Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[CH:19]=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.037 g, 0.12 mmol), 6-bromo-9H-purine (0.048 g, 0.24 mmol), and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H14F2N7OS (M+H)+: m/z=426.1. Found: 426.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.99 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.53 (1H, d, J=4.8 Hz), 7.24 (1H, m), 7.16 (2H, m), 6.88 (1H, br s), 5.41 (2H, br s), 5.05 (1H, m), 1.27 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.P(Br)(Br)(Br)(Br)[Br:22]>>[Br:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2Cl)cc1
Reactant: BrP(Br)(Br)(Br)Br
Product: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To 15.0 g. (0.0476 moles) of ethyl 2'-chloro-4-biphenylylglycolate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-2'-chloro-4-biphenylylacetate.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])[CH:33]=[CH:32][C:31]=1[C:44]([C:46]1[CH:51]=[C:50]([N+:52]([O-])=O)[CH:49]=[CH:48][C:47]=1[CH3:55])=[O:45]>>[NH2:52][C:50]1[CH:49]=[CH:48][C:47]([CH3:55])=[C:46]([C:44]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])=[CH:35][C:30]=2[Cl:29])=[O:45])[CH:51]=1
Reactant: Cc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 417 (0.39 mmol). The crude product was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[C:8]2[C:12](=[O:14])[CH3:13])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccn1Cc1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])cn1Cc1ccc(F)cc1
Temperature: -78 °C

Procedure:
To a 500 mL round bottomed flask with a stirring bar and a drying tube was added 1-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AI-1-1 (11.64 g, 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to −78° C. and concentrated nitric acid (3.7 mL of 15.9 N solution, 58.24 mmol) was added with a pipette. The cooling bath was allowed to expire and the mixture warmed to 0° C. over 7 h. The acetic anhydride was removed in vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHCO3 solution (2×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 20% EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et2O/hexane to give white crystals of 1-[1-(4-fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDCl3) δ 2.55 (3H, s), 5.54 (2H, s), 7.06 (2H, m), 7.20 (2H, m), 7.47 (1H, d, j=1.8 Hz), 7.63 (1H, d, j=1.8 Hz).
Reaction SMILES: [Br:1]Br.[B:3]([OH:12])([OH:11])[C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([B:3]([OH:12])[OH:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: OB(O)c1ccc(CBr)cc1

Procedure:
5 mL of bromine solution (2.4 g, 1.5×10-2 mole) in 20 mL of carbon tetrachloride was added to a solution of p-tolylboronic acid (2.0 g, 1.47×10-2 mole) in 40 mL of carbon tetrachloride. The reaction was initiated by illumination with a 150 Watt light bulb. The bromine color faded in 5 minutes and the remaining bromine solution was added over 15 minutes. A solid product precipitated during bromine addition. The solid was filtered and crystallized from chloroform. Yield 1.5 g (49%), m.p. 154°-156° C., 1HNMR (DMSO) δ4.18(s,2H,--CH2Br); 7.37 and 7.74(d,4H,--ArH).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[N:11][N:10]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([C:14]23[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])([CH2:16][CH2:15]2)[CH2:20][CH2:21]3)=[N:11][N:10]=1
Reactant: CC(=O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)o3)(CC1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)o3)(CC1)CC2
Temperature: 25 °C

Procedure:
5-(4-{5-[2-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-one (4-H) (0.072 g) was stirred in methanol (2 mL) at 0° C. Sodium borohydride (20 mg) was added. The reaction was allowed to stir to room temperature. The mixture was then layered with ethyl acetate (15 mL) and water (15 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford pure 5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-ol (4-I).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12])#[N:2].[H][H].O.[ClH:34]>CO.C(O)C.[Pd]>[ClH:34].[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(C#N)c3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Yield: 80 %

Procedure:
A mixture of 4-cyano-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione (0.5 g, 1.17 mmol) and 10% Pd/C (0.15 g) in 4 N hydrochloric acid (1 mL) and methanol (40 mL) was hydrogenated in Parr Shaker apparatus under 50 psi of hydrogen overnight. To the resulting slurry was added water (2 mL) to dissolve the product. The reaction mixture was then filtered through Celite and the filtrate was concentrated in vacuo. The residue was slurried in ethyl acetate (10 mL) to afford 0.52 g of the crude product. The product was reslurried in hot ethanol (15 mL) to afford 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione hydrochloride (0.44 g, 80% yield): mp 237-239° C.; 1H NMR (DMSO-d6) δ 8.79 (s, 3H, Ar), 8.04-7.89 (m, 3H, Ar), 7.11-6.91 (m, 3H, Ar), 5.83-5.77 (dd, J=4.2, 10.1 Hz, 1H, NCH), 4.49-4.47 (m, 2H, CH2), 4.41-4.31 (m, 1H, CHH), 4.21-4.13 (m, 1H, CHH), 4.04 (q, J=6.8 Hz, 2H, CH2), 3.73 (s, 3H, CH3), 3.64 (s, 3H, CH3), 1.32 (t, J=6.8 Hz, 3H, CH3); 13C NMR (DMSO-d6) δ 167.48, 166.93, 148.95, 147.87, 135.39, 134.71, 132.82, 131.32, 129.50, 128.30, 123.34, 119.89, 112.55, 111.79, 63.87, 55.52, 53.07, 47.46, 41.08, 36.84, 14.66; Anal. Calcd for C21H25N2O6SCl: C, 53.79; H, 5.37; N, 5.97; S, 6.84; Cl, 7.56. Found: C, 53.49, H, 5.47; N, 5.75; S, 6.61; Cl, 7.51.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Cl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[N:3]1([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:14]=3[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])=[O:11])[CH2:6][CH2:5]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: ClCCOCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (200 mg) obtained in Example 219 is suspended in N,N-dimethyl acetamide (10 ml), and thereto are added bis(2-chloroethyl) ether (73 μl), sodium iodide (185 mg), and sodium carbonate (131 mg), and the mixture is stirred at 50° C. for 5 hours, and then stirred at 80° C. for 3 hours. Bis(2-chloroethyl) ether (73 μl) is further added thereto, and the mixture is stirred at 80° C. for 15 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1, then 1/1) to give trans-3-[4-(morpholin-4-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg). Subsequently, this product is dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml), and the solvent is evaporated under reduced pressure. The resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (65 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH2:7]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: ClCC=Cc1cccc(Cl)c1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(Cl)c1)CC2
Yield: 20 %

Procedure:
Prepared from 3-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform in the presence of 1 equivalent of potassium carbonate. Yield: 20% of theory, Melting point: 132°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:35][S:36]([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]>CN(C)C=O.CCOC(C)=O>[CH3:35][S:36]([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:6]5[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:17]4[N:16]=3)[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)N(S(C)(=O)=O)CCC5)nn23)cn1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (95.0 mg, 0.254 mmol) was dissolved in N,N-dimethylformamide (3.00 mL). N,N-diisopropylethylamine (133 uL, 0.761 mmol) was added followed by 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (80.4 mg, 0.355 mmol) and the reaction was stirred overnight. The reaction was taken up in EtOAc (25 mL) and washed three times with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-70% EtOAc/hex as the eluting solvent to obtain the title compound as a yellow solid (54 mg, 47%). m.p.=202-203° C.; LCMS (m/e) 451 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.46 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.53 (dd, 1H, J=2.2 and 8.7 Hz), 7.81 (s, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.19 (d, 1H, J=4.7 Hz), 7.10 (d, 1H, J=8.4 Hz), 7.02-6.93 (m, 2H), 3.93 (s, 3H), 3.74-3.68 (m, 2H), 2.99 (s, 3H), 2.79-2.72 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](CCCC3CCCCC3)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:38].[CH2:39]([OH:41])[CH3:40]>>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:41][CH2:39][CH2:40][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:20]([C:33]([F:34])([F:35])[F:36])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCC3CCCCC3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Product: NC(CO)(CO)CCc1ccc(OCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 9-2 (760 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (525 mg) as a white powder. MS(ESI)m/z: 404[M+H]
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2ccc(F)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(OCC2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 3-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (300 mg, 1.03 mmol; which may be prepared as described in Step 1) in dichloromethane (6.8 mL) was added dropwise HCl 4N in dioxane (5.0 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (267 mg, quantitative) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[C:21]([C:17]1[CH:16]=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:23])[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C#N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(C(=O)N2CCNCC2)c1
Yield: 75 %

Procedure:
A solution of 4-(3-cyano-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (590 mg, 1.87 mmol) in 1,4-dioxane.HCl (3 mL) was stirred at 0° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 350 mg (75%) of (3-cyano-phenyl)-piperazin-1-yl-methanone.hydrochloride.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:24])C1C=CC=CC=1.[C:26]([OH:29])(=[O:28])[CH3:27]>[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[NH2:10][C@@H:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1=[O:24]
Reactant: O=C(N[C@@H]1CC(=O)N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@@H]1CC(=O)N(Cc2ccccc2)C1=O
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A solution of 7.80 g of (R)-(1-benzyl-2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester (93% (R)-isomer) in 160 ml of acetic acid was treated with 0.78 g of 10% Pd/C (commercially available from Degussa; 1835) and hydrogenated at 30° C. for 20 min whereupon TLC and HPLC indicated completion of the reaction. The reaction mixture was filtered, evaporated and the residue crystallized from EtOAc and n-hexane to give 5.80 g (78%) of 3-(R)-amino-1-benzyl-pyrrolidin-2,5-dione acetic acid (1:2) as white crystals; HPLC (100%): HP 1050, nucleosil 100-5 C18 column, CH3CN, H2O, TFA system buffered with TBAHS; GC (99.8% as free amine): J and W, DB-1, 15 m×0.32 mm, carrier gas He, program: 50-320° C. (5° C./min); injector temp. 250° C.; FID: 320° C.; 91% (R)-isomer, analyzed as the corresponding trifluoroacetamide by GC (BGB-177): 15 m×0.25 mm, carrier gas: He; program: 150° C.-200° C. at 1° C./min; injector temp. 210° C.; FID: 220° C.; NMR (CDCl3, 400 MHz; 1.6 eq AcOH) 7.32 (m, 5H, H-ar), 5.64 (bs, 4H, NH), 4.65 (s, 2H, PhCH2O, 3.92 (dd, J=5.4 and 7.8, 1H, NCH), 3.05 (dd, J=7.8 and 18, COCH2, 1H), 2.50 (dd, J=18 and 5.4, COCH2, 1H), 2.08 (s, 2×CH3CO2, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OCOc2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 87.1 %

Procedure:
To a solution of 23.3 g of methyl{p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 300 ml of carbon tetrachloride is added 14.2 g of N-bromosuccinimide. The mixture is stirred and refluxed for 24 hours or until reaction is complete. The mixture is cooled, filtered and the filtrate poured through a column of silica gel (60-200 mesh). Cuts (250 ml) are taken with carbon tetrachloride eluent. The product is collected in fractions 2-6 to give 25.5 g of product as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCCCCCC)CCCCCCCC)CCCCCCC.C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:55][N:54]=[N:53][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
A mixture of 5 g of 2-butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, 30.2 g of trioctyltin azide (tri-n-octyltin azide), 25 ml of toluene and 1 ml of dimethylformamide was stirred for 24 hours at 115° C. in nitrogen streams. The reaction mixture was, after cooling, concentrated, and there were added 40 ml of ethanol and a solution of 5.2 g of sodium nitrite in 19 ml of water, whose pH was adjusted at 3.4 with conc. hydrochloric acid. The resultant mixture was subjected to extraction with methylene chloride, and the extract was concentrated under reduced pressure. To the concentrate was added hexane, then resulting crystalline precipitates were collected by filtration. The crystals were washed with hexane, then dried to afford 5.27 g (yield 94.7%) of 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole. The NMR spectrum of the product was in good agreement with that described in J. Med. Chem., 1991, 34, 2525.
Reaction SMILES: C1(C)C(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)(=O)=O)=CC=CC=1.Cl.[CH:25]12[O:33][CH:29]([CH2:30][NH:31][CH2:32]1)[CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:31]2[CH2:32][CH:25]3[O:33][CH:29]([CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]3)[CH2:30]2)=[CH:20][CH:19]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 85 °C
Reaction time: 22 h

Procedure:
A 2 L three-necked flask was equipped with a magnetic stirrer, a thermometer and a reflux condenser. The flask was charged with a solution of 4-(4-cyanophenyl)butyl toluenesulphonate (72 g, 0.218 mol, see step (iii) above) in dimethylformamide (0.55 L). tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (48.2, 0.182 mol, see Preparation B(I)(iv) above) was added, followed by potassium carbonate (62.9 g, 0.455 mol). The heterogeneous mixture was stirred for 22 hours at 85° C. TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to room temperature and diluted with water (0.5 L). The mixture was extracted with ethyl acetate (3×0.4 L) and the organic fractions were combined. After washing with Water (2×200 mL) and brine (200 mL), the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum. The crude brown oil was purified by chromatography on silica gel, eluting with 3:2 hexanes/ethyl acetate affording 34 g (48% yield) of sub-title compound as an off-white solid.