:67])[C:79]([O:81][CH:82]([C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)=[O:80])=[O:77])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:27])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)[C@@](N)(COC(=O)Cl)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N(N)C(=O)OC[C@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)C)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 12, 4.56 g of 3-acetoxymethyl-7β-[(2R)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate are reacted with 3.8 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride and 0.95 ml of pyridine in 135 ml of tetrahydrofuran and worked up. Th resulting crude product is chromatographed over 400 g of silica gel (500 ml fractions), fractions 1-12 being eluted with toluene/ethyl acetate (3:2) and the later fractions with toluene/ethyl acetate (1:1). By reprecipitating fractions 9-23 from CH2Cl2 /ether/hexane, 3-acetoxymethyl-7β-{(2R)-2-[4-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. [α]D20 =+8°±1° (0.82% in CHCl3).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C@@H:48]([CH2:51][CH3:52])[CH2:49][NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:50][CH2:49][C@@H:48]([CH3:47])[CH2:51][CH3:52])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC[C@H](C)CN
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC[C@@H](C)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-(−)-2-methylbutylamine (Alfa) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: CC[N:3](CCCC(NC1C=C(/C=C/C2C=CC=CC=2Cl)N=C2C=C(Cl)C=CC=12)C)CC.Cl[C:33]1[C:34]2[CH2:42][CH2:41][N:40](C3C=CC=CN=3)[CH2:39][C:35]=2[N:36]=[CH:37][N:38]=1>>[N:36]1[C:35]2[CH:39]=[N:40][CH:41]=[CH:42][C:34]=2[C:33]([NH2:3])=[N:38][CH:37]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: Clc1ncnc2c1CCN(c1ccccn1)C2
Product: Nc1ncnc2cnccc12

Procedure:
Appropriate 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine derivatives are prepared starting from 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinoline derivate is reacted with appropriate alkylating agent to give the N-substituted nitroquinoline, which is reduced using standard procedures known in the art to yield 7-aminoquinoline derivative. The resulting aminoquinoline derivated is then condensed with the appropriate 4-chloro-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine to give the desired 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine derivative. As a representative example, preparation of the N-morpholionethyl derivative is depicted in Scheme 6.