Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([O:21]C)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([OH:21])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc2c1CC(NS(=O)(=O)c1ccccc1)CC2
Agent: BrB(Br)Br
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Product: O=S(=O)(NC1CCc2cccc(O)c2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.6 g (30 mmol) of 7-benzenesulphonylamino-1-methoxy-5,6,7,8-tetrahydronaphthalene are dissolved in 150 ml of analytical grade CH2Cl2, 40 ml of 1 molar (40 mmol) of boron tribromide solution are added dropwise at room temperature, the reaction mixture is subsequently stirred at room temperature for 1 hour and poured onto ice-water containing a little L-(+)-tartaric acid, the CH2Cl2 is separated off and the mixture is dried over MgSO4 and concentrated in vacuo, crystalline residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[NH:21][C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:26](N(CC)CC)C.COS(OC)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:26])[C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCn1c(=O)[nH]c(=O)c2c1nc(C#Cc1ccc(OC)c(OC)c1)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-3,7-dihydro-purine-2,6-dione (1.52 g, 4.4 mmol) in 10 ml of dimethylformamide (DMF) was added triethylamine (3 ml, 20 mmol) and dimethylsulfate (0.65 ml, 7 mmol). The mixture was stirred at room temperature for 0.5 h. The product was precipitated by addind water (40 ml), filtered under reduced pressure, washed with water and dried at 70° C. (310 mg, 20%).
Reaction SMILES: [C:1]([CH:3]([CH3:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH:3]([CH3:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CC(C)C#N)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(C)CN)OCC

Procedure:
A solution of 17.0 g of ethyl 2-cyanopropyl(diethoxymethyl)-phosphinate in 150 ml of ethanol is added to 155 g of an 8% solution of ammonia in ethanol. To this are added 10 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-2-methylpropyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31P=+45.8 and +45.7 ppm (CDCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[O-]CC.[Na+].[Br:26][CH2:27][CH2:28][CH2:29]Br>C(O)C>[Br:26][CH2:27][CH2:28][CH2:29][N:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(CONS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: BrCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CON(CCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
N-(p-methoxybenzyloxy)-p-toluenesulfonamide (61.4 g) was added to a solution of sodium ethoxide in absolute ethanol (Na: 4.6 g, absolute C2H5OH: 540 ml) and stirred at 70° C. for 1.5 hours. After cooling at ambient temperature, 1,3-dibromopropane (121.2 g) was added to the mixture, and then the mixture was refluxed with stirring for 2 hours and filtered. The filtrate was concentrated under reduced pressure. To the residue was added a mixture of ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oil, which was crystallized from a mixture of ethyl acetate and n-hexane to give N-(3-bromopropyl)-N-(p-methoxybenzyloxy)-p-toluenesulfonamide (75.1 g). MP: 89.5°-91.5° C. In substantially the same manner as described in the above example, there were obtained the following compounds.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20](=[O:21])[CH2:19][CH:18]([CH3:23])[CH3:17])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)CC(=O)Cl
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)CC(C)C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 3-methylbutanoyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:88]I>C1(C)C=CC=CC=1>[I:88][CH2:22][C:21]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: II
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
2,2,2-Tris(octadecyloxymethyl)ethanol (500 mg, 560 μmol) was dissolved in toluene (10 ml), triphenylphosphine (294 mg, 1.12 mmol), imidazole (76.2 mg, 1.12 mmol) and iodine (284 mg, 1.12 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, toluene (10 ml) was added, and the mixture was partitioned and washed three times with water (5 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with acetonitrile (10 ml) to give 1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane (555 mg, 553 μmol, yield 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[N:5]1[NH:6][N:7]=[N:8][C:9]=1[C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1
Reactant: COCCl
Reactant: COc1ccc(CC(=O)Nc2sccc2-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1nnc(-c2ccsc2NC(=O)Cc2ccc(OC)cc2)n1
Reaction time: 72 h

Procedure:
Chloromethyl methyl ether (0.20 ml, 2.63 mmol) was added to a heterogeneous mixture of N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide (Example 8.1., 580 mg, 1.84 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in DMF (10 ml). After stirring for 72 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was directly purified by HPLC to yield N-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide. Method [7] Retention time 6.60 min by HPLC (MH+ 360). 1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 7.47 (d, J=5.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (d, J=5.7 Hz, 1H), 5.77 (s, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][C:14]([NH:16][C@@H:17]2[C:44](=[O:45])[N:19]3[C:20]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)=[O:33])=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:22][S:23][C@H:18]23)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]=1>ClCCl>[O:45]=[C:44]1[N:19]2[C@H:18]([S:23][C@@H:22]3[C:21](=[C:20]2[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[O:33])[C@@H:51]2[C@H:46]3[CH2:47][CH2:48][CH2:49][CH2:50]2)[C@@H:17]1[NH:16][C:14](=[O:15])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1=CCCCC1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3[C@H]4CCCC[C@H]4[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 16 h
Yield: 44.2 %

Procedure:
Potassium carbonate (9.5 mg, 0.068 mmol) was added to a solution of p-methoxy-benzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (20 mg, 0.034 mmol) and cyclohexene (17.3 μl 0.17 mmol) in dichloro-methane (1.5 ml). The mixture was stirred for 16 h, then chromatographed to give the title compound (7.8 mg, 44%) as a cream solid, mp. 234°-236° C. (EtOAc) (Found: M+, 518.1882. C29H30N2O5S requires M, 518.1875); νmax (CH2Cl2) 1784, 1718, 1685 cm-1 ; δH (CDCl3) 1.00-1.99 (8H, m), 2.39 (1H, br q, J 8.2), 3.47 (1H, taut, J 9.3, 8.4, 2.6), 3.63 (2H, ABq, J 16.3), 3.80 (3H, s), 4.26 (1H, dd, J 8.7, 2.6), 4.90 (1H, d, J 4.9), 5.17 (2H, ABq, J 11.9), 5.75 (1H, dd, J 8.9, 4.9), 5.98 (1H, d, J 8.8), 6.86 (2H, d, J 8.7), 7.25-7.37 (7H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2(COC3C=C4C(=[CH:43][C:33]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:24]1[CH:43]=[CH:33][CH:26]=[CH:27][C:32]=1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 122-123° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m, 1H), 2.22-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 156.8, 155.4, 153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1, 123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:39])=[C:14]([C:18]4[C:30]5[C:29]6[CH:28]=[CH:27][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:25][C:24]=6[NH:23][C:22]=5[C:21]([C:36](O)=[O:37])=[N:20][N:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[Cl-].[NH4+].CC[N:44](C(C)C)C(C)C.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:39])=[C:14]([C:18]4[C:30]5[C:29]6[CH:28]=[CH:27][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:25][C:24]=6[NH:23][C:22]=5[C:21]([C:36]([NH2:44])=[O:37])=[N:20][N:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)nnc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Yield: 31.6 %

Procedure:
A yellow, homogeneous solution of 1-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylic acid (0.0206 g, 0.038 mmol), ammonium chloride (8.12 mg, 0.152 mmol), DIPEA (0.032 mL, 0.182 mmol), N-methylmorpholine (5.42 μL, 0.049 mmol) and BOP (0.065 g, 0.148 mmol) in DMF (0.379 mL) was stirred for 1 hr. It was diluted with MeOH (1 mL) and purified by reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.0064 g, 0.012 mmol, 30.9% yield) as a white solid. LC/MS (M+H)=542.15; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for major atropoisomer) δ ppm 12.22 (s, 1H), 8.71 (s, 1H), 7.98 (s, 1H), 7.80-7.85 (m, 1H), 7.74-7.76 (m, 2H), 7.73 (d, J=1.1 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 5.05 (d, J=17.8 Hz, 1H), 4.98 (d, J=17.5 Hz, 1H), 4.14-4.21 (m, 2H), 3.72 (dd, J1=5.4 Hz, J2=3.8 Hz, 2H), 3.32 (s, 3 H), 1.88 (s, 3 H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8]>C(#N)C>[N:1]([CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CCl)cc2[nH]1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Sodium azide (1.79 g, 27.48 mmol) was added in one portion to a solution of J.30 (S)-tert-butyl 2-(6-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (10.0 g, 27.48 mmol) in acetonitrile (200 mL) and stirred at 60° C. for 16 h. The reaction mixture was concentrated to ⅕ volume, diluted with ethyl acetate, and washed with water and brine prior to being dried (Na2SO4). Concentration gave J.31 (S)-tert-butyl 2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate 6.8 g (48%) as a golden orange foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.22/8.03 (s, 1H), 7.80-7.75 (m, 1H), 7.65/7.56 (d, J=8.5 Hz, 1H), 4.99-4.93 (m, 3H), 3.60 (br. s, 1H), 3.46-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.89 (m, 3H), 1.40/1.06 (s, 9H). LC (Cond.-D2): 1.97 min; LC/MS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.19; found: 371.32. HRMS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.1832; found: 371.1825.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:32]>>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1ccccc1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Agent: Cl
Product: OC1(C(CN2CCN(CCc3ccccc3)CC2)c2cccc(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 117,1-{1-(3-chlorophenyl)-2-[4-(2-phenylethyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and phenylacetaldehyde. MS (ESI) m/z 427/429 ([M+H]+); HRMS: calcd for C26H35ClN2O.2.00 HCl, 498.1971; found (ESI), 427.2505.
Reaction SMILES: [CH2:1]([O:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH2:5])[CH3:2].Br[C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[CH:22][CH:21]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:4]([O:3][C:1]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[CH:22][CH:21]=1)=[CH2:2])[CH3:5]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(-n2cnc(C)c2)c(OC)n1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
1-Ethoxyvinyltri-n-butyltin (3.7 mL) was added to a suspension of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazole-1-yl)pyridine (2.66 g) and bis(triphenylphosphine)palladium (II) chloride (350 mg) in dioxane (25 mL), and the mixture was stirred at 100° C. for five hours and 45 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. The target fraction was concentrated. The resulting powder was triturated with diethyl ether-n-hexane and dried under reduced pressure to obtain 1.57 g of the title compound. Then, the mother liquor was concentrated to obtain 858 mg of the title compound. The property values of the compound are as follows: 1H-NMR (CDCl3) δ (ppm): 1.45 (t, J=7.2 Hz, 3H), 2.30 (s, 3H), 3.98 (q, J=7.2 Hz, 2H), 4.04 (s, 3H), 4.38 (d, J=1.6 Hz, 1H), 5.48 (d, J=1.6 Hz, 1H), 6.97 (s, 1H), 7.38 (d, j=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.78 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1cc(Cl)c2cccnc2n1
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 259 mg (1.00 mmol) 4-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine and 104 mg (1.10 mmol) 4-aminopyridine in 5 ml dioxane 236 mg (2.10 mmol) potassium tert.-butylate were added, the mixture heated to 80° C. and kept at this temperature for 1 hr. After cooling to ambient temperature water was added to the reaction mixture. The precipitate formed was filtered off, washed with water and dried in vacuum. This yielded [2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine as beige crystals; HPLC-MS: [M+H] 317. 1H-NMR (d6-DMSO): δ [ppm]=7.34 (d, J=5.9 Hz, 2H), 7.38 (dd, J1=11.8 Hz, J2=8.2 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.57 (m, 1H), 7.66 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.83 (s, 1H), 8.12 (t, J=7.8 Hz, 1H), 8.46 (d, J=5.9 Hz, 2H), 8.81 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 9.1 (dd, J1=4.3 Hz, J2=1.8 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]1([Li])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.ClCCl.[O-2].[O-2].[Mn+4]>[C:15]1([C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[C:13]4[C:8](=[CH:7][CH:6]=3)[CH:9]=[CH:10][CH:11]=[N:12]4)[N:1]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: [Li]c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(-c2ccc3ccc4cccnc4c3n2)cc1

Procedure:
A compound E-1 was synthesized by the following method. 1,10-phenanthroline (9.64 g) was reacted with phenyl lithium (100 ml) (1.07 M cyclohexane/ether solution) at 0° C. for 1.5 hours in toluene (250 ml) and treated by a conventional method. The resulting product was reacted with manganese dioxide (93.0 g) at room temperature for 56 hours in dichloromethane (300 ml) and treated by a conventional method to obtain 9.44 g of 2-phenyl-1,10-phenanthroline. To 25 ml of a THF solution of 1,3-dibromobenzene (0.34 ml) was added an t-butyl lithium (1.53 M pentane solution) (7.35 mL) at −78° C., and the resulting mixture was stirred for 1 hour, and then its temperature was raised to 0° C. The resulting solution was added to 85 ml of a THF solution of the obtained 2-phenyl-1,10-phenanthroline (1.44 g), and the resulting mixture was stirred at room temperature for 20 hours, and treated by a conventional method. The resulting product was reacted with manganese dioxide (8.50 g) at room temperature for 23 hours in dichloromethane (85 ml) and treated by a conventional method to obtain 1.08 g of a compound E-1.
Reaction SMILES: [CH2:1]([C:3]1([C:35]([O:37]CC)=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)=[CH:12][N:13]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([C:3]1([C:35]([OH:37])=[O:36])[CH2:8][CH2:7][N:6]([C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])=[N:19][C:18]=4[CH:28]=3)=[CH:12][N:13]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)s3)cc(-c3ccccn3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)s3)cc(-c3ccccn3)c2s1
Temperature: 70 °C

Procedure:
To a solution of ethyl 4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]thiazol-2-yl]piperidine-4-carboxylate (30 mg, 0.053 mmol) in EtOH (1 mL) was added aqueous NaOH (0.3 mL, 3.5 M). The solution was heated to 70° C. for 22 h then cooled to rt and the pH of the solution adjusted to 4-5. The mixture was extracted with EtOAc (3×1 mL) and the combined organic layer dried over Na2SO4, filtered then evaporated under reduced pressure. The residue was adsorbed to a 0.5 g silica plug then purified using a 4 g silica column, using a MeOH:DCM elution gradient. Compound 221 was isolated as an off-white solid (2.0 mg, 11% yield). 1H NMR (MeOD) δ 8.75 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.97-7.90 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.38 (ddd, J=7.5, 4.9, 0.9 Hz, 1H), 3.87 (dd, J=9.6, 3.7 Hz, 2H), 3.39-3.32 (m, 2H), 3.25 (td, J=13.3, 2.9 Hz, 2H), 2.23 (d, J=13.3 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 1.61-1.52 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H). MS: 537.13 [M+H]+.