Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.C(N(CC)CC)C.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:28]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1 g, 4.03 mmol), DMAP (49.2 mg, 0.40 mmol) and triethylamine (611 mg, 6.05 mmol) in DMF (50 mL) was added tert-butylchlorodimethylsilane (665 mg, 4.43 mmol). After stirred overnight at 50° C., the resulting mixture was concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 2-5% MeOH in dichloromethane to give compound 8 as a yellow solid (1.0 g, 65%). (ES, m/z): [M+H]+ 263.0; 1H NMR (300 MHz, CDCl3) δ 6.33-6.35 (d, J=6.3 Hz, 1H), 4.35-4.39 (t, J=5.7 Hz, 1H), 4.18-4.21 (t, J=4.5 Hz, 1H), 3.81-3.84 (m, 3H), 3.62-3.67 (m, 1H), 3.05 (s, 6H), 0.93 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]([C:49]1[C:50](=[O:66])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[C:58]([O:64][CH3:65])[CH:57]=2)=[N:53][N:54]=1)[CH3:48]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:46][CH:47]([C:49]1[C:50](=[O:66])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[C:58]([O:64][CH3:65])[CH:57]=2)=[N:53][N:54]=1)[CH3:48])=[O:7])[CH3:3]
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC

Procedure:
1.01 g (4.55 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 0.67 g (4.96 mmol) of 1-hydroxy-1H-benzotriazole, 1.05 g (10.3 mmol) of 4-methylmorpholine, 0.95 g (4.96 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1.20 g (4.13 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-(1-hydroxyethyl)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-tri azin-6-yl]-ethyl)}5-phenylpentanamide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:54]([O:61][CH2:62][CH2:63][CH2:64]O)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Si:54]([O:61][CH2:62][CH2:63][CH2:64][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([C:57]([CH3:58])([CH3:59])[CH3:60])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 53.4 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (136 mg, 0.519 mmol), 3-(tert-butyldimethylsilyloxy)propanol (0.111 mL, 0.519 mmol) and 40% DEAD-toluene solution (0.237 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-[3-(tert-butyldimethylsilyloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (58.6 mg, yield 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>ClCCl>[F:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]([CH:15]2[CH2:17][CH2:16]2)=[O:19])=[CH:7][N:6]=1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)nc1)C1CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 5-amino-2-fluoropyridine (6.63 g, 0.059 mol) and pyridine (5.16 g, 0.065 mol) in dichloromethane (120 ml) was stirred at room temperature. Cyclopropane carboxylic acid chloride (6.2 g, 0.059 mol) was added dropwise to the reaction mixture at such a rate to maintain the temperature at 20°-30° C. After complete addition the reaction mixture was stirred at temperature for a further one hour, then washed with 5% sodium hydroxide (100 ml), water (100 ml) and dried over anhydrous magnesium sulphate. Removal of the solvent gave a dark brown solid which was purified by column chromatography (silica eluted with dichloromethane : tetrahydrofuran=9:1) to give N-(2-fluoro-5-pyridyl)cyclopropane carboxamide (7.7 g, 72%) as an orange brown solid m.p. 116°-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(Br)cc1C(=O)NCc1cccnc1
Yield: 87.2 %

Procedure:
In 238 ml of dimethylformamide were dissolved 23.8 g of 2-amino-5-bromobenzoic acid, 13.1 g of 3-aminomethylpyridine and 24.5 g of triethylamine, and the solution was chilled with ice. To this solution was dropwise added 33.3 g of diphenylphosphoryl azide in 10 minutes, and the resultant mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice water. The precipitated solid was filtered, washed with water and dried to give 29.4 g of the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[C:13]([C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]>>[OH:22][C:21]1[CH:20]=[C:19]([CH3:23])[N:18]([CH3:24])[C:17](=[O:25])[C:16]=1[C:13](=[O:15])[CH:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: O=Cc1cccc(OCCO)c1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCO)c2)c(=O)n1C
Yield: 16 %

Procedure:
According to the same manner as that of Example a-1 except that 4.90 g of 3-(2-hydroxyethoxy)benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and 4.86 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 1.41 g of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (40a)] was obtained as a yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[N:8]=1)=[O:14])[CH3:21]
Reactant: CCO
Reactant: O=C(O)c1ccc2cc(O)ccc2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(O)ccc2n1

Procedure:
6-Hydroxy-quinoline-2-carboxylic acid (2.3 g, 0.012 mol) was dissolved in absolute ethanol (150 ml). Sulfuric acid (0.550 ml, 0.0096 mol) was added and the mixture was refluxed for 16 hours. After cooling to room temperature the ethanol was evaporated and 60 ml of ethyl acetate, 50 ml of cooled water were added. The pH was adjusted to 7 with solid NaHCO3. Extraction and concentration of the organic phase gave the title product as a light yellow solid that was used for the next steps without purification (2.1 g, 81% of theory). MS (m/e)=218.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:26][O:27][CH2:28][C:29](OCC)=[O:30].[NH4+].[Cl-]>C1COCC1>[CH3:26][O:27][CH2:28][C:29](=[O:30])[CH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)COC
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(=O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A solution of 4-(4′-trifluoromethylphenyl)phenyl methyl sulfone (1.0 g, 3.33 mmol) in THF (50 mL) at −78° C. was treated with n-butyllithium (2.5M/hexanes, 1.4 mL, 3.50 mmol), stirred at −78° C. for 1.5 hours and then treated with ethyl methoxyacetate (0.78 mL, 6.66 mmol), stirred at −78° C. for three hours, treated with saturated NH4Cl solution, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and purified on silica gel with 30-50% ethyl acetate/hexanes to provide 902 mg (73%) of the title compound as a white solid. MS (APCI) m/z 390 (M+NH4)+, 371 (M−H)−, 470 (M+Cl)−.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B1OC(C)(C)C(C)(C)O1.CCN(C(C)C)C(C)C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cccc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, methyl 6-bromo-5-fluoropyridine-2-carboxylate (Frontier Scientific, 200.2 mg, 0.8555 mmol) was added followed by 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Combi-Blocks, 310.2 mg, 1.292 mmol), and bis(tri-tert-butylphosphine)palladium (87.5 mg, 0.171 mmol). The vial was sealed with a PTFE-lined septum, evacuated and backfilled with nitrogen three times. 1,4-Dioxane (3.0 mL) was added via a syringe, followed by DIPEA (0.30 mL, 1.7 mmol) and deoxygenated water (0.1 mL). The mixture was heated at 100° C. for 2 h and was then allowed to cool to room temperature. The mixture was diluted with EtOAc (40 mL), washed with water (40 mL) and brine (40 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a white solid (210.2 mg, 92%). LCMS calc. for C13H9F3NO2 (M+H)+: m/z=268.1. found 268.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18](N1CCOCC1)=[O:19]>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[CH:3][CH:4]=1
Reactant: O=CN1CCOCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2OCCO2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 2-(4-bromo-phenyl)-1,3-dioxolane (8 g, 34.9 mmol) was added dropwise n-butyl lithium (19.6 mL, 2.67 M hexane solution, 52.4 mmol) at −78° C. After 1 hour of stirring at −78° C., N-formylmorpholine (4.42 g, 38.4 mmol) was added to the mixture, and stirred for 3 hours at the same temperature. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (6.3 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].[Li]CCCC.Cl[C:14]1[N:19]=[C:18]([S:20][CH3:21])[N:17]=[C:16]2[N:22]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:15]=12>C1COCC1>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:15]2[C:16](=[N:17][C:18]([S:20][CH3:21])=[N:19][C:14]=2[CH2:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[N:22]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:23]=1
Reactant: CN(C)S(C)(=O)=O
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1nc(CS(=O)(=O)N(C)C)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of N,N-dimethyl methanesulfonamide (419 mg, 3.40 mmol) in 5 mL dry THF at 5° C. was added n-BuLi (2.2 mL of 1.6M solution in hexanes 3.50 mmol) dropwise. To this stirring solution was added dropwise a solution of 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.500 g, 1.13 mmol) in 1 mL dry THF. The reaction mixture was stirred for 2 hours and allowed to warm to room temperature during this time. The reaction was quenched by addition of 10 mL water and 1 mL of 1.2M HCl, and the resulting aqueous solution was extracted twice w2ith 20 mL methylene chloride. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% EtOAc in hexanes) to give 421 mg of C-[3-(2-Chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:15]1=2)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1.C(O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:15]2[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18][S:17][C:16]=2[CH:20]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCN1CCSc2cc(N)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of phenyl methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (100 mg, 0.268 mmol) in tetrahydrofuran (4 mL) and ethanol (4.00 mL) under argon was added 10% Pd—C (28.5 mg, 0.027 mmol). The resulting mixture was stirred at room temperature overnight under an atmosphere of hydrogen (balloon pressure). The mixture was then filtered through a pad of Celite and concentrated, giving the desired product (81 mg, 88%) as a dark oil. MS-EI: (m/z, %) 343 (M+, 64), 179 (100), 151 (45).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (200 mg; 0.36 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (80 mg; 1.2 equiv.) in toluene (5 ml) was treated with (2-biphenyl)-di-tert-butylphosphine (6 mg; 5 mol %), tris(dibenzylidene)palladium(0) (10 mg; 2.5 mol %) and sodium tert-butoxide (50 mg; 1.4 equiv.) then heated at 120° C. for 30 minutes in a CEM explorer microwave synthesiser. The reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (Biotage SP4—25S, 25 ml/min) eluting with DMAW 240-120-90 followed by evaporation of product containing fractions gave 105 mg of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{5-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1,3-dihydro-isoindol-2-yl}-methanone as the acetic acid salt.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]2[C@H:11]([NH:12][C:13](=[O:29])/[C:14](=[N:21]\[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)[C:10](=[O:30])[N:9]2[S:31]([OH:34])(=[O:33])=[O:32])[C:3]1=[O:35].Cl.[N:37]1([C:42](=N)[NH2:43])C=CC=N1>>[NH2:20][C:17]1[S:18][CH:19]=[C:15](/[C:14](=[N:21]/[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:13]([NH:12][C@@H:11]2[C:10](=[O:30])[N:9]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:8]2[CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:42]([NH2:43])=[NH:37])[C:3]2=[O:35])=[O:29])[N:16]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@@H](N)C1=O)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@@H](NC(=N)N)C1=O)c1csc(N)n1)C(=O)O

Procedure:
Prepared in analogous manner to example 20, using 2-(((Z)-(2-(((2R,3S)-2-(((R)-3-amino-2-oxopyrrolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid and 1H-pyrazole-1-carboximidamide HCl. LCMS: m/z=574.1 (M−1); 1H NMR (400 MHz, D2O): δ 6.93 (s, 1H), 5.28 (d, J=5.6 Hz, 1H), 4.53 (m, 1H), 4.24 (t, J=9.6 & 9.2 Hz, 1H), 3.85 (dd, J=9.2 & 9.2 Hz, 1H), 3.51 (m, 1H), 3.40 (t, J=9.2 & 8.8 Hz, 1H), 3.32 (dd, 1H), 3.34 (dd, 1H), 2.43 (m, 1H), 1.87 (m, 1H), 1.36 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]([F:20])=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O.Cl>CO>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:12]1[N:11]=[C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[C:19]([F:20])=[CH:18][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(F)c(N2CCN(C(C)=O)CC2)nc1Nc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 98.1 %

Procedure:
In 3.9 ml of methanol was suspended 130 mg of methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 3.33 ml of 2N aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was subjected to reaction under reflux for 2 hours. To the reaction mixture was added 2 ml of water, and the pH thereof was adjusted to 8.5 with 1N hydrochloric acid, after which the crystals thus deposited were collected by filtration and washed with 2 ml of water to obtain 110 mg (yield 98.2%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinic acid having a melting point of 279°-281° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:18])[C:16]=1[F:17])[C:11]([OH:13])=[O:12].[CH2:19](I)[CH3:20]>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:18])[C:16]=1[F:17])[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCI
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c(F)c(Cl)c1
Temperature: 80 °C

Procedure:
Potassium carbonate (36 g, 0.26 moles) was added to a stirred mixture of 3,5-dichloro-4-fluorobenzoic acid (27.6 g, 0.13 moles), ethyl iodide (41.2 g-0.26 moles) and dry dimethylformamide (300 ml) under nitrogen. The reaction was heated to 80° C. for 6 hours. The dimethylformamide was removed in vacuo and the residue treated with water (200 ml) acidified with dilute hydrochloric acid and extracted with ethylacetate (2×250 ml). The organic layer was washed with water, dried over magnesium sulphate and evaporated in vacuo, to give an orange oil which was purified by chromatography on silica, using a 4:1 mixture of petrol and diethylether as eluent. The pink oil obtained crystallised on standing, and washing with ice-cold 40-60 petrol gave white crystals of ethyl 3,5-dichloro-4-fluorobenzoate (29 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([O:17][CH3:18])[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>Cl.O1CCOCC1>[ClH:1].[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([O:17][CH3:18])[C:6]([NH:8][NH2:9])=[O:7]
Reactant: COC(CCCCl)(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(CCCCl)(C(=O)NN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 216.8 %

Procedure:
tert-Butyl N′-[5-chloro-2-(4-fluorophenyl)-2-methoxypentanoyl]hydrazinecarboxylate (90 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane (1 mL), and the reaction solution was stirred at room temperature for 70 minutes. The reaction solution was concentrated under reduced pressure to obtain 81 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:24]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 435.13 g/mol.