Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.[I-].[Na+]>O.CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Br)ccc1C(Cl)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 231.4 %

Procedure:
A reaction mixture of 4-bromo-1-(1-chloro-4,4,4-trifluorobutyl)-2-methylbenzene (369 g), sodium carbonate (245% g), methyl 4-aminobenzoate (194 g), sodium iodide (347 g) and DMA (1.2 L) was stirred at 50° C. for 3 hr. The reaction mixture was added to water. This reaction was performed for 3 batches, the obtained respective reaction mixtures were combined, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with petroleum ether to give the title compound (1164 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][OH:32])[CH:25]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Reactant: Nc1cccc(CCO)c1
Product: OCCc1cccc(Nc2ncc(Cl)c(Nc3cccc(O)c3)n2)c1
Yield: 65 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3-aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 65% yield. LCMS for C18H18ClN4O2 (M+H)+: m/z=357.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9]1([C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)O)O>O>[CH:4]1[C:3]2[NH:8][C:11]3[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1N
Reactant: Oc1ccccc1O
Solvent: O
Product: c1ccc2c(c1)Nc1ccccc1N2
Temperature: 170 °C
Yield: 101.4 %

Procedure:
To a 12 L Morton flask is charged 702 g 1,2-diaminobenzene and 2.1 Kg catechol (3 equivalents based on 1,2-diaminobenzene). Heat is applied by a heating mantle, and at the end of 30 minutes, all materials are melted and the temperature has risen to 90° C. Over the next 40 minutes, the temperature is increased to ca. 170° C. The temperature is maintained in the range of 151° C. to 187° C. over a 4½ day period. The reaction mixture is cooled to 80° C. and 8 L deionized water added over 30 minutes. The mixture is allowed to cool to room temperature overnight, and a filter candle used to remove water. A further 8 L water is added and heated to 70° C., cooled to 40° C., and the water again removed. A further wash with 8 L water is again performed, with the wash temperature lowered only to 60° C. during removal of water. The product is filtered on a filter funnel and air dried for 30 minutes to yield ca. 1200 g of moist 5,10-dihydrophenazine containing approximately 20% water. Yield of dry 5,10-dihydrophenazine is 960 g (68% of theory, based on 1,2-diaminobenzene).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:21]([C:17]2[CH:16]=[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccccc3)c2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 3-biphenylsulphonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:11]([O-:18])(OCC)OCC.[Cl-].[NH4+]>C(OCC)C>[C:1]1([CH2:7][CH2:8][PH:11](=[O:18])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=[PH](CCc1ccccc1)CCc1ccccc1
Yield: 66.7 %

Procedure:
To a solution of 25 mmol of (2-phenyl)ethylmagnesium bromide in 25 ml of diethyl ether was added dropwise with cooling (ice bath) 0.92 ml (7.14 mmol) of diethyl phosphite. The resulting solution was heated at reflux for 2 h, cooled, and treated with aqueous ammonium chloride. The product was extracted with ether, dried over MgSO4, and concentrated in vacuo. Flash chromatography using ethyl acetate gave 1.23 g (64%) of the desired compound (Rf 0.64, 10% methanol in chloroform) as a colorless oil. 1H NMR (CDCl3) δ 2.0-2.2 (m, 4H), 2.85-3.1 (m, 4H), 6.89 (dm, J=455 Hz, 1H), 7.15-7.4 (m, 10H). Mass spectrum (M+H)+ =259.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with azetidine (1.2 equiv) to give 157 (15.9 mg, M+1 353.0)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH:12]=O.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CO.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: O=CCc1ccc([N+](=O)[O-])cc1Cl
Reactant: NCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCNCc2ccc(F)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
2-(2-Chloro 4-nitro-phenyl)acetaldehyde (3.0 g, 15.03 mmol) and 4-fluorobenzylamine (1.88 g, 15.02 mmol) were added to methanol (45 mL) at RT and stirred for 15 minutes. The reaction mixture was cooled to 0° C. and acetic acid (15 mL) followed by solid NaBH4 (0.56 g, 15.0 mmol) were added. The reaction mixture was allowed to warm to RT and stirring continued for 2 hours. The volatiles were then removed under reduced pressure. Dichloromethane (60 mL) and water (60 mL) were added and the mixture was stirred for 15 minutes. The separated organic layer was washed with water (60 mL), brine (60 mL), dried (Na2SO4) and the solvents removed under reduced pressure to afford the title compound (3.1 g, 67%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:27][CH2:28][CH3:29])=[N:5][C:4]=1[C:30](=[O:33])[CH2:31][CH3:32])#[N:2].[CH3:34][Mg]Br>O1CCCC1>[C:1]([C:3]1[N:7]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]([CH2:27][CH2:28][CH3:29])=[N:5][C:4]=1[C:30]([OH:33])([CH3:34])[CH2:31][CH3:32])#[N:2]
Reactant: CCCc1nc(C(=O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCc1nc(C(C)(O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure described in Preparation 17, but using 5.00 g of 5-cyano-4-propionyl-2-propyl-1-tritylimidazole (prepared as described in Preparation 16) and 12.5 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran, 3.32 g of the title compound were obtained as a crystalline powder, melting at above 120° C. (softening at 110° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:22])[NH:44][CH2:43][CH2:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCc1ccccn1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with 3-(pyridin-2-yl)propylamine; ESI-MS [M+H]+: 579.2.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CN(SSc1ccccc1)C(=O)F
Reactant: CC1OCSC1=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1OCSC1=NOC(=O)N(C)SSc1ccccc1

Procedure:
4-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 5.0 g (0.0375 m) of 5-methyl-4-oximino-1,3-oxathiolane, 8.15 g (0.0375 m) of N-methyl-N-(phenylthiosulfenyl) carbamoyl fluoride and 3.79 g (0.0375 m) of triethylamine in 100 ml of dioxane. The crude residual oil was purified using silica gel column to yield 3.5 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CNN
Solvent: CCO
Product: CNN=Cc1ccc(Cl)cc1
Yield: 97 %

Procedure:
56.2 g (0.4 mol) of 4-chlorobenzaldehyde were added dropwise to a solution of 18.4 g (0.4 mol) of methylhydrazine in 100 ml of ethanol. The mixture was then refluxed for 4 hours. After cooling, the reaction mixture was concentrated. The residue was taken up in methyl tert-butyl ether. The ether phase was finally washed with water, dried over magnesium sulfate and then concentrated. Yield: 97%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 36 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a yellow crystalline solid (yield 36%). MS (m/e): 500.1 (M+H+, 100%), 517.2 (M+NH4+, 69%).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([B:25]4[O:29]C(C)(C)C(C)(C)[O:26]4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:3]1.COCCN(S(F)(F)[F:44])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([F:44])[CH2:3][C@H:4]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:29])[OH:26])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1c1ncc(-c2ccc(B(O)O)cc2)[nH]1
Temperature: -78 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 1-2c (1.5 g, 3.3 mmol) was added as a solid to a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.91 mL, 5.0 mmol) in 15 mL CH2Cl2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH2Cl2. Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown oil. The oil was chromatographed on silica gel with 5% MeOH/CH2Cl2 to yield 4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenylboronic acid as a tan solid (0.46 g, 37%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][OH:11].[H-].[Na+].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][O:11][CH2:18][CH2:17][C:16]([NH2:20])=[O:19]
Reactant: C=CC(N)=O
Reactant: CN(C)CCOCCN(C)CCO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOCCN(C)CCOCCC(N)=O

Procedure:
A 50 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 19.0 g of 2-{[2-(2-dimethylamino ethoxy)ethyl]methylamino}ethanol. Sodium hydride, 0.03 g, was then added carefully to the 2-{[2-(2-dimethylamino ethoxy)ethyl]methylamino}ethanol solution with stirring. The mixture was stirred at a constant rate for two minutes before 7.10 g of acrylamide was added. After the addition of acrylamide, the reaction mixture was stirred at 55° C. for 6 hours. The mixture was cooled to ambient temperature and neutralized with 0.80 g of concentrated sulfuric acid. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application without further purification. Quantitative 1H NMR showed that the product was 94% pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.I[C:16]1[CH:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: O=c1ccc(I)c[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
5-methoxybenzofuran boronic acid (230 mg, 1.2 mmol), 5-iodo-2-pyridone (221 mg, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) and NEt3 (317 μL, 2.4 mmol) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (20 mg). 1H NMR δ ppm 11.95 (br. s., 1 H) 7.94 (dd, 1 H) 7.88 (s, 1 H) 7.44 (d, 1 H) 7.00-7.20 (m, 2 H) 6.84 (dd, 1 H) 6.48 (d, 1H) 3.78 (s, 3 H); MS m/z 242 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([Cl:26])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:33][Si:34]([CH2:37][CH2:38][O:39][CH2:40]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:21]([CH2:40][O:39][CH2:38][CH2:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([Cl:26])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 24.6 %

Procedure:
A mixture of 8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.9 g, 2.44 mmol), K2CO3 (1.01 g, 7.32 mmol) in DMF (10 ml) were cooled to 0° C. and added SEM-Cl (1.3 ml, 7.32 mmol). The reaction mixture was stirred at 25° C. for 20 hours. To this reaction mixture water (100 ml) was added and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with brine (30 ml) and dried over Na2SO4. The organic layer was evaporated to dryness and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 10-15% ethyl acetate in hexane as an eluent to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.3 g, 25%) as a off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][CH2:13][CH:14](N)[CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]1[NH:11][CH:14]([CH3:15])[CH2:13][N:12]=1
Reactant: CC(N)CN
Reactant: Cc1cccc(C)c1CC#N
Product: Cc1cccc(C)c1CC1=NCC(C)N1

Procedure:
rac-2-(2,6-Dimethyl-benzyl)-5-methyl-4,5-dihydro-1H-imidazole was prepared from 2,6-dimethyl-phenyl-acetonitrile and 1,2-diaminopropane in analogy to Example 19 b): orange powder; MS (EI): 202.3 (M+.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[CH3:18]>CCO.[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[N:5]1[CH2:4][C@@H:3]2[CH2:8][C@H:6]1[CH2:7][N:2]2[CH3:1])[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1N1C[C@@H]2C[C@H]1CN2C
Reaction time: 2 h

Procedure:
2-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-nitrotoluene (3.3 g) was dissolved in EtOH (50 mL) and transferred to Parr hydrogenation flask. Catalyst, Pd/C (450 mg), was added and the mixture subjected to hydrogenation at 30 PSI for 2 h. The reaction mixture was filtered through Celite and the Celite filter cake washed with EtOH. Concentration of the combined filtrate provided 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline, as a tan solid (2.52 g, 86%). 1H NMR (DMSO-d6): δ 6.58 (d, 1H, J=8.8 Hz), 6.34 (s, 1H), 6.27 (d, 1H, J=8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H), 3.24 (s, 1H), 3.16 (d, 1H, J=9.3 Hz), 2.93 (dd, 1H, J=1.8 and 9.3 Hz), 2.61 (qt, 2H, J=9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J=9.1 Hz), 1.63 (d, 1H, J=9.1 Hz). LCMS: purity: 97%; MS (m/e): 218 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[C:15]2[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1>[N+](C)([O-])=O>[N+:6]([C:12]1[CH:11]=[CH:10][C:15]2[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20][C:14]=2[CH:13]=1)([O-:9])=[O:7]
Reactant: O=C1CCc2ccccc2CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of cold (0° C.) concentrated sulfuric acid (15 mL) was added 70% nitric acid (15 mL) dropwise over 30 min. The addition was controlled to maintain the internal reaction temperature below 5° C. After the addition, the resulting solution was transferred into an addition funnel and was added dropwise to a solution of 8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (14 g, 87.5 mmol) in nitromethane (80 mL) at 0° C. over a period of 40 min. After the addition, the reaction mixture was stirred at 0° C. for 2 h. Then ice water (˜80 mL) was added to the reaction mixture, and the mixture was stirred for additional 30 min. Then the mixture was transferred to a separatory funnel where the layers were separated. The aqueous layer was extracted with ethyl acetate (3×80 mL). The combined layers were washed with cold water, sat. NaHCO3 solution and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography on silica gel (hexanes/EtOAc=3:1 to 2:1) to afford the mixture of nitro regioisomers (˜15 g), which was then purified by recrystallization from MTBE (tert-butyl methyl ether, 180 mL) to yield 7.3 g of 2-nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (40% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ: 8.10-8.06 (m, 2H), 7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H); LC-MS: 206 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH:13]=[N:12][CH:11]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.044 g, 1.09 mmol) in DMF (2 mL) was added pyrrolidin-2-one (0.081 g, 0.945 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromo-5-chloromethyl-pyridine (0.15 g, 0.727 mmol) was added and the resulting suspension was heated at 60° C. over night. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.217 g, 87%) as a white solid. MS: 251.1, 257.1 (M+H+).