Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[C:16]([C:18]([CH3:26])([CH3:25])[C:19]([O:21]C(C)C)=[O:20])[N:17]=2)[N:14]=1)(=O)=O.[C:27]1([CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[C:40]1([CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]2[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][NH:8][C:9]3[CH:10]=[CH:11][C:12]4[N:13]([CH:15]=[C:16]([C:18]([CH3:25])([CH3:26])[C:19]([OH:21])=[O:20])[N:17]=4)[N:14]=3)[CH2:38][CH2:39]2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(C)OC(=O)C(C)(C)c1cn2nc(NCCOS(C)(=O)=O)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C(=O)O)c1cn2nc(NCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
1.24 g of isopropyl 2-[6-[2-(methanesulfonyloxy)ethylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 15 ml of N,N-dimethylformamide; 977 mg of 1-(diphenylmethyl)piperazine, 642 mg of potassium iodide and 535 mg of potassium carbonate were added, followed by stirring at room temperature for 1 hour and at 60° C. for 1.5 hours. Ice water and sodium chloride were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected, concentrated under reduced pressure and dried to yield 570 mg of the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13].[N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>ClCCl>[OH:22][N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: CCOC(=O)/C=C/C=O
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-ethyl 3-formylacrylate (128 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Cl.[CH2:35]([NH2:37])[CH3:36].C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[CH2:35]([NH:37][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1)[CH3:36]
Reactant: CCN
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CCC[C@H]4CCl)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC[C@@H]1CCCN1c1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 80 °C
Yield: 29.7 %

Procedure:
In a sealed tube, a solution of 6-[5-((S)-2-chloromethyl-pyrrolidin-1-yl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one (0.066 g, 0.185 mmol) in CH3CN (2.5 mL) was mixed with K2CO3 (0.064 g, 0.464 mmol), TEA (0.188 g, 1.85 mmol), sodium iodide (0.028 g, 0.185 mmol) and ethanamine hydrochloride (0.151 g, 1.85 mmol). The reaction mixture was then heated to 80° C. over night. The mixture was diluted with EtOAc, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography, eluting with a 0 to 15% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.02 g, 30%) as an orange gum. MS: 365.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[Cl-]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: COCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCCOS(C)(=O)=O

Procedure:
A solution of non-polydispersed triethylene glycol monomethyl ether molecules (4.00 mL, 4.19 g, 25.5 mmol) and triethylamine (4.26 mL, 3.09 g, 30.6 mmol) in dry dichloromethane (50 mL) was chilled in an ice bath and place under a nitrogen atmosphere. A solution of methanesulfonyl chloride (2.37 mL, 3.51 g, 30.6 mmol) in dry dichloromethane (20 mL) was added dropwise from an addition funnel. Ten minutes after the completion of the chloride addition, the reaction mixture was removed from the ice bath and allowed to come to room temperature. The mixture was stirred for an additional hour, at which time TLC (CHCl3 with 15% MeOH as the elutant) showed no remaining triethylene glycol monomethyl ether.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1(=O)=O.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](=O)[O:32]C)[N:23]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][S:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:32])[N:25]=1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2c1CS(=O)(=O)C2
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3c2CSC3)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A suspension of 0.74 g of the sulfonamide prepared in Example 13 in 50 ml of methylene chloride was cooled to 10° to 15° under nitrogen, and 1.7 ml of a 2M solution of trimethylaluminum in toluene was added slowly. The suspension was allowed to warm to room temperature, 0.67 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture was heated at reflux overnight. The turbid solution was cooled to 0°-5° and 50 ml of 5% hydrochloric acid was added dropwise. The two-phase suspension was allowed to warm to ambient temperature, then filtered. The solid was washed with 1-chlorobutane and dried giving 0.31 g of 1,3-dihydro-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzo[c]thiophene-4-sulfonamide, 2,2-dioxide, m.p. 170°-173°(d).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>CN(C)C=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]([CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]([CH3:25])[CH2:23][O:22][C:3]=2[C:2]=1[F:1]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC
Temperature: 80 °C

Procedure:
To a solution of 791 mg of the compound obtained in Example 4 in 5 ml of anhydrous N,N-dimethylformamide (hereinafter abbreviated as DMF), 207 mg of potassium carbonate and a catalytic amount of 18-crown-6-ether were added, and the mixture was heated at 80° C. for 8.5 hours. To the mixture were added ethyl acetate and water. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield the titled compound as crystals in quantitative yield. The physical data of the product were identical to those of the authentic specimen as described in Reference Example B-1.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:36]=12.CCOC(C)=O>CN(C=O)C.[Cu]I.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>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:42]4[S:43][C:36]5[C:37](=[N:38][CH:39]=[CH:40][C:35]=5[Cl:34])[CH:41]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (180 mg, 0.34 mmol) and 7-chloro-2-tributylstannanyl-thieno[3,2-b]pyridine (162 mg, 0.35 mmol) in DMF (3 mL) were added copper(I) iodide (13.5 mg, 0.071 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 90° C. then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic extracts were dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 11 g, CH2Cl2 100% to CH2Cl2:EtOAc 4:6 in 25 min) to afford 180 mg (82%) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[CH:19][N:20]([CH3:32])[C:21]=2[C:22]2[S:31][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:30])[C:24]=3[CH:23]=2)[CH:14]=[CH:15][CH:16]=1>C1COCC1>[NH2:30][C:29]1[C:24]2[CH:23]=[C:22]([C:21]3[N:20]([CH3:32])[CH:19]=[N:18][C:17]=3[C:13]3[CH:12]=[C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH:16]=[CH:15][CH:14]=3)[S:31][C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(NC(=O)Nc3ccccc3)c2)c1-c1cc2c(N)ncnc2s1
Yield: 63.9 %

Procedure:
Phenyl isocyanate (28 mg) was added to a stirred suspension of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) (40 mg) in THF (6 mL) under an inert atmosphere. After 30 minutes methylethylenediamine-polystyrene (200 mg) was added, the reaction mixture filtered, filtrate loaded onto a MCX column washed with DCM/MeOH (1:1) then eluted with 5% triethylamine in DCM/MeOH (1:1) to give the title compound as a colourless solid (35 mg, 67%);
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([N:19]([CH3:21])[CH3:20])[N:3]=1.[CH3:22][NH2:23]>>[CH3:20][N:19]([C:4]1[N:3]=[C:2]([NH:23][CH3:22])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH3:21]
Reactant: CN(C)c1nc(Cl)nc2c1ncn2Cc1ccccc1F
Reactant: CN
Product: CNc1nc(N(C)C)c2ncn(Cc3ccccc3F)c2n1

Procedure:
2.5 g (8.2 mmol) of 2-chloro-6-(N,N-dimethylamino)-9-(2-fluorobenzyl)-9H-purine (Example 1) and 10 ml of ethanolic N-methylamine solution (16%) are heated for 120 hours at 80° to 85° in an autoclave. The reaction mixture is then concentrated by evaporation under reduced pressure. The residue is taken up in dichloromethane. The dichloromethane phase is washed twice with water, dried over magnesium sulfate and concentrated by evaporation. the residue is chromatographed on silica gel with toluene/ethyl acetate (10:1) as eluant. The eluate is concentrated by evaporation and the residue obtained is recrystallised from dichloromethane/hexane. In this manner 6-(N,N-dimethylamino)-9-(2-fluorobenzyl)2-(N-methylamino)-9H-purine is obtained in the form of colourless needles having a melting point of 100°.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([O:19]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:27](=[O:29])[CH3:28])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14]([C:15]([F:16])([F:17])[F:18])=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Add 20% palladium hydroxide on carbon (11.0 g, 15 mmol) to a solution of 1-(2,4-bis-benzyloxy-3-trifluoromethyl-phenyl)-ethanone (6.00 g, 15 mmol) in ethanol (75 mL) and cyclohexene (75 mL) and stir. Purge the reaction vessel with argon. Heat to reflux. After 18 hours, cool to ambient temperature, filter and concentrate under reduced pressure to yield the title compound as a grey solid (3.00 g, 91%): 1H NMR (CD3CN) δ 2.55 (s, 3H), 6.51 (d, 1H), 7.88 (d, 1H), 13.91 (bs, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[C:39]([OH:42])([CH3:41])[CH3:40])[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-]>C(OCC)(=O)C>[OH:42][C:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH3:41])[CH3:40]
Reactant: C=CCC1C(C(C)(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Temperature: -78 °C

Procedure:
The cis-isomer of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(2-hydroxy-2-propyl)azetidin-2-one (10) (0.188 g) was dissolved in ethyl acetate (14 ml). An excess of trifluoroacetic acid (0.37 g) was added and the mixture cooled to -78° C. Ozone was passed into the reaction mixture until it was pale blue in colour. Argon was then bubbled through the solution until all the excess ozone had been removed. A solution of triphenylphosphine (0.085 g) in ethyl acetate was added and argon bubbled through the mixture for a further ten minutes. The reaction flask was then transferred to an ice bath and a saturated aqueous solution of sodium bicarbonate (20 ml) was added and the mixture stirred vigourously under argon for thirty minutes. The ethyl acetate layer was separated, washed with brine and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].[N:25]1([C:35](N2C=C[N+](C)=C2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:35]([N:25]1[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]1)=[O:36])[CH:15]=2
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)c1
Yield: 21.2 %

Procedure:
The title compound (50 mg, 21% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccccc2OC)sc1C(=O)OCC
Temperature: 25 °C
Yield: 135.8 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (747 mg, 1.49 mmole), 2-methoxyphenylboronic acid (663.3 mg, 4.36 mmole), cesium carbonate (2.13 g, 4.76 mmole) and tetrakis(triphenylphosphine)palladium (252 mg, 0.16 mmole) in dioxane (7 ml) was refluxed for 5 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.07 g). MS: (+) m/z 551.20 (M+Na+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13](Br)[N:12]=1.CC(C)([O-])C.[Na+].O>O1CCOCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:10][C:11]1[N:12]=[C:13]([NH:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: COc1ccnc(N)c1
Reactant: Cc1cc(Br)nc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(Nc2cc(C)cc(Br)n2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To a solution of 4-methoxypyridin-2-amine (620 mg, 5 mmol) and 2,6-dibromo-4-methylpyridine (1123 mg, 5.25 mmol) in dioxane (18 mL) was added 1,1′-bis(di-tertbutylphosphino)ferrocene palladium dichloride (280 mg, 0.5 mmol) and sodium tert-butoxide (437 mg, 5.25 mmol). Then the mixture stirred under microwave irradiation for 1.5 hours at 80° C. Then the mixture was poured into water (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried and concentrated. The residue purified by silica gel chromatography using a solvent system of 75% petroleum ether/EtOAc. The product containing fractions were collected and concentrated to give 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (627 mg, 50%). MS ESI calcd for C12H12BrN3O [M+H]+ 294, found 294.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]=1[C:22]([OH:24])=O.[C:25]([O:29][C:30](=[O:57])[CH:31]([NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)=[O:43])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:57])[CH:31]([NH:41][C:42]([C:44]1[CH:45]=[CH:46][C:47]([C:50]2[CH:51]=[CH:52][C:53]([NH:56][C:22]([C:14]3[O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH3:12])=[O:24])=[CH:54][CH:55]=2)=[CH:48][CH:49]=1)=[O:43])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3)cc2)oc2ccccc12
Yield: 12.4 %

Procedure:
EDCI coupling between 3-Methylbenzofuran 2 carboxylic acid (139 mg, 0.79 mmol) and 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (358 mg, 0.79 mmol, 1 equiv.) was carried out according to the procedure in step C of Example 5 to give 2-({4′-[(3-Methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 12.4% yield (60 mg). MS (ESI) m/z 611.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>O>[N+:1]([C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=1[O:13][CH3:14])([O-:4])=[O:2]
Reactant: COc1ccc(OC)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1ccc(OC)c([N+](=O)[O-])c1

Procedure:
To a mixture of 100 ml concentrated nitric acid and 200 ml water is added 34.20 (0.30 mole) 1,4-dimethoxybenzene over a period of half an hour. After an additional fifteen minutes of stirring, the mixture is poured over ice. The resulting crystals are collected by filtration and crystallized from ethanol yielding bright yellow needles with a melting point of 68°-70° C.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: ClI
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 42 h
Yield: 93.4 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (6.50 g) in mL glacial Acetic acid was added a solution of 9.205 g ICl (iodine monochloride) in 8 mL of acetic acid, with addition carried out at a rate such that the temperature of the resulting mixture did not exceed 24 degrees C. Water (11.0 mL) was added and the resultant mixture was stirred at 25 degrees C. for 42 hours. Excess ICl was decomposed by the addition of aqueous solution of sodium bisulfite (3.5 mL) at a rate such that the temperature of the reaction mixture did not exceed 20 degrees C. Water (40 mL) was added, and the precipitate was collected by filtration and air-dried to give 8.86 g of crude 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. A suspension of the crude product in 90 mL water was made basic by addition of 50% NaOH, and the resulting solution was extracted into warm EtOAc. The combined organic layers were filtered and EtOAc was replaced by isopropanol via distillation. To the hot isopropanol solution was added 3.4 mL of 6N HCl and the resultant mixture was cooled slowly to 15 degrees C. Crystals of the resulting HCl salt were isolated by filtration, rinsed with isopropanol, and dried under vacuum at 70 degrees C. to give 6.08 g (58.8%) of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine hydrochloride salt, m.p.=262.0-263.0° C., MS (M+H)=401.