Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH2:27][OH:28])[CH:26]=1)[O:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][C:15]2[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]1=[O:23].[H][H]>[Pd].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH2:27][OH:28])[CH:26]=1)[O:5][CH2:6][C@H:7]1[C:8](=[O:23])[CH2:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(CCC[C@H]2C=CC(=O)[C@@H]2COc2cc(Cl)cc(CO)c2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCC[C@H]2CCC(=O)[C@@H]2COc2cc(Cl)cc(CO)c2)s1
Reaction time: 6 h
Yield: 29 %

Procedure:
Palladium on carbon (10 wt. %, 1 mg) was added to a mixture of 12 and 13 (10 mg, ˜0.022 mmol) in EtOAc (0.42 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (10×) and the reaction mixture was stirred under a balloon of hydrogen for 6 h. The reaction mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo. Purification of the resulting crude residue by flash column chromatography on silica gel (10% MeOH/CH2Cl2) afforded 7 mg (˜68%) of ester 14 and 2.7 mg (30%) of title compound 15.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)=O)=CC=1.[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26]O.CC(C)([O-])C.[K+].C(O)C>O1CCCC1>[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCCCCOCCCC(F)(F)C(F)(F)F
Temperature: 200 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a stirred solution of the product of step (a) (500 mg) and 4,4,5,5,5-pentafluoropentan-1-ol (284 mg) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) and the reaction was stirred at 200° C. for 2 hours. An additional charge of potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) was added and the reaction was stirred for a further 18 hours. Ethanol (5 ml) was added and the reaction was stirred for 30 mlnutes. The reaction mixture was partitioned between dichloromethane (300 ml) and water (300 ml). The organic layer was dried over magnesium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel (5 g Bond Elut cartridge) eluting with 20% ethyl acetate in cyclohexane gave the title compound as a clear oil (100 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9]>ClCCCl.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:15])([O-:10])=[O:9]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCO
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
H--2-Trimethylsilylethyl 3-nitrobenzoate may be prepared as follows: a solution of 41.8 g of 2- trimethylsilylethanol in 200 cm3 of 1,2-dichloroethane and 51 cm3 of triethylamine is added to a solution of 66.0 g of 3-nitrobenzoyl chloride in 1000 cm3 of 1,2-dichloroethane cooled to 5° C. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then the insoluble product is separated by filtration and washed with 2 times 50 cm3 of 1,2-dichloroethane. The filtrate is concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 76.9 g of 2-trimethylsilylethyl 3-nitrobenzoate are thus obtained in the form of an oil used as it is in subsequent syntheses.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:13]([C:31](=[O:34])[CH2:32][CH3:33])=[C:12]2[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:1](=[O:3])[CH3:2])(=[O:28])=[O:29])=[CH:25][CH:26]=1)[C:13]([C:31](=[O:34])[CH2:32][CH3:33])=[C:12]2[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(C)=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 515 and using acetic anhydride and 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide. 1H NMR (CDCl3) δ: 0.49 (3H, t, J=7.2 Hz), 1.71 (2H, q, J=7.2 Hz), 2.00 (3H, s), 5.36 (2H, s), 7.23-7.30 (2H, m), 7.39 (2H, d, J=8.4 Hz), 7.43-7.52 (4H, m), 7.68 (1H, dd, J=2.1, 8.7 Hz), 7.96 (2H, d, J=8.4 Hz), 8.38 (1H, d, J=8.7 Hz). HPLC analysis: purity 99.4% (retention time: 4.50 min). MS (ESI+): 567 (M+H), 569.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: O=Cc1cccc(F)c1Br
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2ccncc2c1Br
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:27][C:28]1[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=1[C:30]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[CH3:27][C:28]1[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=1[C:30]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:38])=[CH:35][CH:34]=1)=[O:31]
Reactant: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in 100 ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4 and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 40% ethyl acetatehexane to give 1.0 g of the desired product as a solid; mass spectrum (M+ H)494.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7].[CH2:11](O)[CH2:12]C>S(=O)(=O)(O)O>[CH2:1]([O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH2:11][CH3:12]
Reactant: CCCO
Reactant: COC(=O)CCC(=O)CCl
Agent: O=S(=O)(O)O
Product: CCCOC(=O)CCC(=O)CCl

Procedure:
To a solution of 5-chlorolevulinic acid methyl ester (10 g) in 1-propanol (50 ml) and concentrated sulfuric acid was added (0.5 ml) and the reaction mixture was refluxed for 3 h. Thereafter, the methanol and the excess 1-propanol were distilled in vacuo. Dichloromethane was added to the residue and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and water. Drying of the organic layer with Na2SO4 followed by distillation of the solvent in vacuo yielded 5.4 g (quant.) 5-chlorolevulinic acid propyl ester. The NMR data agreed with the data for the product obtained according to Example 4.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-(4-Amino-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.11 g, 0.33 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.02 g, 17% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4])[OH:2].O[CH2:10]C(CO)(CO)CO>>[CH2:1]([C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:4][CH3:10])[OH:2]
Reactant: OCC(CO)(CO)CO
Reactant: CC(CO)(CO)CO
Product: CCC(CO)(CO)CO

Procedure:
1,1,1-trimethylolethane; pentaerythritol;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].S(Cl)(Cl)=O.C[N:18](C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: COc1cc(Br)cc(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(C(N)=O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-5-(methyloxy)benzoic acid (9.6 g, 41.6 mmol) in toluene (60 mL) were added thionyl chloride (9.89 g, 83.1 mmol) and DMF (0.10 mL) and the mixture stirred at 50° C. for 4 h. The mixture was allowed to cool to room temperature, and then the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was added to a solution of ammonia (25%, 50 mL). A precipitate formed and was filtered off using Celite, and dried to afford 3-bromo-5-(methyloxy)benzamide (8.70 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OCC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylmethoxy-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=417.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.CC1C=CC(O)=C([N+]([O-])=O)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([NH2:9])[CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cc1ccc(O)c([N+](=O)[O-])c1
Product: Nc1cc(F)ccc1Sc1ccccc1

Procedure:
4-Fluoro-2-nitrophenol was reacted according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-fluoro-2-nitrophenol for 4-methyl-2-nitro phenol to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (265 g., 1.50 mole) and isovaleryl chloride (200 g., 1.64 mole) in methylene chloride (1.2 l.) is cooled to 5° C. and treated with aluminum chloride (220 g., 1.64 mole) during a two-hour period. The reaction is allowed to warm to 25° C. and after 24 hours is poured into ice water (3 l.) and hydrochloric acid (600 ml.). The organic phase is washed with 10% sodium hydroxide and water and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane affording 295 g. of 2',3'-dichloro-4'-methoxyisovalerophenone which melts at 49°-54° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[F:21][C:22]([F:24])([F:23])[C:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
A mixture of 1,3-dibenzyloxy-2-propanone (2 g) and (trifluoromethyl)trimethylsilane (2.56 ml, 2.3 equivalents) in dichloromethane (20 ml) was stirred and cooled to 0° C. A solution of 1M tetrabutylammonium fluoride in THF (4 ml) was added dropwise over 3 minutes. Initial addition of a few drops gave an exotherm of 10° C. Throughout the addition the batch temperature was maintained below 10° C. After completing the addition the dark brown mixture was stirred at +5° C. for 5 minutes when HPLC analysis indicated the reaction to be complete. The reaction mixture was stirred for an additional 5 minutes and then washed with 1M aqueous hydrochloric acid (15 ml), saturated sodium bicarbonate (15 ml) and 1% w/v aqueous sodium chloride solution (2×15 ml). The organic extract was concentrated in vacuo to give 2.5 g of the desired product as dark oil in 99.3% yield. The NMR spectrum of the product was concordant with a reference sample.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][O:8][C:7](=[O:10])[CH:6]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=1.CO>O1CCCC1>[Cl:21][C:19]1[CH:20]=[C:15]([CH2:14][N:4]([CH2:3][CH2:2][F:1])[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH:16]=[N:17][C:18]=1[Cl:22]
Reactant: O=C1C=C(NCCF)CO1
Reactant: Clc1cc(CBr)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(CCF)Cc2cnc(Cl)c(Cl)c2)CO1
Temperature: 25 °C

Procedure:
217 mg (1.49 mmol) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one (VI-1) and 90 mg (2.24 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 2 hours. After cooling to room temperature, 360 mg (1.49 mmol) of 3-(bromomethyl)-5,6-dichloropyridine are added, and the mixture is heated under reflux for a further 3 hours. After cooling to room temperature and addition of methanol, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. After concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (5:1), 260 mg (56% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](2-fluoroethyl)amino]furan-2(5H)-one are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:26])[F:24])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:54]2[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: CN1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCN(C)CC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219 and 1-methylpiperazine (0.17 ml) as starting material, 287 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62].[B].[Br:68][C:69]1[CH:70]=[C:71]2[C:77](I)=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1>>[Br:68][C:69]1[CH:70]=[C:71]2[C:77]([C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[CH2:52][NH:51][C:49]([C:45]3[C:44](=[O:62])[N:43]([CH2:42][C:41]4[CH:63]=[CH:64][C:65]([F:66])=[C:39]([F:38])[CH:40]=4)[CH:48]=[CH:47][CH:46]=3)=[O:50])=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(Br)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 12.169 (s, 1H) 10.093 (t, J=5.8 Hz, 1H) 8.422 (d, J=7.1 Hz, 1H) 8.387 (s, 1H) 8.309 (s, 1H) 8.228 (d, J=6.5, 1H) 7.943 (s, 1H) 7.672 (s, 1H) 7.580 (d, J=7.9 Hz, 1H) 7.469-7.372 (m, 3H) 7.202 (d, J=7.7 Hz, 1H) 7.183-7.130 (m, 1H) 6.602 (t, J=6.9 Hz, 1H) 5.210 (s, 2H), 4.586 (d, J=5.6 Hz, 2H); MS m/z=548.98 M+H.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(O)cc1
Temperature: -75 °C
Yield: 80 %

Procedure:
A solution of 6.4 g of N-(2,6-dimethylphenyl)-4-methoxybenzamide in methylene chloride was cooled to -75° C. Boron tribromide (25 g) was added over a 15 minute period. The reaction mixture was allowed to warm over 2 hours and then heated at reflux for 2 hours. The reaction was again cooled to -75° C. and 50 ml of water were added. The mixture was allowed to warm and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methanol/water affording the desired title product in 80% yield, m.p. 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:5]2[OH:21].O=S(Cl)Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14]([C:6]1[C:7](=[O:13])[O:8][C:9]2[C:4]([C:5]=1[OH:21])=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=2[Cl:12])=[O:15])[CH3:27]
Reactant: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O

Procedure:
To a mixture of [(6,8-dichloro-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid (100 mg, 0.30 mmol) in ethanol (6 mL) was added SOCl2 dropwise. Resulting mixture was refluxed for 1.5 h. After cooled, white precipitate was collected, rinsed with ethanol and dried to give the title compound (94 mg). MS ESI(+) m/e: 362, 360 (M+1).