Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([S:20]([C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Cl:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[CH2:5][CH2:6]OS(C1C=C(C)C(Cl)=CC=1C)(=O)=O)([CH3:3])[CH3:2].[F:32][C:33]1[CH:47]=[CH:46][C:36]2[NH:37][C:38]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:39][C:35]=2[CH:34]=1>>[Cl:30][C:26]1[C:27]([CH3:29])=[CH:28][C:23]([S:20]([N:4]([CH2:5][CH2:6][N:43]2[CH2:42][CH2:41][CH:40]([C:38]3[NH:37][C:36]4[CH:46]=[CH:47][C:33]([F:32])=[CH:34][C:35]=4[N:39]=3)[CH2:45][CH2:44]2)[CH:1]([CH3:2])[CH3:3])(=[O:21])=[O:22])=[C:24]([CH3:31])[CH:25]=1
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: Cc1cc(S(=O)(=O)OCCN(C(C)C)S(=O)(=O)c2cc(C)c(Cl)cc2C)c(C)cc1Cl
Product: Cc1cc(S(=O)(=O)N(CCN2CCC(c3nc4cc(F)ccc4[nH]3)CC2)C(C)C)c(C)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D8 and 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine (D17). MH+ 507/509.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][NH:11][N:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH3:14])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:11]=[N:12][CH:13]=[C:8]2[CH:7]=[C:6]([CH3:14])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:9]=12
Reactant: Cc1cc2c(n1CC(C)C)CNN=C2
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2cnnc(Cl)c2n1CC(C)C
Yield: 75 %

Procedure:
3.8 g (12 mmol) of 1-isobutyl-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine are reacted at 100° C. for 2 h in 30 ml of phosphorus oxychloride. Purification: chromatography on silica gel (eluent: toluene/dioxane=2:1). Yield: 75%. M.p.: 96°-99° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C@@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)[NH:22][C:23]=2[CH2:24][CH2:25][C:26]23[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]4)[CH2:27]2)[CH2:33]3)=[O:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:44])[NH:22][C:23]=2[CH2:24][CH2:25][C:26]23[CH2:35][CH:30]4[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]4)[CH2:33]2)[CH2:27]3)=[O:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc([C@@H]3CCCN3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CN1CCC[C@H]1c1nc(C(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a rapidly stirred solution of (S)-3-{[5-(2-adamantan-1-yl-ethyl)-2-pyrrolidin-2-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester (Example 136, step d) (180 mg, 0.33 mmol) and formaldehyde (100 μl, 37% aqueous) in dichloroethane (5 ml) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol). After stirring for 1 h at room temperature the reaction mixture was diluted with DCM and the solution was washed with saturated sodium bicarbonate. The organic layer was dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/IPA, 9:9:2) to afford the product as a white solid (130 mg, 71%). 1H NMR (300 MHz, CDCl3) 9.70 (1H, br s), 9.12 (1H, s), 8.17 (1H, d), 8.12 (1H, s), 7.77 (1H, d), 7.47-7.35 (6H, m), 5.37 (2H, s), 3.41 (1H, m), 3.20 (1H, m), 3.06 (2H, m), 2.30 (4H, s+m),1.96-1.55 (19H, m), 1.42 (2H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=O)[CH:18]=[N:19][CH:20]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[N:19][CH:20]=1
Reactant: COc1cncc(C=O)c1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cncc(C=C2N=C(c3cccs3)OC2=O)c1
Temperature: 90 °C
Yield: 46.6 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 40 mg of the above-captioned compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:12][OH:13])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ncc(C=O)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(C=NO)c(N)n1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a mixture of 8.6 g of 2-methyl-4-amino-5-formylpyrimidine and 340 ml of methanol, while stirring at room temperature, was added dropwise gradually 40 ml of an aqueous solution of 5.20 g of hydroxylamine hydrochloride and 7.80 g of sodium carbonate. As the reaction proceeded, crystals precipitated. Four hours later, the crystals were collected by filtration, washed with methanol and water, followed by drying under reduced pressure to give 7.84 g (82.3%) of 2-methyl-4-amino-5-pyrimidine aldoxime. The mother liquor was subjected to high performance liquid chromatography to quantitatively determine 2-methyl-4-amino-5-pyrimidine aldoxime (by absolute calibration curve method) to confirm that 1.41 g (14.8%) of the object compound was produced. The total yield of the crystals and the object compound in the mother liquor was 97.1%. The mother liquor was concentrated to dryness under reduced pressure, followed by recrystallization from a mixture solvent of methanol/ether to isolate 0.8 g of 2-methyl-4-amino-5-pyrimidine aldoxime.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl>[Cu].[Cu]I.CN(C)C=O>[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCOc1ccc(O)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOc1ccc(Oc2ccccc2C(=O)O)cc1
Temperature: 0 °C
Yield: 45.1 %

Procedure:
First, 2-(4-butoxyphenoxy)benzoic acid was prepared. A stirred mixture of 2-chlorobenzoic acid (10.0 g, 64 mmol), 4-butoxyphenol (12.7 g, 77 mmol), potassium carbonate (17.6 g, 128 mmol), copper powder (0.24 g, 3.8 mmol), copper (I) iodide (0.20 g, 1.3 mmol), dithioerithritol (0.20 g, 1.3 mmol), and 75 mL of N,N-dimethylformamide was heated at reflux for 5 h and then cooled to ambient. The reaction mixture was poured onto a mixture of 300 g of ice plus 100 mL of 10% aqueous HCl. The precipitated product was extracted into diethyl ether. The product was purified by extraction into 5% aqueous NaOH, followed by acidification with concentrated HCl. The precipitate was collected, washed with water, and dried in vacuo over CaSO4 to provide 8.27 g (45% of theory) of 2-(4-butoxyphenoxy)benzoic acid as a brown powder.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[C:10](=[O:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[S:1][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: Cc1ccc(-n2c(S)nc3ccccc3c2=O)cc1
Agent: Cl
Product: Cc1ccc(-n2c(SCc3ccncc3)nc3ccccc3c2=O)cc1
Yield: 60.8 %

Procedure:
The title compound was prepared in a yield of 60.8%, using 2-mercapto-3-(4-methylphenyl)-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl-4methylpyridine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][NH2:29]>O1CCCC1.O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:29][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A suspension of 5-bromo-3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (2 g, 4.9 mmol) and Na2CO3 (1.55 g, 14.60 mmol) in tetrahydrofuran (30 mL) was treated with methanamine (3.6 mL of 2 M, 7.3 mmol) in THF. The reaction mixture was heated at 60° C. for 1 h. The reaction was cooled, diluted with water and the organic layer was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 5-bromo-3-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (1.7 g, 97%) as a yellow solid, which was used without purification in the next step. LC/MS m/z 363.5 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([NH2:11])[NH:8][N:7]=1.[C:12]([C:14]([C:24](=O)[CH3:25])=[CH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)#[N:13].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:15]2[N:8]3[N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[N:10]=[C:9]3[NH:11][C:24]([CH3:25])=[C:14]2[C:12]#[N:13])=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Reactant: Nc1nc(-c2cccs2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 3-(2-thienyl)-1H-1,2,4-triazole-5-amine (318 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). The product was obtained as a solid (73.7 mg, 91% pure, 12% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:27]([C:25]1[CH:26]=[C:21]([CH2:20][CH2:19][N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(CCNCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCN(CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 59.7 %

Procedure:
Stir a solution of 4.5 g (9.3 mmols) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]amine, 1.8 g (9.3 mmols) of 1-bromooctane, and 2.0 g (18.7 mmols) of sodium carbonate in 50 mL of acetonitrile for 17 hours at reflux temperature. Add another 0.3 g (1.6 mmols) of 1-bromooctane and stir at reflux for an additional 18 hours. After cooling, concentrate the reaction mixture, in vacuo, dissolve the resulting oil in 50 mL of toluene, and wash with water (2×50 mL). Dry the organic phase over magnesium sulfate and concentrate in vacuo. Flash column chromatography (120 g silica gel 60, 230-400 mesh, EM), using heptane followed by 1.5% isopropyl alcohol/heptane as the eluting solvents, gives 3.3 g (60.0%) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]octylamine as a slightly colored oil which GC area % analysis shows to be 99.0% pure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][CH2:14][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(OCCC(c2ccccc2)c2ccccc2)cc1
Yield: 103.5 %

Procedure:
A mixture of 4-bromophenol (1.73 g, 10 mmol), 1-methanesulphonyloxy-3, 3-diphenylpropane (3.05 g, 10 mmol) and anhydrous potassium carbonate (2.07 g, 15 mmol) in acetonitrile (25 mL) is stirred and heated to reflux under nitrogen for 24 h. The reaction mixture is filtered, washed with acetone and the combined filtrate and washings are evaporated to dryness in vacuo. The residue is taken up in Et2O washed with successive portions of 5% aqueous NaOH and H2O, dried (Na2SO4), filtered and concentrated in vacuo to give an oily residue (3.8 g) which crystallizes upon standing: mp 70°-71° C.; 1H NMR (CDCl3) d 7.35-7.16 (m, 12H), 6.70 (d, 2H, J=8.98), 4.22 (t, 1H, J=7.9), 3.85 (t, 2H, J=6.), 2.54 (q, 2H). IR 1592, 1490, 1470, 1291 cm1 ; MS 366-368 (MH+, one Br); Anal. calc'd. for C21 H19Br O: C, 68.86, H, 4.95. Found C, 68.60, 5.18.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11])=O.O.[NH2:19][NH2:20]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:8]2[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:20][N:19]=1
Reactant: COC(=O)c1ccccc1C(=O)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccs2)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(thiophene-2-carbonyl)benzoate (0.445 g, 1.81 mmol) and hydrazine hydrate (0.40 mL, 7.1 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to give the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.42-8.28 (m, 1H), 8.23-8.09 (m, 1H), 7.95 (dtd, J=19.0, 7.3, 1.5, 2H), 7.82-7.69 (m, 1H), 7.68-7.55 (m, 1H), 7.33-7.19 (m, 1H), 4.12 (s, OH), 1.91 (s, OH), 1.74 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:38]([C:40]1[CH:41]=[C:42]([CH:52]=[CH:53][CH:54]=1)[O:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)#[N:39]>C(#N)C.[Cl-].[Na+].O.CN(C)C=O.CCOCC>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:49]1[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][O:43][C:42]2[CH:52]=[CH:53][CH:54]=[C:40]([C:38]#[N:39])[CH:41]=2)[CH2:51][CH2:50]1)#[N:2]
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCO)c1ccc(C#N)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1ccc(C#N)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
In acetonitrile (10.0 ml) was dissolved 400 mg (1.61 mmol) of 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol, followed by cooling to 0° C. To the mixture were added 0.26 ml (1.85 mmol) of triethylamine and 0.14 ml (1.77 mmol) of mesyl chloride, followed by heating to room temperature. After 20 minutes, ether and brine were added thereto. The ether layer was washed with an aqueous saturated sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The half amount (ca. 0.1 mmol) of the crude mesyl compound was dissolved in 8.00 ml of dimethylformamide. To the mixture were added 724 mg (4.83 mmol) of sodium iodide, ill mg (0.81 mmol) of potassium carbonate and 243 mg (1.05 mmol) of 1-[2-(3-cyanophenoxy)ethyl]piperazine, followed by heating to 60° C. After completion of the reaction, brine was added thereto, and the objective product was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to Cromatorex NH silica gel (eluted with ethyl acetate/hexane=1/1), to give 289 mg (0.63 mmol, 77.3%) of the title compound as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]2C=CC=[CH:16][C:15]=2F)=[C:10]([O:21][CH3:22])[C:9]([O:23][CH3:24])=[CH:8][C:7]=1[CH3:25])=[O:5].C(OC1C(C(=O)C2C(C)=CC=CC=2C)=C(C)C=C(OC)C=1OC)C1C=CC=CC=1>>[CH2:13]([O:12][C:11]1[C:6]([C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[C:7]([CH3:25])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=1[O:21][CH3:22])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(OCc2ccccc2F)c1OC
Agent: COc1cc(C)c(C(=O)c2c(C)cccc2C)c(OCc2ccccc2)c1OC
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-dichloro-4′,5′-dimethoxy-6′-(2-fluorobenzyloxy)-2′-methylbenzophenone (coded BB-2); 6′-benzyloxy-4′,5′-dimethoxy-2,6-dimethyl-2′-methylbenzophenone (coded BB-3); and 3-bromo-2′,6-dimethyl-2,40 ,5′,6′-tetramethoxybenzophenone (coded BB-4).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[F:12]
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CN1CCOCC1)c1ccc(Br)c(F)c1

Procedure:
To a 0° C. solution containing 0.55 g of 2-bromo-1-(4-bromo-3-fluorophenyl)ethanone (1.86 mmols) in 9 mL of THF was added 0.32 mL of morpholine (3.72 mmols). After 18 h the reaction mixture was diluted with 100 mL of dichloromethane and washed with water (1×10 mL) and saturated brine solution (1×10 mL). The organic layer was dried over MgSO4, filtered through a frit, and concentrated to a yellow-orange oil which was used without further purification. MS (ES) m/e 302, 303 [M+H]+.
Reaction SMILES: [CH: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][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:37])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OCC(Cl)(Cl)Cl)=O)[CH2:14]1>C(O)(=O)C.[Zn]>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C:29](=[O:37])[O:28][CH2:27][CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccccn1)OCCOc1ccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(Nc1ccccn1)OCCOc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 25(b), by treating 2,2,2-trichloroethyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-pyridin-2-ylcarbamoyloxy-ethoxy]-phenyl]-piperidine-1-carboxylate with zinc in glacial acetic acid there was obtained (3RS,4RS)-2-[4-[3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-ethyl pyridine-2-yl-carbamate as a colourless solid; MS: 498 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-])[CH3:2].C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[N:4]=1)#[N:15]
Reactant: CCc1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
2-Ethylpyridine N-oxide (3.0 g, 24.4 mmol) was dissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.4 g, 24.0 mmol) and N,N-dimethylcarbamoyl chloride (2.4 g, 21.9 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (1.0, 31%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5]CC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18]Br)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:14](=[N:15][CH:16]=1)[NH:17][C:3](=[O:5])[C:2]([CH3:8])([CH3:9])[CH2:18]2
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of activated Zn (1.0 g, 15 mmol) and ethyl 2-bromo-2-methylpropanoate (1.24 mL, 6.4 mmol) in THF (8 mL) were added together at 0° C. and stirred for 6 h while warming to room temperature. To this mixture a dropwise solution of 5-bromo-3-(bromomethyl)pyridin-2-amine in THF (5 mL) was added via canula and the reaction mixture was stirred for a further 19 h at rt. The mixture was diluted with ethyl acetate (25 mL) and washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), dried over magnesium sulphate, and concentrated in vacuo. The crude yellow solid product was triturated with diethyl ether and filtered to obtain the white solid product. Yield 158 mg (49%); 1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 2.81 (s, 2H), 1.04 (s, 6H); ESI MS m/z 255, 257 [C10H11N2OBr+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:14]=1[C:15]([NH:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CCSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 67 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-t-butoxycarbonylaminopropoxy)-4-(ethylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a solid (2.04 g, 67%).