Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>C1COCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([B:12]([OH:17])[OH:13])=[CH:4][C:5]=1[F:11]
Reactant: COc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1F
Yield: 78.6 %

Procedure:
Then, 9.6 g of magnesium was added to 230 ml of THF, and the solution thus formed was slowly added dropwise with 70.9 g of the 4-bromo-2-fluoroanisole obtained by the procedure mentioned above to prepare a Grignard reagent. The reagent was added dropwise to a mixture of 123.8 g of triisopropyl borate and 391 ml of THF at a temperature of -60° C. to -50° C. with stirring. After the dropping of the reagent was finished, the solution was subjected to reaction at an ambient temperature for 2 hours, added with 242 ml of a 1N-aqueous hydrochloric acid solution, subjected to further reaction for 1 hour, extracted with an ether, washed with water, and concentrated under a reduced pressure to obtain 46.2 g of 4-methoxy-3-fluorobenzene boronic acid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.3 mmol) was reacted with 2-hydroxy-fluoren-9-one (0.30 g, 1.5 mmol) in the presence of potassium carbonate (0.21 g, 1.5 mmol) and dimethyl formamide (10 ml) to give 8-(9-oxo-9H-fluoren-2-yloxy)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.43 g, 63%; purified by column chromatography using silica gel and ethyl acetate: heptane=1:1 as eluent). MS (M−H+)=442.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18](OC2CCCC(=O)C=2)=[O:19])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C:37]([CH3:41])([OH:40])[C:38]#N.[C:42](O)(=O)[CH2:43][C:44](CC(O)=O)(C(O)=O)[OH:45]>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([C:38]2[C:44](=[O:45])[CH2:43][CH2:42][CH2:41][C:37]=2[OH:40])=[O:19])[C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C1C=C(OC(=O)c2cc3cccnc3n(Cc3ccccc3)c2=O)CCC1
Reactant: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCC(O)=C1C(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C

Procedure:
2.13 g (5.7 mmol) of 3-oxo-1-cyclohexenyl 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in dichloromethane (60 mL), and 0.97 mL (6.9 mmol) of triethylamine and 0.54 g (6.3 mmol) of acetone cyanohydrin were added to the above solution. The resulting mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was washed with methanol, and 1.31 g of the title compound was obtained as dark yellow crystals (yield: 62%).
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[C:10]#[N:11])(=O)C.[OH-].[Na+]>C(O)C.O>[OH:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[C:10]#[N:11]
Reactant: CCCCCC(CCCN(C#N)CCCCCC(C)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(C#N)CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 7-[N-(4-acetoxynonyl)cyanamido] -2-methylheptanoate (7.6 g., 0.02 mole) in ethanol (50 ml.) is added a solution of sodium hydroxide (1.6 g., 0.04 mole) in water (15 ml.) and the reaction is stirred at ambient temperature for 20 hours. Then most of the ethanol is removed in vacuo and the residue taken up in water (150 ml.). The solution is extracted once with ether then acidified with hydrochloric acid (dil.). The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate, then removed under vacuum to give 7-[N-(4-hydroxynonyl)cyanamido]-2-methylheptanoic acid as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:36][CH2:37][CH3:38])=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH2:37]([O:36][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][C:11]=1[C:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[CH:18]=1)=[O:16])[CH3:38]
Reactant: CCOc1c(OCc2ccccc2)cccc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(O)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Yield: 38.8 %

Procedure:
To a solution of (3-benzyloxy-2-ethoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (664, 195 mg, 0.37 mmol) in a mixture of methanol (20 mL) and tetrahydrofuran (50 mL) was added palladium on carbon (50 mg, 10% wt., 0.2 mmol). The mixture was stirred under hydrogenation for seventeen hours. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes to provide the compound as a white solid (665, 63 mg, 95%). MS(ESI) [M+H+]+=439.37.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)[C:20](Cl)=[O:21])([CH3:15])[CH3:14]>ClCCl>[CH:13]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)[C:20]([N:3]([O:4][CH3:5])[CH3:2])=[O:21])([CH3:15])[CH3:14].[OH:26][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([OH:16])[CH:25]=1)[C:20]([OH:21])=[O:4]
Reactant: CNOC
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(OC(C)C)cc(OC(C)C)c1
Product: O=C(O)c1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropoxybenzoic acid (compound F, 10 g, 41 mmol) was dissolved in benzene (100 mL) in a 500 mL round bottom flask. Thionyl chloride (12.2 mL, 168 mmol) was added and the reaction heated at reflux for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was redissolved in dichloromethane and concentrated again to give 3,5-diisopropoxybenzoyl chloride. In a separate 200 mL flask, N,O-dimethylhydroxylamine-HCl (4.0 g, 42 mmol) was suspended in 80 mL dichloromethane at 0° C. Triethylamine (12.4 mL, 88 mmol) was added slowly, followed by crude 3,5-diisopropoxybenzoyl chloride. The reaction flask was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water and extracted with three portions of dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the resulting brown oil by column chromatography (30% acetone/hexane) gave the Weinreb amide (compound G) as a yellow oil in 60% yield from 3,5-dihydroxybenzoic acid: Rf 0.33 (30:70 acetone/hexane); IR (cm−1): 2977, 1647, 1590, 1441, 1374, 1184, 1155, 1113, 1037, 964; 1H NMR (250 MHz, C6D6): δ 1.06 (dd, J=2.5, 5.9 Hz, 12H), 3.00 (s, 3H), 3.05 (s, 3H), 4.19 (qn, J=6.2 Hz, 2H), 6.69 (t, J=2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 2H); 13C NMR (63 MHz, C6D6): 21.9 (4C), 33.4, 60.4, 69.8 (2C), 106.6, 108.1 (2C), 137.0, 159.3 (2C), 169.8.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[OH-].[Na+].O.Cl>C(O)C>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(Cl)c2ccccc2c1O
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 9.23 g of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (33 mmol), 90 ml of 2.5 N aqueous sodium hydroxide solution, water (20 ml) and ethanol (110 ml) was refluxed with stirring for 2 h. Then the pH of the mixture was adjusted to 2 by the addition of concentrated aqueous hydrochloric acid. During the addition the temperature of the mixture was kept at 20° C. by cooling with an ice bath. Stirring was then continued for 1 h before the solid component was separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85° C. to give a white powder. 6.64 g of the title compound were obtained; MS-(+)-ion: M+1=224.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][CH:37](Cl)[CH3:38])(=[O:35])[CH2:33][CH3:34].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:37]([O:36][C:32](=[O:35])[CH2:33][CH3:34])[CH3:38])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(=O)OC(C)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer, 100 g) in dimethylsulfoxide (650 ml) was added potassium carbonate (21.6 g). Thereto was added 1-chloroethyl propionate (42.8 g) at 40° C. and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into a mixture of ice-water (3 l) and ethyl acetate (2 l), and the separated organic layer was washed in turn with 5% aqueous sodium bicarbonate (300 ml×2), water (300 ml) and an aqueous sodium chloride, followed by drying over magnesium sulfate. After treating with activated charcoal, the solvent was removed by evaporation, and the residue was pulverized with diisopropyl ether to give 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer, 80 g).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]=[C:18]2[C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][C:12]=1[O:33][CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(#N)C>[I-:2].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N+:17]([CH3:1])=[C:18]2[C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][C:12]=1[O:33][CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CCCC1)=NCC2
Solvent: CC#N
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CCCC1)=[N+](C)CC2
Product: [I-]

Procedure:
Methyl iodide (15 ml) was added to a solution of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentyl]-6-methoxy-3,4-dihydroisoquinoline (13 g, prepared as described in Example CA34) in acetonitrile (100 ml). The mixture was heated under reflux for 24 hours, cooled and the resulting solid collected by filtration. The solid was washed with ether and dried in air to give 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentyl]-6-methoxy-2-methyl-3,4-dihydroisoquinolinium iodide (10 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][S:52][CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH2:51][S:52][CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CSC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of the compound of Example 1 (5.0 g, 6.9 mmol) and methyl sulfide (4.1 mL) in acetonitrile (35 mL) at 0° C. was added benzoyl peroxide (6.7 g) in four portions over 20 minutes, and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 33-100% ethyl acetate in chloroform to give the title compound (4.56 g, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoate (D56) (120 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 8 hours. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise to pH around 3. Extracted with EtOAc (100 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoic acid (E34) (70 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.57-1.71 (4H, m), 2.27 (2H, t), 2.77 (2H, t), 4.88-4.92 (1H, m), 7.21 (1H, t), 7.26 (1H, d), 7.47 (1H, d), 7.80 (1H, d), 7.94 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.82 (1H, s), 12.00 (1H, br s). MS (ES): C24H24ClN3O4 requires 453. found 454.2 (M+H+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27]C(OC)=O)=[CH:22][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[ClH:32]>CO.O>[ClH:32].[F:3][C:4]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COCCNc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCNc1ccc2c(Nc3cc(O)c(C)cc3F)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2M Aqueous sodium hydroxide solution (760 μl, 1.5 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-7-(2-methoxyethylamino)quinazoline (304 mg, 0.76 mmol) in methanol (8 ml) at 5° C. and the mixture then stirred for 30 minutes at ambient temperature. The mixture was diluted with water and adjusted to pH6 with 2M hydrochloric acid. The precipitated solid was collected by filtration and then suspended in methylene chloride/methanol. A 5M solution of hydrogen chloride in isopropanol (0.4 ml) was added and the volatiles were removed from the resulting solution by evaporation. The residue was triturated with ether, the solid product collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline hydrochloride (260 mg, 90%) as yellow solid.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1>C1COCC1>[Cl:13][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Methylamine 2M in THF (67 mL, 134 mmol) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (12, 93 g, 67 mmol) in THF (100 mL) at 0° C. and the resulting mixture was stirred at RT for 16 hr. The reaction was concentrated under reduced pressure; the residue was partitioned between water and EtOAc and both phases separated. The aq. layer was extracted with EtOAc, the combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (25% EtOAc/hexane) to afford the title product (10.54 g, 53.4 mmol, 80% yield) as yellow solid. tR: 0.96 min (LC-MS 2); ESI-MS: 187 [M+H]+ (LC-MS 2); Rf=0.72 (25% EtOAc/hexane).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([OH:22])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>C(O)=O>[CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([O:22][CH2:29][C:30]([OH:32])=[O:31])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(I)c(O)c(I)c1)c1c(Cc2ccccc2)oc2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=CO
Product: O=C(O)COc1c(I)cc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1I

Procedure:
This compound was prepared from (2-benzyl-benzofuran-3-yl)-(3,5-diiodo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2. Formic acid was used in the place of trifluoroacetic acid. The product was obtained as an off-white solid, mp 144-146° C.; MS m/e 638 (M+); Analysis for: C24H16I2O5 Calc'd: C, 45.17; H, 2.53 Found: C, 44.19; H, 2.42
Reaction SMILES: CN(C)C(N(C)C)=N.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=3)=[N:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:36]([O:40][C:41]([NH:43][CH:44](P(OC)(OC)=O)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C:44](=[CH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:24][N:25]=2)=[CH:35][CH:34]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=O)cc3)s2)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=C(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A stirring mixture of 1,1,3,3-tetramethylguanidine (86 μl, 0.69 mmol) was added to a suspension of 4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685 mmol) and methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (185 mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at −70° C. The reaction mixture was stirred at −70° C. for 1 h then at room temperature for 18 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), passed through a phase separation cartridge and the organic phase concentrated in vacuo to afford a yellow solid. The solid was triturated with EA/EtOH (20 mL) and the collected solid washed with EtOH (10 mL) and Et2O to afford 284 mg (79%) of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate as a yellow solid. LCMS-ESI (m/z) calculated for C31H38N2O5S: 550.7. found 551.0 [M+H]+, tR=3.11 min. (Method 8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(CC2C=CC=CC=2)C=CC=CC=1.[OH2:21]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[O:21]
Reactant: O
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: Nc1ccccc1
Product: C=O

Procedure:
A further improved and thus preferred embodiment of the process according to the invention is achieved in that a partial quantity (D") of the organic phase (D) leaving extraction stage (3) is separated and extracted countercurrently in an upstream, preferably multistage, extraction stage (2) with at least a partial quantity, preferably with the entire stream of (C) and the partial stream (D") is calculated in such a manner that the polyamine contained in (D") is as far as possible transferred into the aqueous phase leaving the extraction unit (2), the said aqueous phase, optionally after the addition of water from stream (Y) and/or auxiliary amine and/or further aqueous phase from stream (C) is introduced into extraction stage (3) and the organic phase (R) arising in (2), which is substantially composed of hydrophobic solvent and optionally auxiliary amine, is also introduced into extraction stage (3) and, as a constituent of the organic phase (B), is used as a solvent for the starting polyamine (A). The auxiliary amine used is preferably aniline and the polyamine mixture of the diphenylmethane series used is preferably a polyamine mixture of the kind obtained during acid-catalyzed aniline/formaldehyde condensation.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([N:9]3[CH2:10][CH2:11][C@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)[CH:13]=2)[CH2:18]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Brc1nc2ccccc2o1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2nc4ccccc4o2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-benzooxazole.