Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[C:17]1([CH2:27][NH2:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:28][CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Yield: 75.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-naphthalenemethylamine (0.24 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl1 and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 76%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.74 (3H, s); 4.47 (2H, d, J=6.0 Hz); 6.69 (1H, d, J=16.0 Hz); 7.32-8.32 (13H, m).
Reaction SMILES: Cl[S:2][N:3]([CH2:12][CH2:13][CH3:14])[P:4](=[S:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH3:15][NH:16][C:17](=[O:30])[O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=1.[O-][Si]([O-])=O.[Mg+2].C(OCC)C>CN(C)C=O.CCCCCC>[CH2:6]([O:5][P:4]([N:3]([CH2:12][CH2:13][CH3:14])[S:2][CH2:15][NH:16][C:17](=[O:30])[O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:27])[CH3:28])=[C:21]([CH3:29])[CH:20]=1)([O:8][CH2:9][CH3:10])=[S:11])[CH3:7]
Reactant: CCCN(SCl)P(=S)(OCC)OCC
Reactant: CNC(=O)Oc1cc(C)c(N(C)C)c(C)c1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN(SCNC(=O)Oc1cc(C)c(N(C)C)c(C)c1)P(=S)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude O,O-diethyl N-(chlorothio)-n-propylphosphoramidothioate (prepared in Preparation I) is cooled in an ice-bath and 2.79 gm. (0.013 mole) of 4-(dimethylamino)-3,5-xylyl methylcarbamate dissolved in 20 ml dimethylformamide (with 2 ml triethylamine added) are mixed as a batch. This reaction mixture is stirred at 25° C. for four hours, and then diluted with hexane. The organic solution is washed with water, dried over anhydrous sodium sulfate, and the organic solvents are removed by evaporation under reduced pressure. The residue thus obtained is transferred to a column of "Florisil". The chromatogram is developed first with a solvent mixture consisting of 10 percent diethyl ether in petroleum ether, and finally with 30 percent diethyl ether in petroleum ether. After collecting the later eluate and removing the solvents by evaporation under reduced pressure, there is obtained the desired 4-(dimethylamino)-3,5-xylyl [[(diethoxyphosphinothioyl)-n-propylamino]thio]methylcarbamate as a yellow oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:43])[CH2:22][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]2)[CH2:20][C:19]([CH3:42])([CH3:41])[NH:18]1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7]([N:23]([CH:21]2[CH2:22][C:17]([CH3:43])([CH3:16])[NH:18][C:19]([CH3:42])([CH3:41])[CH2:20]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[N:6]=2)[CH:31]2[CH2:32][C:33]([CH3:40])([CH3:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH2:36]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc(NCC=C)n1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCNc1nc(NCC=C)nc(N(CCCCCCN(c2nc(NCC=C)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Reaction time: 2.5 h

Procedure:
46.5 g (0.206 mole) of 2,4-bis-allylamino-6-chloro-1,3,5-triazine and 39.5 g (0.1 mole) of N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine are dissolved rapidly by stirring in 200 ml of xylene in an atmosphere of nitrogen, a clear solution being formed initially. A precipitate of the hydrochlorides begins to form after approx. 10-15 minutes. The mixture is stirred for a further 2.5 hours at reflux temperature. A total of 8.8 g (0.22 mole) of finely powdered solid sodium hydroxide is then added in 5 portions in the course of 5 hours, and stirring is continued for a further 10 hours at reflux temperature. The reaction mixture is worked up by being filtered while hot (approx. 125°) through a preheated suction filter, the residue is washed with a little warm xylene, and the filtrate is induced to crystallise by stirring and cooling (0°-5°). The crystalline precipitate is filtered off and recrystallised from special boiling point gasoline (boiling point 110°-140°), which gives N,N'-bis-[2,4-di-(allylamino)-1,3,5-triazin-6-yl]-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine of melting point 161°-163°. This product is identical with the product prepared in accordance with Example 1b) (stabiliser No. 1).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.CC(=O)CCCCCCCC.[Cl-].[Cs+].[CH2:20]1[O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27]CO[CH2:24][CH2:23][O:22][CH2:21]1>>[CH2:3]1[O:2][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:1][O:5][CH2:4]1
Reactant: O=C1OCCO1
Reactant: C1COCCOCCOCCOCCO1
Agent: CCCCCCCCC(C)=O
Agent: [Cl-]
Agent: [Cs+]
Product: C1COCCOCCOCCOCCOCCO1
Reaction time: 8 h

Procedure:
According to this invention, 22 grams of ethylene carbonate, 11 grams of 2-decanone and 0.565 grams of CsCl were placed in a 100 ml round-bottomed flask which was fitted with a thermometer, distillation head and a cold trap. The flask was heated in an oil bath (with magnetic stirring) at about 150° C. to about 175° C. for about 8 hours. Analysis of the reaction mixture by gas chromatography showed that 15-Crown-5 and 18-Crown-6 were formed.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>CN(C=O)C.O>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 5-cyanooxindole (213 mg, 1.35 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (54 mg, 1.35 mmol, prewashed with hexane) in DMF (2 ml). The mixture was stirred for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (152 mg, 0.45 mmol), (prepared as described for the starting material in Example 5), was added and the mixture was heated at 70° C. for 1 hour. The mixture was allowed to cool and then was diluted with water and adjusted to pH1 with 2M hydrochloric acid. The solution was washed with ether and then basified with aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water, ether and dried under vacuum. The solid was purified by flash chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20). The purified solid was dissolved in methylene chloride/methanol and 5M methanolic hydrogen chloride (0.5 ml) was added. The solution was concentrated by evaporation to a total volume of 2 ml and ether (15 ml) was added. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (120 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[Cl:11][C:4]1[S:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COC(=O)c1cc(Cl)sc1N
Product: CCOC(=O)C(=CNc1sc(Cl)cc1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-5-chlorothiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a similar manner to that used in Reference Example 10 yields diethyl (5-chloro-3-methoxycarbonylthienyl)aminomethylenemalonate as crystals melting at 89.5°-90.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17]CC)=[O:16])=[C:7]2[OH:20])[CH3:2].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([OH:17])=[O:16])=[C:7]2[OH:20])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc2c(O)c(C(=O)O)cnc2nc1C
Temperature: 25 °C

Procedure:
A mixture of ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (10.0 g), 5M sodium hydroxide solution (200 ml), IMS (64 ml) and water (64 ml) was boiled under reflux for 2 hours. The mixture was cooled to ambient temperature and then filtered. The residue was dissolved in water, acidified to pH 5 with glacial acetic acid and filtered. The residue was triturated with hot IMS, cooled and filtered to give 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid, m.p. 259°-261° C.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.[NH2:34][CH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([NH:34][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: NC1CCc2ccccc21
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1CCc2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added 2.5 g triethylamine, and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed to come to room temperature and then stirred 2 hours. To the reaction mixture is then added, dropwise, 3.4 g 1-aminoindan, and the reaction mixture then stirred for 16 hours. The reaction mixture is then extracted several times with 2 N hydrochloric acid, then with 2 N aqueous sodium hydroxide solution, washed well with saturated aqueous sodium chloride, dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The resulting residue is rapidly filtered over silica gel, with methylene chloride as solvent. The necessary fractions indicated to contain reaction product by thin layer chromatography of samples are pooled and solvent removed by evaporation under vacuum to give title product as a viscous oil, characterized by NMR (in CDCl3); triplet at 5.15 ppm (4 protons) and doublet at 6.4 ppm (1 proton).
Reaction SMILES: C([NH:8][C:9]1[N:13]([CH2:14][CH2:15][O:16][CH3:17])[N:12]=[C:11](Br)[C:10]=1[N+:19]([O-])=O)C1C=CC=CC=1.[ClH:22]>C(O)C.[Pd]>[ClH:22].[ClH:22].[NH2:19][C:10]1[CH:11]=[N:12][N:13]([CH2:14][CH2:15][O:16][CH3:17])[C:9]=1[NH2:8]
Reactant: COCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCCn1ncc(N)c1N
Reaction time: 1 h

Procedure:
A mixture of 5-benzylamino-3-bromo-1-(2′-methoxyethyl)-4-nitropyrazole (4 g, 2.8 mmol) in ethanol (500 ml) comprising a 10% Pd/C catalyst (Johnson-Mattey Type 487, dry weight 0.5 g) and 36% hydrochloric acid (0.57 g, 5.6 mmol) was hydrogenated in a Parr Autoclave (1 l) at 1 MPa for 1 hour. The catalyst was then removed by filtration and washed with ethanol, and the filtrate was evaporated under reduced pressure. A crude orange-colored solid (2.8 g) was thus obtained, and was triturated in EtOAc (20 ml) for 1 hour. The solid was then filtered off and washed with cold EtOAc (20 ml) and then dried under vacuum to give the 4,5-diamino-1-(2′-methoxyethyl)pyrazole in the form of a beige-colored solid (0.7 g, 27%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccc(C2CCN(CCO)CC2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CCO)CC5)cc4)nn23)c1

Procedure:
The titled compound was prepared in analogous fashion as Example 522 using N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide, 2-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanol and N-phenylbis(trifluoromethanesulphonimide) to give N-tert-butyl-3-(2-{4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a orange lyophilate (150.9 mg, 82% yield). LCMS (E/I+) 549 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.27 (s, 1H), 9.04 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.72 (d, 2H, J=7.6 Hz), 7.60 (s, 1H), 7.21 (m, 3H), 7.0 (d, 1H, J=4.5 Hz), 3.78 (t, 2H, J=5 Hz), 3.61 (d, 2H, J=11 Hz), 3.38 (m, 1H), 3.18 (m, 2H), 3.12 (m, 2H), 2.76 (m, 1H), 1.97 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic (25.0 g, anhydride (250 ml) was heated at reflux for two hours. The reaction mixture was then cooled and poured into water (750 ml) with stirring. After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered, washed with water and dried to give 26.5 g (85%) of the title product as a white flaky solid. mp 175-176° C. 1H NMR (CDCl3): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:22]1[C@@H:18]([CH2:17][O:16][C:14]2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[C:10]3[C:15]=2[C:6]([NH:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[N:7][CH:8]=[N:9]3)[CH2:19][C@H:20]([OH:23])[CH2:21]1)(=[O:32])[CH3:31]
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(=O)O
Product: COc1cc(OC[C@H]2C[C@H](O)CN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 59 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (120 mg) with acetic acid (18 μl) to give the title compound as a white solid in 59% yield; NMR spectrum (DMSO-d6) 9.95 (s, 1H), 8.46 (s, 1H), 8.16-8.14 (m, 1H), 7.73-7.70 (m, 1H), 7.46 (t, 1H), 6.85 (s, 1H), 6.84 (s, 1H), 5.10 (m, 1H), 4.67-4.63 (m, 1H), 4.47-4.38 (m, 2H), 4.26-4.21 (m, 1H), 3.94 (s, 3H), 3.59 (dd, 1H), 3.41 (dd, 1H), 2.11-2.05 (m, 2H), 2.00 (s, 3H); Mass spectrum MH+ 461.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:22]([O:24]C)=[O:23])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:22]([OH:24])=[O:23])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbmethoxy-6-chloroindole from above, in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide and stir for 8 hours at 40° C. Dilute the reaction with water(10 mL) and ethyl acetate (10 mL). Separate the layers and acidify the aqueous layer. Extract the aqueous with ethyl acetate, dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize from ethyl acetate/hexane to yield the title compound (75 mg); mp 250°-255° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([C:11](=[O:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.C(O[Al](OC(C)C)OC(C)C)(C)C.CC(O)C.Cl>C1(C)C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[C:8]([C@@H:11]([OH:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCOC2
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCOC2

Procedure:
A mixture (S)-tert-butyl 1-(4H-benzo[d][1,3]dioxin-7-yl)-1-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at +65° C. for 15 hours. The reaction mixture was allowed to cool down and poured into 1M HCl (50 mL) and extracted with EtOAc (2×50 mL). The organic phase was washed with water, brine, dried over MgSO4, filtered and solvents removed by evaporation to afford a crude product as a colourless solid. The crude product was first purified by Flash chromatography, (solvent A=Heptane, solvent B=EtOAc+10% MeOH). An gradient of 10% B to 50% B in A was used. The obtained product was crystallised from DCM/Heptane to afford the subtitle compound colourless needles. Yield 414 mg (60%)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[CH3:10][C:6]1[N:5]=[C:4]([CH:1]([NH2:17])[CH3:2])[CH:9]=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cccc(C)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C(C)N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of 2-acetyl-6-methylpyridine (4.7 g, 34.8 mmol) in anhydrous methanol (100 ml) was added ammonium acetate (26.8 g, 348 mmol) and sodium cyanoborohydride (1.75 g, 27.8 mmol) and the resulting mixture stirred at RT overnight. The mixture was evaporated and the residue dissolved in water and basified by the addition of KOH and extracted with DCM (×3). The DCM layers were combined and washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica to afford the title compound (i-14) (eluent: 5% MeOH in DCM) to give 2.8 g (59%) as a clear oil. 1H NMR (CDCl3): 1.41 (d, J 6.7 Hz, 3H), 1.78 (brs, 2H), 2.54 (s, 3H), 4.21 (q, J 6.7 Hz, 1H), 6.99 (d, J 7.6 Hz, 1H), 7.09 (d, J 7.7 Hz, 1H), 7.52 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:16])[N+:3]=1[O-:17].Cl[S:19]([OH:22])(=[O:21])=[O:20].C(NC(C)C)(C)C>C(Cl)(Cl)Cl>[OH-:17].[NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15]2)[CH:5]=[C:4]([CH3:16])[N+:3]=1[O:17][S:19]([OH:22])(=[O:21])=[O:20]
Reactant: Cc1cc(N2CCC=CCCC2)cc(N)[n+]1[O-]
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Product: Cc1cc(N2CCC=CCCC2)cc(N)[n+]1OS(=O)(=O)O
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2-amino-6-methyl-4-(3,4,7,8-tetrahydro-1-(2H)-azocinyl)-pyridine-1-oxide, 1.00 grams of chlorosulfonic acid, and 2.5 grams of diisopropylamine in 25 ml of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered and washed with ether to give the crude product. This is recrystallized from DMF and ethyl acetate to yield the purified 2-amino-6-methyl-4-(3,4,7,8-tetrahydro-1(2H)-azocinyl)-1-(sulfooxy)-pyridinium hydroxide, inner salt.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>C1COCC1>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.