Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc(F)c(F)cc4F)nc23)CC1
Yield: 87.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 2,4,5-trifluorobenzoyl chloride, 0.015 gm (86%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C@@H:1]12[CH2:8][C@@H:4]([C@@H:5]([OH:7])[CH2:6]1)[CH2:3][C@@H:2]2[OH:9].C1OCCOCCOCCOCCOC1.O1CCCC1.[OH-].[Na+].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:7][C@H:5]1[CH2:6][C@H:1]2[CH2:8][C@@H:4]1[CH2:3][C@@H:2]2[OH:9])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2O
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (1R,2S,4R,5S)-bicyclo[2.2.1]-heptane-2,5-diol (1.15 g, 8.97 mmol) and 15-crown-5 (0.054 mL, 0.269 mmol) in tetrahydrofuran (30.0 mL, 8.97 mmol) were added at 10° C. (ice/water bath) finely ground sodium hydroxide (2.15 g, 53.8 mmol) and 1-(bromomethyl)benzene (1.07 mL, 8.97 mmol). After stirring at 10° C. for 3 h, the mixture was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water, and the organic portions were washed with brine, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 80% of ethyl acetate in hexanes). The title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h

Procedure:
A solution of 25.0 g (144 mmol) of 2-amino-5-bromopyridine in 50 mL of acetic acid and 250 mL of acetic anhydride was heated at reflux for about 2 hours. The reaction mixture was then cooled and poured into 750 mL of water with stirring. After about 1 hour, the solution was adjusted to pH=10 with 50% sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give 26.5 g of the title product as a white flaky solid, mp 175-176° C. 1H nmr (deuteriochloroform): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.[CH3:20][CH:21]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH3:22].N1C=CN=C1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:20])[CH:13]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C(CSc1cccc(O)c1)c1ccc(F)cc1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cccc(SCC(=O)c2ccc(F)cc2F)c1)(C(C)C)C(C)C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a 100 mL three-neck round bottom flask was added 9n (1.4 g, 5 mmol) and TIPSCl (1.15 g, 6 mmol) in CH2Cl2 (40 mL) under nitrogen at room temperature. Then a solution of imidazole (816 mg, 12 mmol) in CH2Cl2 (20 mL) was added dropwise. The resulting mixture was stirred for 24 h. The mixture was filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography eluted by hexane:ethyl acetate (6:1) and the correct product was obtained as a slightly yellow oil; yield 96% (2.1 g); H NMR (400 MHz, CDCl3): d 1.13 (m, 18H, 6×CH3), 1.29 (m, 3H, CH), 4.26 (s, 2H, SCH2), 6.75 (m, 1H, Ar), 6.89-6.97 (m, 4H, Ar), 7.15 (m, 1H, Ar), 7.95 (m, 1H, Ar); CNMR (100 MHz, CDCl3): δ 21.6, 17.7, 29.3, 104.3, 111.5, 118.5, 119.2, 121.5, 122.7, 129.5, 131.4, 135.9, 153.6, 156.3, 159.5, 162.3, 164.9; IR ν (cm−1) 2944, 2983, 2866, 1682, 1610, 1584, 1475, 1423, 1266, 1245, 1186, 1145, 1095, 997, 970, 943, 881, 852, 776, 683; ESI HRMS m/z calcd for C23H31F2O3SSi (M+OH)+ 453.17258, found 453.17226.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].O>C(O)C>[CH2:26]([NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and butylamine (170 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (358 mg, 99.1% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1)#[N:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].CN(C)C=O>O>[C:11]1([C:8]2[C:7]3[CH:17]=[C:3]([C:1]4[NH:22][N:21]=[N:20][N:2]=4)[CH:4]=[CH:5][C:6]=3[O:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2occ(-c3ccccc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2coc3ccc(-c4nnn[nH]4)cc23)cc1
Temperature: 20 °C

Procedure:
A mixture of 61.4 g. (0.28 mole) of 5-cyano-3-phenylbenzofuran (described in U.S. Pat. No. 4,067,993, Example 1), 16.5 g. (0.31 mole) of ammonium chloride and 20.2 g. (0.31 mole) of sodium azide in 250 ml. of N,N-dimethylformamide is stirred at 110°-120° C. for 16 hours. The mixture is cooled to about 20° C. and poured into about 1 liter of water. A light brown solid forms which is collected by filtration, washed with water, and then recrystallized from ethanol to provide brown crystals of 3-phenyl-5-(1H-tetrazol-5-yl)benzofuran.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.OS(O)(=O)=O.[CH3:14]O>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:14])=[O:7])=[N:2]1
Reactant: CO
Reactant: O=C(O)c1cc[nH]n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc[nH]n1

Procedure:
1H-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in MeOH (250 ml). Concentrated H2SO4 (30 ml) was added to the solution. The resulting mixture was refluxed for 12 h and concentrated. The residue obtained was quenched by saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated. Yield 12.05 g. 1H-NMR (400 MHz; CDCl3): δ 3.98 (s, 3H), 6.86 (d, 1H), 7.85 (d, 1H), 11.9 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[F:23].O>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:3][C:4]#[N:5])=[CH:17][C:16]=1[F:23]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1ccc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
Diethylcyanomethyl phosphonate (3.2 ml, 18.9 mmol) was taken up in dry THF (20 ml) at 0° C. under nitrogen, and stirred as a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added portionwise over ca. 10 min. The resulting grey suspension was then stirred at 0° C. for 1 h, before a solution of 4-chloro-3-fluoro benzaldehyde (Lancaster Synthesis) (3 g, 18.9 mmol) in 5 ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60 h. Water (5 ml) was added, and the mixture extracted with EtOAc (3×50 ml). The combined organics were were dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product as a mixture of geometric isomers (2.4 g, 70%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS+199.1 (M+NH4+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]=2[NH2:25])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[C:10]=2[NH:25][C:28](=[O:32])[C:29]([NH:25][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:30])=[CH:7][CH:8]=1
Reactant: Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1)C(=O)Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4,4″-Bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-ylamine (700 mg, 1.84 mmol) in pyridine (5 mL) was treated with oxalyl chloride (73 μL, 0.837 mmol). The resulting suspension was stirred at rt overnight under Ar, then poured into H2O. The precipitate was filtered, washed with H2O and dried in vacuo. The resulting solid was crystallized from toluene/heptane, then recrystallized from toluene to afford N,N′-Bis-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yl)-oxalamide (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]2[S:15]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:16])=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][NH:34][CH3:35])[C:30]([CH3:36])=[N:29]1.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][N:34]([CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([S:15]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=3[F:26])=[O:16])=[N:10][CH:11]=2)[CH3:35])[C:30]([CH3:36])=[N:29]1
Reactant: CNCc1cn(C)nc1C
Reactant: O=Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nn(C)cc1CN(C)Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carbaldehyde (33) (39 mg, 0.10 mmol), 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (15 mg, 0.11 mmol), sodium cyanoborohydride (30 mg, 0.11 mmol) and DMF/acetic acid (10/1, 1 mL) was stirred at room temperature overnight. The reaction mixture was directly loaded on to reverse phase preparative HPLC column and purified to yield 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazol-5-yl)methyl)-N-methylmethanamine (501). 1H NMR (400 MHz, CDCl3) δ: 7.63 (s, 1H), 7.52 (s, 1H), 7.45-7.36 (m, 1H), 7.24-7.09 (m, 4H), 6.90-6.85 (m, 1H), 4.87 (d, J=13.0, 1H), 4.58 (d, J=13.0, 1H), 4.27 (d, J=14.5, 1H), 4.11 (s, 1H), 3.99 (d, J=13.2, 1H), 3.90-3.79 (m, 4H), 2.57 (s, 3H), 2.18 (s, 3H). LC-MS ESI m/z; found 506.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)(OC)OC.[H-].[Na+].[C:20]([OH:23])(=[O:22])[CH3:21]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:21][C:20]([OH:23])=[O:22])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(Br)cc2C1=O
Temperature: 25 °C

Procedure:
6-Bromo-1-indanone (142 g, 672 mmol) in tetrahydrofuran (1200 mL) was added slowly to refluxing dimethyl carbonate (143 mL, 1680 mmol), sodium hydride (80.6 g, 2020 mmol, 60% in oil, washed with pentane after weighing) and tetrahydrofuran (1200 mL). After refluxing the mixture for 2.5 hours, acetic acid (240 mL) was added dropwise at 0° C. and then allowed to warm to room temp. The mixture was partitioned between diethyl ether/dichloromethane and dilute aqueous hydrochloric acid. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, and brine and was then dried over sodium sulfate to obtain a brown solid after removing solvent under vacuum, (176 g, 97%, crude), 124.5-127.5° C. m.p. 1H-NMR (300 MHz, CDCl3) (a ratio of approximately 3:1 enol to ketone tautomers) 7.91 (d, 0.27H), 7.77 (d, 0.73H, J=1.8), 7.73 (dd, 0.27H), 7.54 (dd, 0.73H, J=8.1, 1.8), 7.39 (d, 0.27H), 7.34 (d, 0.73H, J=7.9), 3.86 (s, 2.19H), 3.83 (m, 0.27H), 3.80 (s, 0.81H), 3.50 (m, 0.27H), 3.47 (s, 1.46H), 3.32 (m, 0.27H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: O=C(CCNc1cccc(Br)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)N(CCC(=O)c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 280.7 %

Procedure:
To the solution of 3-(3-bromophenylamino)-1-phenylpropan-1-one (0.03 mol) in anhydrous THF (30 mL) was added K2CO3 (0.06 mol) and methyl chloroformate (0.033 mol) at 0° C. under N2 atmosphere. Then the reaction mixture was stirred at rt for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was washed with H2O, 1N HCl and brine and then extracted with EtOAc. The combined organic layers were concentrated to give crude product, which was purified by column chromatography to afford methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (30.5 g, 95%). 1H NMR (400 MHz, CDCl3): δ=3.22 (m, 2H), 3.62 (s, 3H), 4.02 (m, 2H), 7.05-7.20 (m, 2H), 7.3-7.5 (m, 4H), 7.8 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH3:23].O>C(C(C)=O)C>[CH2:22]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:7]1[CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: CCBr
Reactant: Clc1ccc(CC2CCCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCN1CCCCCC1Cc1ccc(Cl)cc1

Procedure:
Boil together (under agitation) 4 g of 2-(4-chlorobenzyl)perhydroazepine, 2.5 g of anhydrous potassium carbonate and 2.9 g of ethyl bromide under reflux for 26 hours in 30 ml of ethylmethylketone. Cool the thus-produced reaction mixture to ambient temperature. Mix the cooled reaction mixture with water and then extract it with diethyl ether. Dry the resulting organic phase over sodium sulfate, remove the ether and distil the residue to obtain 5.12 g (70% of theory) of the title compound with a BP of 112° at 0.005 mm of Hg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:20][C:6]3[C:7]4[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=4[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=3[CH2:4][CH2:3]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product of Example 15 (0.15 g, 0.5 mmol), phenylisocyanate (0.1 g, 1 mmol) and triethylamine (0.1 g) in 5 mL dimethylformamide were stirred at room temperature for 18 h. The solvent was removed by rotoevaporation and the residue suspended in methanol/dimethylformamide. After heating, the solid was collected by filtration and dried in vacuo. CHN calc'd for C19H17N5O5.0.5H2O.HCON(Me)2 : C, 55.34; H, 5.27: N, 17.60 found-C, 55.38: H, 4.95; N, 17.04. H-NMR (400 MHz, dmso) 1H, s, 12.1; 1H, s, 11.45; 1H, s, 8.4; 1H, s, 7.95; 1H, s, 7.7; 2H, d, 7.4; 2H, t, 7.23; 1H, t, 6.9 1H, d, 6.35; 1H, t, 4.1; +ring protons.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:22])[C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCNC(=O)n1c(=O)[nH]c2ncccc21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)n1c(=O)n(C)c2ncccc21

Procedure:
In 2.5 ml of DMF, N-hexyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxamide (65 mg, 0.248 mmol), iodomethane (70 mg, 0.5 mmol) and cesium carbonate (80 mg, 0.25 mmol) were stirred at RT for 5 h. After concentration, the mixture was admixed with water and ethyl acetate, and the organic phase was removed, concentrated and purified by means of preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 16 mg (23%), M+H+: 277.17.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][C:3]=1[CH:13]=[O:14]
Reactant: COC(Cl)Cl
Reactant: Oc1ccc(O)c2c1CCCC2
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c2c(c1O)CCCC2
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene (164 mg, 1 mmol) in dichloromethane (5 ml) is added titantetrachloride (569 mg, 3 mmol). Then 1,1-dichlorodimethyl ether (173 mg, 1.5 mmol) is added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally hydrochloric acid 5% (1 ml) is added under ice-cooling. The organic phase is separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue is crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde in about 60% yield (108 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[CH3:46])[N:37]=[CH:38][C:31]=12>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[CH3:46])[N:37]=[CH:38][C:31]=12)[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1c(F)cccc1-n1ncc2c(Cl)ncnc21
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE2 using (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) and 4-chloro-1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AF5). 1H NMR (400 MHz, DMSO) d 0.94 (9H, s), 1.96 (3H, d), 3.81-3.63 (7H, m), 4.09-4.02 (1H, m), 4.13 (1H, m), 5.89 (1H, m), 7.50-7.30 (9H, m), 7.63 (4H, m), 8.49 (1H, s), 8.59 (1H, s). m/z (ES+) (M+H)+=629; HPLC tR=3.43 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([Cl:13])[N:5]=1.[CH3:14]I.O>O1CCCC1>[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH3:14])=[C:6]([Cl:13])[N:5]=1
Reactant: CI
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
Sodium hydride (60% in mineral oil, 2.53 g, 63.5 mmol) was added to an ice-cooled solution of 2,6-dichloropurine (10.0 g, 52.9 mmol) in tetrahydrofuran (75 mL) and the mixture was stirred for 30 min. Methyl iodide (3.29 mL, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2,6-dichloro-7-methyl-7H-purine (1.19 g, 11%) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2,6-dichloro-9-methyl-9H-purine (3.0 g, 28%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C(=Cc1ccc(-c2nnn[nH]2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.15 g (3.17 mmol) of 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile 1.03 g (15.86 mmol) of sodium azide, and 1.83 (15.86 mml) of pyridine hydrochloride in 15 ml of DMF is heated at 100° C. for 48 hours and then poured into ice water. The precipitate that forms is filtered off and suspended in hot methanol and filtered to give 5-(4-(4-(2-quinolinylmethyloxy)styryl)phenyl)tetrazole. (M.P. 241° C.-243° C.)