Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[OH:10].[N+]([C:14]1[CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])([O-])=O.O>CN(C)C=O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[O:10][C:23]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=[CH:15][CH:14]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)OC
Reaction time: 5 h

Procedure:
2.4 g (0.012 mole) of sodium salt of 2,4-dichlorophenol and 2.4 g (0.010 mole) of dimethyl 4-nitrophthalate are dissolved in dry dimethylformamide and stirred at 130°-150° C. for 5 hours. After cooling, the mixture is poured into cold water, extracted with benzene, successively washed with dilute aqueous caustic soda, dilute hydrochloric acid and water, dried over sodium sulfate and then concentrated to obtain 2.5 g of an oily product. It was purified by column chromatography and there was obtained 1.6 g of the intended compound as a viscous oily product. Yield 45%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>CN(C=O)C>[C:25]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:8]1[CH:20]=[CH:21][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N+:22]([O-:24])=[O:23])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(C)=O)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in DMF (3.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.50 g (1.55 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, acetic anhydride (0.20 ml (2.12 mmol)) was added dropwise. After one hour's stirring at room temperature, water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Crystals separated was added to diethyl ether, filtered and washed to give 0.51 g (90%) of the title compound as pale yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([O-:10])=[O:9].ClC(OCC(C)C)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>ClCCl>[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:45][CH:43]([C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=1)[CH3:44])=[O:16])([O-:10])=[O:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Reactant: CC(N)c1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
2.4 g (0.011 mol) of triethylamine are added at −10° C. to a solution of 3 g (0.011 mol) of 3-nitro-2-benzyloxybenzoic acid in 40 ml of dichloromethane. After the mixture has been stirred for 5 minutes, 2.8 g (0.011 mol) of isobutyl chloroformate are added dropwise at −10° C., and the mixture is stirred for a further 30 minutes. A solution of 1.53 g (0.011 mol) of 1-(4-fluorophenyl)-ethylamine in 10 ml of dichloromethane is added at −10° C., and stirring is continued for 12 hours without further cooling. The mixture is treated with sodium halogen carbonate solution, and the organic phase is separated off, washed with water and dried over sodium sulphate. After the solvent has been distilled off, 2.5 g (56% of theory) of 3-nitro-2-benzyloxy-N-[1-(4-fluorophenyl)-ethyl)-benzamide are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][Mg+].[Br-]>C1COCC1.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2([NH2:10])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC[Mg+]
Reactant: COc1cccc(C#N)n1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2(N)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of 6-methoxy-pyridine-2-carbonitrile (1.50 g, 11.2 mmol) in THF (75 mL) at room temperature was added Ti(OiPr)4 (7.21 mL, 24.6 mmol). EtMgBr (14.9 mL, 44.7 mmol) was added dropwise. and the clear brown solution became heterogeneous. The reaction mixture was stirred for 1 h at room temperature. The reaction was diluted with water (10 mL), extracted with EtOAc (3×25 mL) and dried with MgSO4. After filtration, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC to afford 380 mg (22%) of 1-(6-methoxy-pyridin-2-yl)-cyclopropylamine, m/z 166.3 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([Br:18])=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][CH2:30]Cl)[CH3:28]>CN(C)C=O>[OH:1][C@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:30][O:29][CH2:27][CH3:28])[C:13]([Br:18])=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirring suspension of (R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 8.4 mmol) and potassium carbonate (1.50 g, 10.5 mmol) in dimethylformamide (70 ml) was added chloromethyl ethyl ether (0.83 g), 8.8 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (200 ml) and was stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml) and dried under vacuum to provide (R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.5 g, 74% yield) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (1.5 g, 07.5 mmol) in dry DCM (40 mL) was added triethylamine (2.59 mL, 18.8 mmol) and 4-chlorobenzenesulfonyl chloride (3.15 g, 10.5 mmol) and the reaction stirred at room temperature for 48 h. To the reaction was added resin supported-triamine (5 g) and the mixture stirred for 4 h. The reaction mixture was filtered and the filtrate washed with 0.5 M HCl (aq., 100 mL) followed by water (100 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was dissolved in DCM (40 mL) and TFA (10 mL) was added. The solution was stirred for 20 min. The solvent was evaporated and the residue tajen up in DCM (40 mL) and washed with 50% aqueous sodium bicarbonate (100 mL) followed by water (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound (1.62 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCCCCOc1ccc(B(O)O)cn1
Product: CCCCCCOc1ccc(-c2cnc(Cl)nc2)cn1

Procedure:
A reaction of 5-bromo-2-chloropyrimidine and 2-hexyloxypyridine-5-boronic acid is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives a colorless solid.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:10][C:11]1([CH3:18])[NH:15][C:14](=[O:16])N[C:12]1=[O:17].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:5][Si:4]([CH3:7])([CH3:6])[N:15]1[C:11]([CH3:18])([CH3:10])[C:12](=[O:17])[N:3]([Si:4]([CH3:5])([CH3:6])[CH3:7])[C:14]1=[O:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC1(C)NC(=O)NC1=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N([Si](C)(C)C)C(=O)N1[Si](C)(C)C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
80 ml of hexamethyldisilazane (0.38 mole) were added over 30 minutes to a refluxing suspension of 50 ml of toluene, 40 mg (0.22 mmole) of saccharin and 38.45 g (0.30 mole) of 5,5-dimethylhydantoin and evolution of ammonia started immediately. When half of the hexamethyldisilazane had been added, all solids had gone into solution and after the addition of the hexamethyldisilazane, reflux was continued for 1 hour. Toluene was distilled off and the residue was vacuum dried at 45° C. to obtain 79.0 g (97%) of 1,3-bis-(trimethylsilyl)-5,5-dimethylhydantoin melting at 46°-49° C. According to NMR analysis, the purity of the compound was 91%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH2:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)OCCO4)cc12
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (27.4 mg, 0.152 mmol) and 2N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.7 mg, 10% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.62 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NC(=S)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.5 %

Procedure:
To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in 20 mL of abs. EtOH is added 2,4′-dibromoacetophenone (0.7 g, 2.5 mmol) all at once. The reaction mixture is stirred at room temperature for 3 hours and then chilled in ice bath. The precipitate is collected by filtration, washed with cold EtOH (5 ml×2) and dried in vacuum to give 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole as a white fluffy crystaline solid (1.55 g, 93%). mp.158-9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[C:10]2=[O:32])=[CH:5][CH:4]=1.[CH3:33][O:34]C=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH:26]3[CH2:31][CH2:30][CH2:29][N:28]([CH:33]=[O:34])[CH2:27]3)[C:10]2=[O:32])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCNC3)C2=O)cc1
Reactant: COC=O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCN(C=O)C3)C2=O)cc1
Reaction time: 8 h

Procedure:
3-(4-Methoxy-phenyl)-7-phenylamino-1-piperidin-3-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (95 mg, 0.22 mmol) (from Example 4b supra) was dissolved at room temperature in methylformate (5 mL) (Aldrich). After stirring overnight the reaction mixture was concentrated to the crude product, which was purified by silica gel column chromatography with a 0–100% ethyl acetate in hexanes and then a 0–20% tetrahydrofuran in ethyl acetate gradient. After a precipitation out of dichloromethane with excess of pentane, 3-[3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carbaldehyde was isolated as an off-white solid. (Yield 90 mg, 89%).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:6])=[O:5].Cl[CH2:23][CH2:24][C:25]([OH:27])=[O:26].Cl>O.C(OCC)(=O)C>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:21][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:6])=[O:5]
Reactant: O=C(O)CCCl
Reactant: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1cc(OCCC(=O)O)ccc1Oc1ccccc1
Yield: 23.1 %

Procedure:
4 g of sodium hydroxide was dissolved in 250 ml of water. Therein was dissolved 27.9 g of 3-methylsulfonylamino-4-phenoxyphenol. Thereto was added an aqueous solution obtained by dissolving 10.9 g of 3-chloropropionic acid and 4 g of sodium hydroxide in 30 ml of water. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled and adjusted to pH 8 with 4N hydrochloric acid. 70 ml of ethyl acetate was added thereto. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid and extracted with 100 ml of ethyl acetate. The resulting extracts were washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with diethyl ether. The resulting solid was collected by filtration to obtain 8.1 g (yield: 23.1%) of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)propionic acid having a melting point of 145°-149° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:17]1([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15][B:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:9][CH:10]=2)[O:18]1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(-c3ncccn3)cc2)OC1(C)C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol), 2,2′-(1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (5.1 g, 16.0 mmol), 1.0 M aq K3PO4 (28.3 mL, 28.3 mmol), and Pd(PPh3)4 (330 mg, 0.31 mmol) in DMF (140 mL) was heated to 80° C. and stirred at this temperature for 16 h. Water (100 mL) was added to the reaction mixture and was extracted with EtOAc (3×200 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of 17% EtOAc in n-heptane to afford the title compound as a white solid (0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12H) 7.19 (t, J=4.68 Hz, 1H) 7.93 (d, J=8.00 Hz, 2H) 8.43 (d, J=7.81 Hz, 2H) 8.81 (d, J=4.68 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:39])=[CH:17][N:16]=1>>[Cl:39][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a gray solid (142 mg, 77%). m.p.=281-283° C.; LCMS (m/e) 535 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.52 (bs, 1H), 9.47-9.38 (m, 2H), 8.60-8.54 (m, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.71-7.63 (m, 2H), 7.25 (d, 1H, J=8.4 Hz), 7.09 (bs, 1H), 6.93 (d, 1H, J=8.1 Hz), 3.90 (s, 3H), 2.74 (d, 3H, J=4.0 Hz), 2.58-2.47 (m, 2H), 2.08-1.93 (m, 4H).
Reaction SMILES: B(O)O.Br[C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[O:9]1[C:8]([CH:10]=[O:11])=[CH:7][CH:6]=[C:5]1[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccco1
Reactant: O=Cc1ccc(Br)o1
Agent: OBO
Product: O=Cc1ccc(-c2ccco2)o1

Procedure:
[2,2′-bifuran]-5-carbaldehyde was prepared using the general boronic acid coupling procedure with 5-bromofuran-2-carbaldehyde and furan-2-ylboronic acid (24 mg, 93 mg theoretical, 25.8%). LC-MS m/z 163 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[N:33]([C@@:39]1([CH3:47])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]2=[O:48].CC#N>CN(C=O)C>[CH3:47][C@:39]1([N:33]2[C:32](=[O:48])[C:31]3[C:35](=[CH:36][CH:37]=[C:29]([CH2:28][NH:27][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=4)[CH:30]=3)[C:34]2=[O:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(S(C)(=O)=O)cc4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of 4-(methylsulfonyl)benzoic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and stirring proceeded at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and evaporated. The residue was chromatographed on silica gel using 99:1 methylene chloride-methanol as the mobile phase, providing 0.30 g, in 32% yield. The product was obtained as a white solid; mp 165.5-167.5° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.08 (96.23%); 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 2.22-2.28 (m, 1H), 2.73-2.95 (m, 3H), 3.47 (s, 3H), 4.86 (d, J=5.7 Hz, 2H), 7.98-8.04 (m, 3H), 8.25 (d, J=8.7 Hz, 2H), 8.32 (d, J=8.7 Hz, 2H), 9.58 (t, J=5.7 Hz, 1H), 11.21 (s, 1H); 13C NMR (DMSO-d6) δ 23.0, 30.6, 31.1, 44.8, 45.6, 60.8, 123.7, 125.2, 129.2, 130.3, 131.7, 133.4, 135.5, 140.4, 145.2, 149.0, 167.2, 169.7, 169.9, 174.1, 174.2; Anal. Calcd for C23H21N3O7S+0.3H2O: C, 56.50; H, 4.45; N, 8.59. Found: C, 56.61; H, 4.42; N, 8.30.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH-].[K+].CO.[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C)C=O>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CC(C(=O)O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
25 g (0.15 M) of 2-hydroxyphenylpropanoic acid and 16.9 g (0.12 M) of potassium hydroxide are added to a mixture of 150 ml of methanol and 20 ml of dimethylformamide in a 1000 ml reactor. After stirring for 10 minutes, 30 g (0.15 M) of 2-(4-nitrophenoxy)ethyl bromide are added and the reaction medium is then refluxed for 24 hours with stirring. The methanol is evaporated off and the residue is taken up in water. The aqueous phase obtained is first washed with ethyl acetate and then acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH:12]=[CH2:13])[CH:3]=3)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: C=Cc1cc(I)ccc1OCCO
Product: C=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was obtained analogously to Example 7.1e starting from 2-(4-iodo-2-vinylphenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.66 g (96% of theoretical); C23H18ClNO2 (M=375.847); calc.: molpeak (M+H)+: 376/378 (Cl); found: molpeak (M+H)+: 376/378 (Cl); HPLC-MS: 6.21 minutes (method B).