Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[CH:20][C:19]=1[CH3:29])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:25]([C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:16]([NH:15][C:12](=[O:14])[CH2:11][N:8]2[C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH3:17])=[C:19]([CH3:29])[CH:20]=1)([CH3:27])[CH3:28])#[N:26]
Reactant: O=C(O)Cn1cnc2cccc(F)c21
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(F)c21
Yield: 62.7 %

Procedure:
To a solution of (7-fluoro-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.29 mmol) prepared according to scheme 5, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (260 mg 1.29 mmol) prepared according to scheme 15 and DMAP (156 mg, 1.29 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (490 mg, 1.29 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}-2-(7-fluoro-1H-benzimidazol-1-yl)acetamide (306 mg, 63%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.44 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.35 (s, 3H) 5.02-5.14 (m, 2H) 5.19 (q, J=7.03 Hz, 1H) 6.99 (dd, J=11.52, 7.42 Hz, 1H) 7.19 (dt, J=8.15, 4.98 Hz, 1H) 7.26 (d, J=2.15 Hz, 1H) 7.32 (dd, J=8.01, 2.34 Hz, 3H) 7.39 (d, J=8.20 Hz, 1H) 7.45 (d, J=7.62 Hz, 1H) 8.09 (s, 1H), MS [M+H], calcd: 379.2. found: 379.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1S(Cl)(=O)=O.CN1C=CN=C1.[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([OH:38])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([O:38][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@H](O)COCc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Agent: Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](COCc1ccc(OC)cc1)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 79.1 %

Procedure:
2.03 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.772 mL of 1-methylimidazole were added to a solution of 1.02 g of the (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 20 mL of acetonitrile at room temperature, and the obtained mixture was stirred at room temperature for 1.75 hours, and then at 40° C. for 1.25 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and a solid was removed by filtration. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentan al O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]>O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([C-:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:4][CH:3]=1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: Nc1ccc(I)cc1
Agent: [Fe+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Ic1ccc(-[c-]2cccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
4-Iodoaniline (8.8 g, 40 mmol) was suspended in a mixture of conc. HCl (20 mL) and H2O (50 mL) and cooled to 0° C. A solution of NaNO2 (3.3 g, 48 mmol) in H2O (10 mL) was added dropwise with stirring while the temperature was carefully maintained at 0-5° C. After the addition was completed, the mixture was stirred for 30 min at 0° C. The resulting diazonium salt solution was then added slowly to a solution of ferrocene (3.7 g, 20 mmol) in toluene (100 mL) at 0° C. An instantaneous evolution of gas was observed. After complete addition, the reaction mixture was stirred at 0° C. for 1 h. Then the mixture was warmed to rt and stirring was continued for 16 h. The layers were separated and the aqueous layer was extracted with toluene (3×100 mL). The combined organic layers were washed with satd aq NaHCO3 (3×100 mL), brine (3×100 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:2) to afford 4.2 g (55%) of an orange solid: mp 119-121° C.; 1H NMR δ 4.02 (s, 5H), 4.33 (t, J=1.5 Hz, 2H), 4.61 (t, J=1.5 Hz, 2H), 7.20, 7.58 (AA′BB′, J=7.8 Hz, 4H); 13C NMR δ 66.4, 69.2, 69.7, 84.1, 90.5, 127.9, 137.3, 139.2; FAB-MS obsd 387.9420 calcd exact mass 387.9411 (C16H13FeI).
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=O)([CH3:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]>CC(O)=O.[Pd]>[NH2:10][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCC(C)(C)N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-methyl-4-nitropentanoate (0.8 g, 4.57 mmol) (Moffett (1963) Org. Syn. Coll. 4:652) and Pd/C (1 g, 10% by weight) were suspended in AcOH (15 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated and the crude was used in the subsequent step without further purification. MS: (+) m/z 146.12.91 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2C)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 1.4 (0.0532 g, 0.136 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.500 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by combiflash (0 to 40% EtOAc/hexane) to afford 1 (0.0426 g, 83.1% yield). MS ESI (neg.) m/e: 375.1 (M−H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (3H, m), 7.24-7.31 (2H, m), 6.85-6.95 (6H, m), 5.08 (2H, s), 3.87 (3H, s), 2.99 (2H, t, J=7.8 Hz), 2.73 (2H, t, J=7.8 Hz), 2.34 (3H, s).
Reaction SMILES: COC(=O)[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[OH-].[K+]>CO.O>[CH2:12]([N:7]1[CH2:8][CH2:9][C@H:10]([CH3:11])[C@H:5]([NH2:4])[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCN(Cc2ccccc2)C[C@H]1N
Yield: 37.8 %

Procedure:
A mixture of racemic cis (1-benzyl-4-methyl-piperidin-3-yl)-carbamic acid methyl ester (1.56 g, 5.95 mmol) and potassium hydroxide (9.90 mL, 59.5 mmol, 6M solution) in methanol (50 mL) was heated at reflux for 48 hours. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 7% 2M NH3 in methanol solution in DCM) to afford 460 mg (38%) of racemic cis 1-benzyl-4-methyl-piperidin-3-ylamine. LCMS (Method H, ESI): RT=0.35 min, m+H=204.9; 1H NMR (400 MHz, CDCl3) δ: 7.29-7.28 (m, 5H), 3.45 (s, 2H), 2.76-2.72 (m, 3H), 2.20-2.11 (m, 1H), 1.97 (td, 1H), 1.42 (m, 5H), 0.91 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:25])[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:25])[CH:14]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
The same procedures as in Example 26 were performed except that 1 g (2.75 mmol) of methyl 7-(N-t-butoxycarbonylamino)-3-oxo-2-phenylheptanoate instead of ethyl 7-(N-t-butoxycarbonylamino)-3-oxo-2-phenylheptanoate was dissolved in 6 ml of methanol, 104 mg (2.75 mol) of sodium borohydride was added, and 5 ml of 4N hydrochloric acid was added to the reaction solution, to prepare the target compound as a pale yellow oil in an amount of 0.9 g at a yield of 90.0%. The products were analyzed to result in that the ratio of the syn-form to the anti-form was 9:1. The analytical results on the target compound are given below.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6](C(OC)=O)([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.CS(C)=O>COCCOCCOC>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(C(=O)OC)CCC(OC)OC1
Solvent: COCCOCCOC
Solvent: CS(C)=O
Product: COC1CCC(C(=O)O)CO1

Procedure:
Dimethyl 4,4-dimethoxybutane-1,1-dicarboxylate was prepared by the Michael addition of dimethyl malonate to acrolein followed by acetalization. Subsequent hydroxymethylation with formaldehyde in the presence of potassium hydrogen carbonate gave nearly quantitatively dimethyl 1-hydroxy-5,5-dimethoxypentane-2,2-dicarboxylate. This compound rapidly underwent acid-catalyzed intramolecular cyclization in a dilute solution in benzene, aided by the favored six-membered ring formation, to yield dimethyl 6-methoxytetrahydropyran-3,3-dicarboxylate. The tetrahydropyran derivative was saponified to the free dicarboxylic acid, which was then decarboxylated in diglyme or dimethyl sulfoxide at 120°-140° C. to give 6-methoxytetrahydropyran-3-carboxylic acid as a stereoisomeric mixture in a quantitative yield. The carboxylic acid was then heated in a dilute solution in toluene in the presence of a catalytic amount of p-toluenesulfonic acid to give the desired bicyclic lactone (I). The overall yield based on acrolein was approximately 20%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([O-])=O>CO.[Pd]>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7]2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1ccn2CCCN1CCOCC1
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of crude 4-(3-(4-nitro-1H-indol-1-yl)propyl)morpholine in methanol (100 mL) was added palladium on carbon (10%). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by silica gel chromatography to afford the product 1-(3-morpholinopropyl)-1H-indol-4-amine (5 g, yield 67%, two steps) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12, J=2.4 Hz).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].Cl[CH2:15][C:16]1[C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][CH:23]=2)=[NH+:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:27]([N:26]1[C:22]([C:17]2[C:16]([CH2:15][O:1][C:2]3[C:10]([CH:11]=[O:12])=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[CH:4][CH:3]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: O=Cc1c(O)ccc2cn[nH]c12
Reactant: CC(C)n1nccc1-c1[nH+]cccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nccc1-c1ncccc1COc1ccc2cn[nH]c2c1C=O
Temperature: 50 °C
Yield: 51.5 %

Procedure:
6-Hydroxy-1H-indazole-7-carbaldehyde (0.14 g, 0.86 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (4 ml). 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-1-ium chloride (0.235 g, 0.86 mmol, 1 eq.) and potassium carbonate (0.36 g, 2.6 mmol, 3 eq.) were added and the reaction mixture was stirred in a 50° C. heat block for 16 h. The reaction mixture was then cooled, and ethyl acetate (100 ml) and water (50 ml) were added. The phases were separated and the aqueous phase was extracted with more ethyl acetate (2×50 ml). The combined organic phases were washed with water (50 ml) and aqueous saturated sodium chloride solution (50 ml), and dried over sodium sulfate. After concentration the residue was purified by silica gel chromatography (5-70% ethyl acetate/hexanes). Product fractions were triturated with diethyl ether and lyophilized from acetonitrile/water to give 6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-1H-indazole-7-carbaldehyde (0.16 g, 51%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 10.58 (s, 1H), 8.74 (dd, J=4.4, 1.6 Hz, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.01 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.42 (dd, J=7.9, 4.8 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.36 (d, J=1.8 Hz, 1H), 5.22 (s, 2H), 4.66 (septet, J=6.6 Hz, 1H), 1.46 (d, J=6.6 Hz, 6H). MS (ESI) m/z 362 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[I:24][C:25]1[C:26]([CH3:31])=[N:27][NH:28][C:29]=1[CH3:30]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[CH2:10]([N:9]([CH2:12][CH3:13])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([CH:2]([N:27]2[C:26]([CH3:31])=[C:25]([I:24])[C:29]([CH3:30])=[N:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: Cc1n[nH]c(C)c1I
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(I)c2C)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a stirring solution of 4-[Chloro-(3-methoxy-phenyl)-methyl]-N,N-diethyl-benzamide (1.11 g, 3.32 mmol) in 20 Ml CH3CN was added 4-iodo-3,5-dimethyl pyrazole (1.64 g, 7.40 mmol) and tetra-n-butyl ammonium iodide (619 mg, 1.68 mmol). The mixture was heated to reflux for 24 h, cooled to room temperature and concentrated under reduce pressure. The crude oil was purified by flash chromatography on a 3×20 cm column, eluting with 30% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated under reduce pressure to give the desired product (1.65 g, 96%) as a clear yellow oil. 400 MHz 1H NMR (CDCl3) δ 7.31 (d, J=8.1 Hz, 2H), 7.19-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.79-6.82 (m, 1H), 6.68-6.70 (m, 2H), 6.54 (s, 1H), 3.71 (s, 3H), 3.50 (br s, 2H), 3.23 (br s, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.21 (br s, 3H), 1.08 (br s, 3H); 75 MHz 13C NMR (CDCl3), δ 170.8, 159.7, 149.8, 141.2, 140.3, 140.1, 136.7, 129.6, 128.5, 126.6, 120.8, 114.4, 113.2, 66.5, 55.3, 43.3, 39.3, 14.4, 12.6; MS (M+1) 518.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16](I)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(-c3ccccc3)n21
Yield: 54.8 %

Procedure:
To a solution of tert-butyl(2-{6-iodo-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (100 mg, 0.177 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, 64.7 mg (0.531 mmol) of phenyboronic acid, 7.2 mg (0.009 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepaladium complex with dichloromethane and 172 mg (0.531 mmol) of cesium carbonate, were subsequently added. The mixture was heated at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc/EtOH 6/4/0.5), and further purification by HPLC/MS preparative method 1, 50 mg (54%) of tert-butyl(2-{1-oxo-6-phenyl-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](C(O)=O)[CH2:7][CH2:6]2.C(N(CC)CC)C.[Br:39]N1C(=O)CCC1=O>ClCCl>[Br:39][C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC(C(=O)O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(Br)=C2Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a flask, add 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carboxylic acid (0.4 g, 0.68 mmol), dichloromethane (10 mL), and triethylamine (0.2 mL, 1.43 mmol). Stir the mixture at 25° C. for 10 min. Add N-Bromosuccinimide (0.5 g; 4.13 equiv; 2.81 mmol) in portions. Cool the reaction mixture to room temperature and quench with ice-water. Extract the mixture with ethyl acetate three times and discard the aqueous phase. Dry the combined organic layers over MgSO4, filter, and concentrate to dryness to give 1-(2-(4-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yloxy)phenoxy)ethyl)piperidine as a yellow oil (300 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][C@H:8]([C:15]([OH:17])=[O:16])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])([O-])=O.[H][H]>[Ni]>[NH2:1][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][C@H:8]([C:15]([OH:17])=[O:16])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: O=C(O)CSC[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Ni]
Product: Nc1ccccc1CN[C@@H](CSCC(=O)O)C(=O)O

Procedure:
N-(2-amino-benzyl)-S-carboxymethyl-cysteine was prepared in analogy to Example 1 (b) by reducing N-(2-nitro-benzyl)-S-carboxymethyl-cysteine with hydrogen in the presence of Raney nickel and double the quantity of soda. Melting point: 214° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:10]=1.[OH-].[Na+]>CO.O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:10]=1
Reactant: COC(=O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Yield: 46 %

Procedure:
A solution of methyl 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (1.37 g; 4 mmol) in methanol (20 ml) was treated at reflux for 4 hours with a solution of sodium hydroxide (0.32 g; 8 mmol) in water (24 ml). After evaporation to dryness the residue was acidified at pH 6 with 12N HCl. The resulting solid was triturated with water and subsequently with ether to give 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid. Yield: 46%
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:10][NH:9]1.[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27]Br)[CH3:24]>CN(C=O)C>[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][N:9]1[C:8](=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:10]1)[CH3:24]
Reactant: COC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(Cn1nc(CC(=O)OC)c2ccccc2c1=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing potassium t-butoxide (5.91 g), methyl 4-oxo-3H-phthalazin-1-ylacetate (10.91 g) and DMF (50 ml) was added bromoacetaldehyde diethylacetal (10.83 g), and the reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was poured onto water, extracted with ethyl acetate and the ethyl acetate layer was collected and dried. Upon evaporation of the solvent, a clear oil was obtained which upon standing gave a white solid (yield, 5.2 g; m.p. 68° C.).