Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.57 g, 2.9 mmol) and sodium methoxide (0.18 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue thus obtained was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from dichloromethane-diethyl ether to give the title compound (0.37 g, 1.6 mmol, yield: 61%) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: C1CNCCN1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCNCC4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 69.3 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) and piperazine (0.586 g) was then added and the mixture heated to 110° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.126 g) as a clear gum; NMR Spectrum: (CDCl3) 2.09 (quin, 2H), 2.46 (s(broad), 4H), 2.54 (t, 2H), 2.91 (t, 4H), 3.45 (s, 3H), 3.47 (s, 1H), 3.96 (s, 3H), 4.23 (t, 2H), 4.35 (s, 2H), 6.06 (s, 2H), 7.06 (s, 1H), 7.13 (s, 1H), 7.28 (s, 2H), 8.62 (s, 1H); Mass Spectrum: M+H+ 540/542.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=[C:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(#[N:25])C>>[CH3:21][C:20]1[NH:25][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[N:12][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC#N
Reactant: CCOC(=O)C(=O)C(C)=O
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1C

Procedure:
A mixture of 9.1 g of 1-naphthalenemethylamine, 8.4 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime and 115 ml of acetonitrile was refluxed for 5 hours and then cooled. The solid was collected, giving 7.0 g of 5-methyl-2-(1-naphthalenyl)-1H-imidazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH3:27])=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:18][CH:17]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
1,1-dimethylethyl[(1R)-2-({6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 39, 29 mg) was dissoved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (168 μl, 2.179 mmol). The reaction was stirred during 1 hour at 0° C. and 2 hours at room temperature. The reaction mixture was evaporated. The residue obtained was purified by SCX (3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (21 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:22])=[O:21]
Reactant: CCCc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1ccc(COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of (4-propylphenyl)methanol (116 mg, 0.770 mmol) in THF (5 mL) were added triethylamine (0.220 mL, 1.54 mmol) and methanesulfonyl chloride (89.0 mL, 1.16 mmol), and the mixture was stirred at room temperature for 15 min. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (176 mg, quantitative). This was used for the next step without purification.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH:8]1([C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([OH:18])[N:12]=2)[CH2:10][CH2:9]1>[OH-].[Na+]>[CH:8]1([C:11]2[N:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:6][CH3:7])[N:16]=2)[CH2:10][CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(O)nc(C2CC2)n1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)nc(C2CC2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
76 g (0.6 mol) of dimethyl sulphate were added dropwise to a solution of 76 g (0.5 mol) of 2-cyclopropyl-4,6-dihydroxy-pyrimidine in 250 ml of 2 N sodium hydroxide solution at 50° C. The pH value of the reaction solution was kept at 8 to 8.2 by simultaneously adding 2 N sodium hydroxide solution. The mixture was then stirred at 50° C. for a further 2 hours, control of the pH being continued. The mixture was then cooled to 0° C. and the product which had precipitated was filtered off. 33 g (40% of theory) of 2-cyclopropyl-4-hydroxy-6-methoxy-pyrimidine were obtained in this manner in the form of colorless crystals with a melting point of 186° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: Cc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(C)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 90.5 mg (0.61 mmol) of 4-chloromethyl-2-methyl-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction and dried at 40° C. under reduced pressure. This gives 88.8 mg (66.2% of theory) of product.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:20]([C@@H:22]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])C1C=CC=CC=1.[H][H].C(N(CC)CC)C.[CH:41](/S(Cl)(=O)=O)=[CH:42]\[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>[Pd].C(OCC)(=O)C>[C:43]1(/[CH:42]=[CH:41]/[C:9]([NH:11][C@H:12]([C:20]([C@@H:22]2[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[N:24]([NH2:30])[C:23]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: [H][H]
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1N
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)/C=C/c2ccccc2)C(=O)N1N
Temperature: -15 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
(3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one (200 mg, 0.47 mmol) obtained in example 7, was hydrogenated with 300 mg of 10% palladium on activated carbon in 50 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 2 hrs. After removal of catalyst by filtration, the desubstituted (3S,4S)-3-(L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one in ethyl acetate was cooled to -15 ° C. Then triethylamine (50 mg, 0.5 mmol) and trans-β-styrenesulfonyl chloride (95 mg, 0.47 mmol) were added at -15 ° C. Stirring was continued at a bath temperature of -10 to 5° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1) as eluent and the title compound (200 mg) was obtained as a white solid.
Reaction SMILES: CO[C:3](=O)[C:4]1C=C(C=C(N)[CH:15]=1)C(OCC=C)=O.[CH3:18][O:19][C:20](=[O:33])[C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:23]([C:24]([O-:26])=[O:25])[CH:22]=1.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:19][C:20](=[O:33])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)[C:24]([O:26][CH2:15][CH:4]=[CH2:3])=[O:25]
Reactant: C=CCOC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCOC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Starting material (3(b)) was synthesised as follows. A mixture of mono-methyl-5-nitroisophthalate (13.8 g), allyl bromide (7.96 g), potassium carbonate (13.94 g) and DMF (160 ml) was stirred at ambient temperature for 4.5 h. The solid was filtered and DMF was evaporated away from the filtrate under reduced pressure. The residue was dissolved in diethyl ether (300 ml) and water (100 ml) and stirred for five minutes. The organic layer was separated and washed with saturated sodium bicarbonate solution (220 ml), brine (200 ml), dried over magnesium sulphate and evaporated under reduced pressure to give 5-nitro-isophthalic acid allyl ester methyl ester (3(a)) as a yellow oil (14.74 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[O:21]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[OH:9][CH:10]([C:11]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH:15]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:1][NH:8][C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[O:37])=[CH:3][CH:4]=2)[C:16]1=[O:17]
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Agent: [NH-]CC(O)C(O)C(O)C(O)CO
Product: O=C(O)c1ccc(Oc2ccc(C(=O)NCc3ccc(N4C(=O)C(CCC(O)c5ccccc5)C4c4ccccc4)cc3)cc2)cc1

Procedure:
The benzylamine from ha was reacted with the 2,3,4,5,6-pentahydroxyhexylamide of 4,4′-oxybisbenzoic acid from If as described in Example I. This produced the 2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][OH:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCO)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)[nH]c2c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (11.00 g, 25.1 mmol) and triethylamine (5.25 ml, 37.7 mmol) in chloroform (77 ml) was added dropwise methanesulfonyl chloride (2.33 ml, 30.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]1H-indole-6-carboxylate (12.60 g, yield 97%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C([O-])(=O)C.[K+].[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25]
Reactant: O=Cc1cccs1
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@H]1Cc2ccccc2[C@@H]1NCc1cccs1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Thiophenecarboxaldehyde (80 μL, 0.8 mmol) and potassium acetate (90 mg, 0.9 mmol) were added to a solution of N-{(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Method 5b, 400 mg, 0.9 mmol) in MeOH (10 mL). The reaction was stirred at ambient temperature for approximately 5 mins then macroporous triethylammonium methyl polystyrene cyanoborohydride (540 mg, 0.9 mmol) was added and the reaction stirred at ambient temperature for a further 3 h. The reaction was then filtered and the volatiles were removed by evaporation under reduced pressure to afford N-{(1S,2S)-1-[(2-thienylmethyl)amino]-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide which was used crude in the next stage.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH2:29]([N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:6]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)nc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(=O)n(Cc3ccccc3)c2)cc1

Procedure:
N-{3-[4-(6-Hydroxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (150 mg, 0.5 mmol) was stirred with potassium tert-butoxide (168 mg, 1.5 mmol) and benzylbromide (342 mg, 2 mmol) in 3 ml of NMP at room temperature for 10 h. The batch was admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 22 mg (11%), M+H+: 391.15. N-{3-[4-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide was obtained as by-product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Yield: 78.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.109 g, 0.361 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.100 g, 0.361 mmol) and DIPEA (0.126 mL, 0.723 mmol) were combined in THF (3 mL) and treated with HATU (0.151 g, 0.397 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 60% EtOAc/hexanes to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.16 g, 0.285 mmol, 79% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (t, J=5.63 Hz, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.37-7.54 (m, 3H), 7.25 (s, 1H), 6.75 (dd, J=17.67, 11.08 Hz, 1H), 6.05 (d, J=17.67 Hz, 1H), 5.51 (s, 2H), 5.44 (d, J=10.99 Hz, 1H), 4.50 (d, J=5.59 Hz, 2H), 3.40 (t, J=8.10 Hz, 2H), 0.76 (t, J=8.06 Hz, 2H), −0.07 (s, 9H). LC-MS (ES−) m/z 559.13, 561.19 [M−1]. LC-MS (ES+) m/z 561.14, 563.12 [M+H].
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[S:28][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[CH:9]=1>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:9]=[CH:8][S:28][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Product: Cc1nccn1-c1nc(NCCc2ccc3c(c2)OCO3)c2ccsc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]2[N:31]=[N:32][N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)[N:34]=2)[CH:25]=[CH:26][C:27]=1[Cl:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][N:33]3[N:32]=[N:31][C:30]([CH2:29][C:24]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=4)=[N:34]3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCCCn1nnc(Cc2ccc(Cl)c(Cl)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCCn2nnc(Cc3ccc(Cl)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.61 mmol) in THF (5 ml) was added 5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}-1-pentanol (0.191 g, 0.61 mmol; prepared in similar fashion to Example 35), triphenylphosphine (0.36 g, 1.3 mmol) and finally dibenzylazodicarboxylate (0.40 g, 1.3 mmol). The solution was stirred for 18 h after which Pd(PPh3)4 (0.16 g, 0.137 mmol) followed by morpholine (0.75 ml, 8.3 mmol) was added and the solution stirred at ambient temperature for 6 h. The solution was loaded onto an aminopropyl SPE (5 g) and eluted with MeOH then 5% AcOH/MeOH to yield the title compound containing minor impurities. Further chromatography (silica SPE, 20 g) eluting with ether yielded the title compound as a white solid (0.061 g, 18%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11]1([N:17]2[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>[Pd]>[NH:3]1[C:4]2[CH:9]=[C:8]([N:10]3[CH:23]([CH:20]4[CH2:19][CH2:18][N:17]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:22][CH2:21]4)[CH2:32][NH:31][C:36]3=[O:37])[CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=CC1CCN(c2ccccc2)CC1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(C2CCN(c3ccccc3)CC2)N1c1ccc2nc[nH]c2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 1-phenylpiperidine-4-carbaldehyde (0.570 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2.