Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].CO.[Br:14]N1C(=O)CCC1=O>[H-].[Na+].C(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)cc(OC)c1O
Temperature: -45 °C
Yield: 63.5 %

Procedure:
To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77 g (0.5 mol) of pyrogallol 1,3-dimethyl ether. 5.8 ml of MeOH, and 750 ml of CH2Cl2. To this solution was added 126 mg (5 mmol) of NaH (95%). The solution was stirred while cooling to −45° C. with a dry-ice acetone bath. 94 g (0.53 mol) of powdered N-bromosuccinimide was added rapidly. The reaction mixture was then stirred for 1 hour at −35° C., heated to room temperature over next 30 min, and finally refluxed for 30 min. The CH2Cl2 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110° C.) and heated with stirring to 80° C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3 hr. The white needles was filtered off and dried to yield 74 g (63%) of 17.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.C[O:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:24](=[O:23])[C:25]([CH3:28])([CH3:27])[NH:26][C:12]2=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a suspension of 15 g of 4-tert-butylphenyl-isocyanate in 200 mL of toluene are successively added 31.52 mL of triethylamine and 13.15 g of 2,2-dimethylglycine methyl ester hydrochloride. The reaction mixture is refluxed for 24 h, cooled to room temperature, poured into distilled water and extracted with ethyl acetate. The organic phase is washed successively with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether and the solid formed is filtered off and dried to give 17.75 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)[CH2:2][C:1]#[N:3]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC#N
Solvent: C1CCOC1
Product: N#CCC(O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a stirred solution of acetonitrile (2.46 g, 60 mmol, 3.13 mL) in THF (300 mL) at -78° C. was added N-BuLi (37.5 mL, 60 mmol, 1.6M) dropwise over 30 minutes. The resulting solution was stirred at -78° C. for 15 minutes and then 2-naphthaldehyde (6.24 g, 40 mmol) in THF (50 mL) was added dropwise over 45 minutes. The resulting mixture was stirred for an additional 20 minutes at -78° C. and quenched at -78° C. by the addition of saturated NH4Cl (60 mL). The mixture was warmed to room temperature and the THF removed in vacuo to give a white solid. The residue was partitioned between CH2Cl2 (250 mL) and H2O (200 mL, the layers were separated and the aqueous phase extracted with CH2Cl2 (1×250 mL). The combined organic layers were washed with H2O (1×250 ML), dried (Na2SO4) and concentrated in vacuo to give the title compound as a tan solid (7.88 g, 100%) which was homogeneous by TLC and NMR. This material was used as such without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[N:9]([CH3:13])[C:8](=[O:14])[C:7](=[O:15])[NH:6]2
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2[nH]c(=O)c(=O)n(C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 0.2 g (0.97 mmol) 6-methoxy-1-methylquinoxaline-2,3(1H,4H)-dione in 10 ml concentrated sulfuric acid was added at 0° C. 0.1 g (0.99 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min., and then at 25° C. for 1 h. The reaction mixture was poured into 50 ml ice-water to give a precipitate Recrystallization (dimethylformamide-water) of the crude product gave 0.15 g (62%) 6-methoxy-1-methyl-7-nitroquinoxaline-2,3(1H,4H)-dione. M.p. 356° C. NMR (DMSO-d6): 12.0 (1H, broad s), 7.77 (1H, s), 3.90 (3H, s), 3.47 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.C([N:20](CC)CC)C.C(Cl)(Cl)Cl>C1COCC1>[NH2:20][C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CCN(CC)CC
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(N)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-Chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (13 mg, 0.050 mmol) [Compound (AC) in which Q is a chlorine atom, R2B is methylthio, and —X—Y—Z— is —O—C(c-C3H5)═N—] obtained in Reference Example 3 was dissolved in THF (0.50 mL), then triethylamine (0.007 mL) and a chloroform solution (1.0 mol/L, 0.10 mL) of R1—H [wherein R1 is the same as that defined above: Compound (B)] were added thereto, followed by stirring at 60° C. for 12 hours with hermetic sealing. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated and dried. The residue was dissolved in chloroform (0.60 mL), then benzoyl chloride polymer-bound [about 2.5 mmol/g, 23 mg, Canadian Journal of Chemistry, vol. 55, p. 3351 (1977)], and poly(4-vinylpyridine) (23 mg) were added thereto, followed by further stirring at room temperature for 12 hours. The resin was filtered off from the reaction mixture, and the filtrate was concentrated and dried to give 4-amino-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine [Compound (AD) in which —X—Y—Z— is —O—C(c-C3H5)═N—].
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH:10]1(O)[CH2:15]CC[CH:12]=[CH:11]1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH:5]1([O:4][CH:1]2[CH2:12][CH2:11][CH2:10][CH:15]=[CH:2]2)[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: OC1C=CCCC1
Reactant: CC(=O)OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(C)=O
Product: C1=CC(OC2C=CCC2)CCC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A two-phase reaction mixture containing 2-cyclopentenyl acetate (0.30 g, 2.4 millimols), 2-cyclohexenol (0.50 g, 5.1 millimols), tetrabutylammonium hydrogen sulfate (0.020 g, 0.06 millimols), and water (0.25 g, 13.9 millimols) was heated at 40° C. with vigorous stirring for four hours. Acetone was then added to give a one-phase system for analytical purposes, and the solution was analyzed by gas chromatography using an Apiezon column programmed from 60° to 220° C. The following relative peak areas were observed for the cyclic components:
Reaction SMILES: C(OC([N:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[NH:10]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)c1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Reaction time: 1.5 h

Procedure:
2-(3-(N,N′-di(t-Butoxycarbonyl)guanidino)phenyl)-3-((4-phenylbutyl)-(hydroxy)phosphinoyl)propanoic acid was dissolved in 9 mL 2:1 methylene chloride:TFA. After 1.5 hours, the reaction mixture was concentrated and purified by prep HPLC to afford 2-(3-guanidinophenyl)-3-((4-phenylbutyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 1.25-1.60 (m, 6), 2.00 (m, 1), 2.40-2.50 (m, 2), 3.85 (m, 1), 7.0-7.45 (m, 9) ppm, (2.9 mg),
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:16])[CH:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][C:9]([OH:11])=[O:10]>O.O1CCOCC1>[CH2:12]([CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:6]([OH:16])=[O:5])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)C(CC(=O)O)CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC(CC(=O)O)C(=O)O
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of lithium hydroxide monohydrate (26 mg, 0.61 mmol) in water (250 μl) was added to a stirred solution of (2R) 2-isobutylsuccinic acid 1-methyl ester (100 mg, 0.53 mmol) in 1,4-dioxane (500 μl). The mixture was stirred for 2 hours then lithium hydroxide monohydrate (26 mg, 0.61 mmol) was added and stirring continued for 24 hours. The majority of solvents were removed by distillation in vacuo then the residue was dissolved in water (5 ml) and acidified using hydrochloric acid (1M) to pH=1. The product was extracted into dichloromethane (5×5 ml), dried (Na2SO4) and the solvent removed in vacuo to obtain (2R) 2-isobutylsuccinic acid (49 mg, 53%) as a solid. HPLC-MS (single UV peak with Rt=6.223 mins, 197.1 [M+Na]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>CN(C=O)C>[C:21]1([S:27]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:17]([F:18])[CH:16]=3)[CH:12]=[CH:13]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5-benzyloxy-6-fluoroindole (Intermediate 26, 2.0 g, 8.3 mmol) in dry DMF (30 mL) was sodium hydride (60% in mineral oil, 0.35 g, 8.7 mmol) added at 0° C. The solution was stirred for 30 minutes at room temperature and the reaction mixture was cooled to 0° C. and benzenesulfonyl chloride (1.17 mL, 9.12 mmol) was added dropwise. The reaction mixture was kept at 4° C. overnight, and a drop of methanol was added and the solvent was evaporated. The crude material was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using DCM as the eluent to give the title compound (2.88 g) as a light yellow oil. MS m/z 382 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH3:28][C:26]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:27]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Oc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 122b (336 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (226 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.34 (s, 3 H) 2.74 (s, 3 H) 6.56 (d, J=6.99 Hz, 1 H) 6.64-6.71 (m, 2 H) 6.75-6.81 (m, 2 H) 6.89 (d, J=8.46 Hz, 1 H) 7.26 (dd, J=8.46, 1.84 Hz, 1 H) 7.31 (s, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 8.48 (d, J=6.99 Hz, 1 H) 8.95 (d, J=8.46 Hz, 1 H) 9.34 (s, 1 H) 10.91 (s, 1 H) 14.36 (s, 1 H); MS (ESI+) m/z 358 (M+H−TFA)+.
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:12]([C:16](C)=[O:17])[CH:13]([CH3:15])[CH3:14]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:16](=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(C)C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (13.5 ml, 100 mmol) in isobutylmethyl ketone (30 ml, 200 mmol) was added dropwise at room temperature over 20 minutes. The reaction was heated to 60° C. and stirred at this temperature for one hour. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (4×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 5-methyl-3-oxo-hexanoic acid ethyl ester (20 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.70 (1H, brs), 6.27 (1H, s), 4.25-4.32 (2H, quart), 2.26-2.31 (2H, d) (1H, m), 1.29-1.34 (3H, t), 0.89-0.94 (6H, d) ppm. LRMS (thermospray): m/z [M+NH4]+ 218.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]2[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][C:2]1[N:6]([CH:7]2[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Temperature: 90 °C

Procedure:
A solution of (±)-(1R*, 2S*, 3S*, 5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (750 mg, 1.44 mmole) was stirred in tert-butylamine (Aldrich, 98%, 25 mL) in a Parr bomb maintained at 90° C. (oil bath) for 6 days. Volatiles were evaporated in vacuo and the residual solids refluxed in ethanol (30 mL) with aqueous dimethylamine (Aldrich, 40%, 2 mL) for one hour. Volatiles were evaporated and the residual solids chromatographed on silica gel. Elution with 10% methanol-ethyl acetate gave title compound as colorless glass. Solidification from water gave (±)-(1R*, 2S*, 3S*, 5S*)-5-[2-(tert-butylamino )-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (150 mg, 26%); m.p. 130°-132° C.; 1H-NMR(DMSO-d6) identical with that of the enatiomer described in Example 82.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[N:34][C:35]#[N:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)NCc2ccccn2)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and 2-(aminomethyl)pyridine.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]([OH:21])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Product: N#Cc1ccnc(-n2nc(-c3cccc(Cl)c3)cc2O)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:23]=2[NH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21](=[O:20])[NH:22][C:23]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid. MS: 420.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1
Reactant: Cc1ccc(C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CCCN2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of tert-butyl (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine-1-carboxylate (0.95 g, 3.24 mmol), which had been obtained in Example 1 (1d), in methylene chloride (9 mL) was added with trifluoroacetic acid (2.40 mL, 32.3 mmol), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was added with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with methylene chloride (20 mL×3). After that, the organic layers were dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a yellow oily substance (0.44 g, yield 71%).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH2:10]([N:12]([CH2:24][CH3:25])[C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)[CH3:11]>>[CH3:3][CH:2]([O:20][C:19]1[CH:21]=[CH:22][C:14]([C:13]([N:12]([CH2:24][CH3:25])[CH2:10][CH3:11])=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with vanillic acid N,N-diethyl amide to obtain p-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°-182° C/0.1 mmHg);
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH2:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:39](Cl)([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH:31][C:39]([O:41][CH2:42][CH:43]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:55]1=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:40])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@@H](N)CC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a stirred suspension of (R)-3-amino-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.14 g) in 50% aqueous 1,4-dioxane (40 ml) were added Na2CO3 (1.19 g, 11.2 mmol) and FmocCl (1.28 g, 4.95 mmol). After being stirred for 1 h, the mixture was diluted with sat. brine (100 ml) and extracted with CH2Cl2 (100 ml×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give (R)-3-(9-fluorenylmethoxycarbonylamino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.34 g) which was used for the next step without further purification.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]1(=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH:1]([C:5]1([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[CH2:2]
Reactant: N#CC(C#N)=C1CCCCC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC1(C(C#N)C#N)CCCCC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A solution of vinylmagnesium bromide (1 M in THF, 24 mL, 24 mmol) was added dropwise over 2 min to a solution of the product from Example 145A (730 mg, 4.99 mmol) in THF (8 mL) under nitrogen. The reaction mixture was stirred at room temperature for 13 hours, then quenched by cautious addition of saturated aqueous NH4Cl (25 mL). The mixture was stirred vigorously for 10 minutes, and then diluted with water (10 mL). The aqeuous layer was separated and extracted with EtOAc (25 mL). The combined organic phase was concentrated under vacuum, and the residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc, 90:10-80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.24-1.37 (m, 2H), 1.40-1.68 (m, 6H), 1.85-2.03 (m, 2H), 3.56 (s, 1H), 5.39 (d, J=17.4 Hz, 1H), 5.53 (d, J=10.7 Hz, 1H), 5.73 (dd, J=17.5, 10.7 Hz, 1H).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12](Cl)(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1>CCOCC>[Br:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:1])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1
Reactant: N
Reactant: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Br
Solvent: CCOCC
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1Br
Reaction time: 2 h

Procedure:
To a one-liter flask containing 90 parts of concentrated aqueous ammonia and 150 parts of ether, there is added over three hours, 105 parts of 4-bromo-2,5-diisopropylbenzenesulfonyl chloride in 180 parts of ether. After stirring 2 hours longer, the excess ammonia is neutralized by adding 10% HC1. The organic layer is washed two times with 200 parts of saturated sodium chloride and is dried over sodium sulfate. Removal of the solvent gives 92 parts of 4-bromo-2,5-diisopropylbenzenesulfonamide which may be recrystallized from 1-chlorobutane, m.p. 145°-152°.