Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C(Cl)Cl.[Cu]I>[N:21]1[C:22]2[C:27](=[N:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[CH:3]=[C:2]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)=[N:19][CH:20]=1
Reactant: OCC(F)(F)F
Reactant: Ic1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: FC(F)(F)COc1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Reaction time: 72 h
Yield: 26.1 %

Procedure:
To a solution of N-(2-{4-[(4-iodopyridin-2-yl)oxy]phenyl}ethyl)pteridin-4-amine (300 mg, 0.64 mmol) and 2,2,2-trifluoroethanol (5 mL, 1.27 mmol) in a 45 mL Parr Bomb was added Cs2CO3 (412 mg, 1.27 mmol), 1,10-phenanthroline (22 mg, 0.127 mmol), and CuI (12 mg, 0.064 mmol). The reaction was held at 110° C. for 72 h, diluted with CH2Cl2, and washed with H2O. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to afford pteridin-4-yl-(2-{4-[4-(2,2,2-trifluoroethoxy)-pyridin-2-yloxy]-phenyl}-ethyl)-amine (74 mg, 26%) as a yellow solid: mp 166° C.; EIMS m/z 442 ([M]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.C([Li])CCC.CCCCCC.C[O:35]B(OC)OC>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([OH:35])[CH:9]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(O)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 139.2 %

Procedure:
To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH:9]3[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][C:27]([O-:29])=O)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[CH:1]1([C:4]2[N:8]([CH:9]3[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][C:27](=[O:29])[NH:38][C:32]2[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[CH3:30])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3]1
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)CC1CC(n2nnc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2nnn(C3CC(CC(C)C)C3)c2C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mono-tert-butyl 3-[5-cyclopropyl-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]glutarate (106 mg), 2,4-dimethylphenylamine (0.0356 mL) and DMF (1 mL) were mixed. To the mixture were added HOBt.H2O (48.2 mg) and WSC.HCl (60.3 mg) at ice temperature. After stirring at RT overnight, saturated aqueous sodium bicarbonate was added to the reaction mixture at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/2) to give the title compound (105 mg).
Reaction SMILES: C(O[CH:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1)(=O)CCC.[OH2:15].[OH-].[Na+]>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH2:7][C@H:8]2[OH:15]
Reactant: CCCC(=O)OC1CN2CCC1CC2
Reactant: O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H]1CC2CCN1CC2

Procedure:
The resulting (R) 3-quinuclidinyl butyrate was hydrolyzed with water-NaOH and then recrystallized from toluene to give (R)-quinuclidinol. Specific rotation [α]24D =-45 (1N HCl).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]#[C:11][CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)(=O)[CH3:2].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][CH:1]([C:4]2[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]#[C:11][CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[CH3:2])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: COc1ccc(C(C)=O)cc1C#CCNC(=O)OCc1ccccc1
Product: COc1ccc(C(C)NC2CC2)cc1C#CCNC(=O)OCc1ccccc1

Procedure:
Benzyl [3-(5-acetyl-2-methoxyphenyl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give benzyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxyphenyl}prop-2-yn-1-yl)carbamate [Ex(295-2)] as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:12])[CH3:11])=[CH:18][C:19]=1[CH3:20]
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: Cc1cc(Cl)nnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1Cl
Yield: 15.1 %

Procedure:
A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (5.5 g, 33 mmol, 1.8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0 equiv) and K2CO3 (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) was stirred at 100° C. under a blanket of nitrogen for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was concentrated in vacuo. Purification over silica gel using a 20-35% gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of a yellow oil which was determined by HPLC to be a 5:1 mixture of regioisomers by HPLC.
Reaction SMILES: C[N:2]([C:7]1[C:12]([CH2:13][NH:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:36]=[CH:35][C:34]4[CH:33]5[CH2:37][CH:29]([CH2:30][N:31](C(=O)C(F)(F)F)[CH2:32]5)[C:28]=4[CH:27]=3)[N:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1>[CH:29]12[CH2:37][CH:33]([CH2:32][NH:31][CH2:30]1)[C:34]1[CH:35]=[CH:36][C:26]([NH:25][C:17]3[N:16]=[C:15]([NH:14][CH2:13][C:12]4[C:7]([NH:2][S:3]([CH3:6])(=[O:4])=[O:5])=[N:8][CH:9]=[CH:10][CH:11]=4)[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][N:18]=3)=[CH:27][C:28]2=1
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc3c(c2)C2CC3CN(C(=O)C(F)(F)F)C2)ncc1C(F)(F)F)S(C)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ncccc1CNc1nc(Nc2ccc3c(c2)C2CNCC3C2)ncc1C(F)(F)F
Temperature: 70 °C

Procedure:
A solution 3 and tetrahydrofuran (2.00 mL) was treated with three crystals of benzyl triethyl ammonium chloride and 40% aqueous NaOH (2.00 mL), and the resultant bi-phasic reaction was heated to 70° C. under nitrogen. After sixteen hours, the mixture was allowed to cool to 25° C. The organic phase was collected and the aqueous layer was washed with EtOAc. The combined organic phases were dried over MgSO4, concentrated under reduced pressure, and purified over silica (92:8:0.8 CHCl3:CH3OH: NH4OH) to provide 32 g of 4 as a yellow foam). The yellow foam was dissolved in a minimum amount of CH2Cl2 at ° C., and 15 μL (0.0600 mmol) of 4.0 M HCl in 1,4-dioxane was slowly added. The resultant white slurry was stirred under a gentle flow of nitrogen for one hour and filtered to provide the hydrochloride salt from of 4 as a white solid (25 mg, 0.0474 mmol, 38%). C24H26F3N7O2S HPLC r.t.=5.10 min.; LC/MS (Method F) m/z 534.4 (MH+).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][NH:13][C:12]1=[O:18])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl>O1CCCC1.[Cl-].[Na+].ClCCl>[Si:3]([O:10][CH:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:12]1=[O:18])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CNC(=O)C1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)OCc2ccccc2)C(=O)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
Sodium hydride (39 mg, 0.97 mmol) was added to a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-pyrrolidinone (214 mg, 0.880 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen at 0° C. After 10 min, benzyl chloroformate (0.200 mL, 1.32 mmol) was added, and the mixture was allowed to warm to room temperature. After 24 h, the mixture was diluted with saturated aqueous sodium chloride (30 mL) and dichloromethane (30 mL). Hydrochloric acid (10 mL, 1 N) was then added, and the two phases were separated. The aqueous layer was extracted with dichloromethane (35 mL), and the dichloromethane layers were combined. After washing with saturated aqueous sodium chloride, they were dried over magnesium sulfate and concentrated to a tan oil, which was further purified by column chromatography on silica gel. Elution with 10:1 hexane:ethyl acetate afforded benzyl 3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate as a colorless oil (312 mg, 94%). 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.34 (m, 5H), 5.27 (1/2Abq, J=13 Hz, 1H), 5.21 (1/2Abq, J=13 Hz, 1H), 4.24 (s, 1H), 3.50 (1/2Abq, J=11 Hz, 1H), 3.38 (1/2Abq, J=11 Hz, 1H), 1.12 (s, 3H), 0.92 (s, 9H), 0.90 (s, 3H), 0.13 (s, 3H), 0.10 (s, 3H). ES-LCMS m/z 378 (M+H).
Reaction SMILES: CC(=C(C)C)C.B.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([C@H:27]([CH3:30])[CH:28]=[CH2:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C[O:34]CC1>>[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([C@H:27]([CH3:30])[CH2:28][CH2:29][OH:34])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: C=C[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: B
Agent: CC(C)=C(C)C
Product: C[C@H](CCO)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a 0° C. solution of 2,3-dimethyl-2-butene in THF (43.2 mmol, 1.0 M) is added a solution of borane in THF (43.2 mmol, 1.0 M) dropwise over 20 min. After stirring an additional 60 min at 0° C., tert-butyl (2S,3R)-2-benzyloxycarbonylamino-3-methyl-4-pentenoate (13.15 g, 41.2 mmol) in 20 mL THF is added dropwise, and the resulting solution is allowed to come to 25° C. over 60 min. The solution is cooled again to 0° C. and quenched with 6 ml of 1:1 THF-ethanol, added cautiously, then 40 mL of pH 7.0 phosphate buffer. 40 mL 30% hydrogen peroxide is added and the reaction mixture is stirred at 25° C. for 14 h. The mixture is partially concentrated, added to saturated aqueous sodium chloride, and extracted with ether. The combined organic layers are washed twice with ice-cold saturated aqueous sodium sulfite, water, and saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo and purification by silica gel chromatography (elution with hexanes-EtOAc, 3:2) provides tert-butyl (2S,3R)-2-benzyloxycarbonylamino-3-methyl-5-hydroxypentanoate as an oil (12.3 g, 89%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].Cl.[C:17]1([C@H:23]([NH2:25])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:25][CH:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cccc2c1CCC(NC(C)c1ccccc1)C2

Procedure:
Starting from 16.24 g (0.08 mol) of 5-acetylamino-2-tetralone, 240 ml of methanol, 19.0 g (0.12 mol) of (R)-1-phenylethylamine-hydrochloride and 6.0 g (0.096 mol) of sodium cyanoborohydride, the title compound is obtained analogously to Example 4.1.11 and is crystallised from 75 ml of toluene. Yield 18.5 g (74.9% of theory), melting point 158° C. It consists of approximately equal parts of the (R/R)- and (S/R)-diastereoisomers.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:31]#[N:32])[C:29]#[N:30])=[CH:23][CH:22]=1>>[NH2:32][C:31]1[N:12]2[N:13]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:11]2[CH:10]=[C:27]([C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[C:28]=1[C:29]#[N:30]
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC(C#N)=Cc1ccncc1
Product: N#Cc1c(-c2ccncc2)cc2nc(-c3ccco3)nn2c1N

Procedure:
The title compound, MS m/e (%): 303 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 4-pyridinylmethylen-propanedinitril.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[C:12]#[N:13])[CH2:3]1.[CH3:19][Mg]Cl.[BH4-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.CO.C1COCC1>[F:18][C:2]1([F:1])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[CH:12]([NH2:13])[CH3:19])[CH2:3]1
Reactant: Cn1ccc2nc(C#N)c(N3CC(F)(F)C3)cc21
Reactant: C[Mg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a slurry of 6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (130 mg, 0.524 mmol) in toluene (3.0 mL) at −30° C. was added dropwise methylmagnesium chloride (0.262 mL, 0.786 mmol). The mixture was moved to an ice bath at 0° C. and stirred for 2 hours. The reaction mixture had lots of solid and was about 50% complete by LC/MS. THF (1 mL) was added at 0° C. followed by more methylmagnesium chloride (0.262 mL, 0.786 mmol) and the solution was allowed to sit in a refrigerator at −10° C. for 16 hours. The solution was subsequently warmed to 0° C. and the reaction was quenched with anhydrous methanol (1 mL). A solid formed which dissolved upon stirring. The mixture was added to a solution of sodium borohydride (99 mg, 2.62 mmol) in methanol (5 mL) at 0° C. The resulting mixture was stirred for 30 minutes at 0° C. Excess sodium borohydride was consumed by adding acetic acid (0.300 mL, 5.24 mmol). The solution was allowed to warm to 20° C. and was concentrated in vacuo. The concentrate was taken up in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give the title compound, which was used without further purification (84 mg, 60%). ESI-MS m/z [M+H]+ calc'd for C13H16F2N4, 267; found 267.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])=[CH:19][C:18]=1[Cl:30]>>[Cl:23][C:22]1[CH:21]=[C:20]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:19]=[C:18]([Cl:30])[C:17]=1[O:16][CH2:15][CH2:14][CH2:13][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Product: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of 3.9 g of 4-(trifluoromethyl)aniline and 0.50 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene was stirred at 90° C. to 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was subjected to silica gel chromatography, which afforded 0.37 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl)phenylamino)propyloxy)benzene (62% yield), nD23.5 1.5617.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][OH:25]>C(O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([CH2:23][CH2:24][OH:25])[N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Reactant: OCCBr
Solvent: CCCO
Product: COc1ccc(COc2ccc(-c3nnnn3CCO)cc2)cc1

Procedure:
To 30 ml of n-propanol are added 10-2 mole of 5-[4-(4-methoxy benzyloxy) phenyl] tetrazole and 10-2 mole of 2-bromo ethanol. The mixture is heated to reflux for 25 hours. The solvent is evaporated and the residue taken up in 100 ml of hot ether. The etherated solution is washed with 0.5N NaOH, then with water. After drying on sodium sulfate, the etherated phase is concentrated. The compound of code number 42 is obtained after recrystallization in methanol. The recrystallization solvent is concentrated and the residue is subjected to chromatography on a silica column (eluent:ethyl acetate/petroleum ether:1/4) whereby the compound of code number 51 is isolated.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH:11]=[C:10]1[O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([NH2:37])(=[O:36])=[O:35]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:20][C:10]1[C:9](=[O:8])[C:18]2[C:13]([C:12](=[N:37][S:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH:11]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)COC1=CC(=O)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
triethyl amine (0.12 ml, 0.88 mmol) was added in the mixture of tert-Butyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-yloxy)acetate (7c, 0.115 g, 0.4 mmol) and thiophene-2-sulfonamide (0.078 g, 0.48 mmol) in anhydrous DCM (4 ml), followed by adding TiCl4.2THF. The reaction mixture was heated with μW at 60° C. for 20 min. and poured into EtOAC, then filtered with celite. The filtrate was concentrated under reduce pressure and purified by flash chromatography to give compound 8d as a yellow solid, 22%, m.p.=153-155° C.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].Br[CH2:56][CH:57]1[CH2:59][CH2:58]1>CN(C=O)C>[CH:59]1([CH2:58][N:23]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]4[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]4)[CH:32]=3)[C:28]([F:52])=[CH:27][CH:26]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)[CH2:57][CH2:56]1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CC4CC4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 13.9 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (76.1 mg, 0.106 mmol), NaH (8.29 mg, 0.345 mmol) and (bromomethyl)cyclopropane (0.0155 mL, 0.160 mmol) in DMF (1.0 mL) were reacted to give the desired product (8.4 mg, 13.7%). EI-MS m/z 569(M−H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].O1CCN([CH:24]=[CH:25][N+:26]([O-:28])=[O:27])CC1.Cl.CC(C)=O>O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:6]1[CH:5]=[C:4]([CH2:16][CH3:17])[S:3][C:2]=1[NH:1][CH:24]=[CH:25][N+:26]([O-:28])=[O:27])=[O:15]
Reactant: O=[N+]([O-])C=CN1CCOCC1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(N)s1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 2-amino-3-(2-chlorobenzoyl)-5-ethylthiophene (5.30 g), 1-morpholino-2-nitroethene (3.16 g), 6N HCl (5 ml) and acetone (25 ml) was stirred at room temperature for one hour. Water was added to the mixture, which was extracted with ethene acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off to obtain 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene as crystals (5.65 g, 84.1%). The crystals were recrystallized from acetone to obtain yellow plates, mp: 125°-126° C.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44]>>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Reactant: N#CCCCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(F)c1
Yield: 80.6 %

Procedure:
Following the procedure described for Example 5, Step A, the anion derived 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.684 mmol) and NaHMDS (1M in THF, 0.80 mL, 0.80 mmol) was alkylated with 7-bromoheptanenitrile (142 mg, 0.748 mmol) at 70° C. for 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc to EtOAc to 5% MeOH in CH2Cl2) provided 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (261.7 mg). 1H NMR (CDCl3) δ7.26 (m, 1H), 6.92 (m, 3H), 3.89 (m, 1H), 3.59 (m, 2H), 2.89 (m, 1H), 2.75 (m, 2H), 2.36 (m, 4H), 2.11 (m, 1H), 1.72-1.26 (m, 13H), 0.89 (s, 9H), 0.09 (s, 6H); MS 475.3 (M+1).