Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br-:9].[Br-:10].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CO>[Br:9][C:6]1[CH:7]=[C:8]([Br:10])[C:1]([OH:2])=[CH:3][C:4]=1[OH:5]
Reactant: Oc1cccc(O)c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(O)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
This synthesis was adapted from Shoji Kajigaeshi, Takaaki Kakinami, Tsuyoshi Okamoto, Hiroko Nakamura, Masahiro Fujikawa, Bulletin of the Chemical Society of Japan, 1987, volume 60, pages 4187-4189. To a solution of resorcinol (5.00 grams, 45.4 millimoles, 1.0 equivalent), dissolved in 100 milliliters dichloromethane and 40 milliliters methanol, pyridinium tribromide (29.0 grams, 90.8 millimoles, 2.0 equivalent) was added in small portions over the course of 60-70 minutes. The reaction was stirred at room temperature overnight. The solvent was removed on the rotary evaporator, and the residue taken up in chloroform (1×50 milliliters) and reconcentrated. Addition of ethyl acetate resulted in precipitation of side product. The ethyl acetate phase was separated by decanting, and the precipitate was further washed several times (4×150 milliliters 1:1 ether/ethyl acetate, 1×150 milliliters ethyl acetate, solvent separated by decanting). The combined decanted solvents were concentrated, followed by purification via automated flash chromatography (methanol in chloroform, 0-15%). The product was obtained in the form of an off-white solid (10.9 grams, 40.7 millimoles, 90%). m.p.: 66.4° C.; 1H-NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.74 (s, 1H), 5.46 (s, 2H); 13C NMR (101 MHz, THF-d8) δ 155.60, 136.10, 105.13, 100.74, 67.57; FTIR: 569, 594, 659, 742, 837, 868, 993, 1053, 1138, 1193, 1282, 1326, 1440, 1462, 1494, 1577, 1598, 1711, 2918, 3089, 3379, 3451, 3504 cm−1; UV/Vis: 223, 236, 296 nm; ESI/MS/MS of m/z=267: 267 [M79Br/81Br-H]−, 188 [M81Br-HBr)]−, 186 [M79Br-HBr)]−, 160 [M81Br-HBr—CO)]−, 158 [M79Br-HBr—CO)]−, 81 [81Br]−, 79 [79Br]−; HRMS (ESI−): 374.95735 calc. for C6H3Br2O2− [M-H]−: 264.8505, found 264.8510.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1ccc2ccc(=O)oc2c1)c1ccccc1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
To a solution of 7-hydroxycoumarin (1.62 g, 10 mmol) in acetone (60 ml) were added 2-bromoacetophenone (1.99 g, 10 mmol) and potassium carbonate (5.53 g, 40 mmol). The mixture was refluxed for 3 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 7-(2-oxo-2-phenylethoxy)-2H-1-benzopyran-2-one (4a) (1.53 g, 73.1%) as a needle crystal. mp: 163°-165° C.; IR(KBr) νmax : 1728, 1702, 1627; UV(CHCl3) λmax (log ε): 320 (4.16), 249 (4.13); 1H-NMR (CDCl3): δ5.39 (s, 2H, OCH2), 6.27 (d, 1H, 3-H), 6.80 (d, 1H, 8-H), 6.93 (dd, 1H, 6-H), 7.40 (d, 1H, 5-H), 7.49-7.68 (m, 4H, 4-H and aromatic H). Anal Calcd for C17H12O4 : C, 72.85; H, 4.32. Found: C, 72.98; H, 4.35.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])=[CH:12][CH:11]=1.C=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:16](=[O:26])[C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[O:25][CH2:1]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CNC(=O)c2cc(F)c(F)cc2O)cc1
Reactant: Cc1ccccc1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Product: COc1ccc(CN2COc3cc(F)c(F)cc3C2=O)cc1
Yield: 86 %

Procedure:
To a toluene solution (25 mL) of N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamide (1.5 g, 5 mmol) was added paraformaldehyde (0.450 g, 15 mmol) and para-toluenesulfonic acid (0.01 g, 0.05 mmol) and the reaction heated to 110° C. for 3 hr with azeotropic removal of water. Saturated sodium bicarbonate (50 ml) was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 1.3 g (86%) of 3-(4-methoxybenzyl)6,7-difluor-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.64 min; ES-MS (M+H)+=307.0; 1H-NMR (MeOH-d4) δ (ppm): 7.8 (dd, 1 H), 7.4 (d, 2 H), 6.8 (d, 2 H), 5.1 (s, 2 H), 4.6 (s, 2 H), 3.8 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20])[C:5]([O:7][CH3:8])=[O:6].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=2[F:21])=[CH:14][C:13]1=[O:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)c(Cl)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate (from Step 1) (2.4 g, 8.17 mmol) was taken up in DMF (10 ml). 2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K2CO3 (1.13 g, 8.17 mmol) were added. The reaction stirred for 6 hours at room temperature. At this time, the reaction was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4, filtered, and the solvent removed in vacuo to give amber oil (2.62 g, 77% crude yield). LC/MS, tr=2.79 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 294 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), aniline (0.040 mL, 0.439 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(phenylamino)pyrazine-2-carbonitrile (47 mg).
Reaction SMILES: I[C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C:35]([Zn]C#N)#[N:36]>[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C(=O)C>[C:35]([C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])#[N:36]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(I)c3c2C(=O)NC3)c1
Reactant: N#C[Zn]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(C#N)c3c2C(=O)NC3)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To an oven-dried microwave vial was added tert-butyl (1S,2R)-2-(7-iodo-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (47.0 mg, 0.081 mmol), dicyanozinc (5.74 mg, 0.049 mmol), zinc powder (0.532 mg, 8.14 μmol), dppf (0.451 mg, 0.814 μmol), and Pd2(dba)3 (0.745 mg, 0.814 μmol). N,N-Dimethylacetamide (814 μL) was added and the resulting dark brown solution was degassed with nitrogen for 3 min. The vial was capped and heated at 80° C. with stirring for 1 h. The temperature was increased to 110° C., and the mixture was stirred for an additional 3 h, then cooled to RT, diluted with EtOAc (10 mL), and washed with water (2×10 mL) and brine (10 mL). The organic phase was dried with sodium sulfate and concentrated to give the title compound as a brown residue, which was used without further purification (40 mg, 103%). [M+H] calc'd for C26H32N6O3, 477. found, 477.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C(C)=CC=CC=1.C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]23[CH2:8][CH2:9][C:10](=[O:12])[N:17]2[CH2:16][CH2:15][NH:18]3)=[CH:13][CH:14]=1
Reactant: NCCN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: O=C1CCC2(c3ccc(Cl)cc3)NCCN12
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (40 g, 190 mmol) in xylene (250 mL) were added ethylenediamine (22.6 g, 376 mol), and 12M hydrochloric acid (0.500 mL, 6 mmol). The reaction mixture was stirred at reflux under Dean-Stark for 12 h, and cooled to RT. The solid was collected by filtration and washed with xylene to give the crude residue. This was dissolved in DCM (400 ml) and filtered. The filtrate was concentrated in vacuo to give 36.6 g (62%) of the racemic title compound as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][C:8](=[O:10])[CH3:9].[H-].[Na+].[CH2:13](I)[CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([N:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:8](=[O:10])[CH3:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCI
Reactant: CC(=O)Nc1cccn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(C(C)=O)c1cccn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
N-(1-Methylpyrrol-2-yl)acetamide (3.20 g, 0.0231 mol) in dry dimethylformamide was maintained at a temperature less than 0° C, with stirring under nitrogen, during the slow addition of 50% sodium hydride/oil (1.11 g, 0.0231 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then the temperature allowed to rise to 15° C. when n-butyl iodide (8.50 g, 0.0461 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the resulting oil distilled to give a colourless oil 3.72 g (83%) b.p. (airbath) 100° C/0.4 mm.
Reaction SMILES: [CH2:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].C(OCC)(=O)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH2:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of tert-butyl 9-ethyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (260 mg, 0.937 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (166 mg, 83.0%) as a solid.
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(O)(=O)C>O1CCCC1.C(OCC)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2
Reactant: BrCCCBr
Reactant: BrCC1CC2C=CC1C2
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: BrCCCCC1CC2C=CC1C2
Reaction time: 1 h

Procedure:
In a 250 mL three neck bottle magnesium turnings (5.2 g, 214 mmol, 2.35 eq.) are mixed with tetrahydrofuran (10 ml). Whilst stirring 5-(bromomethyl)-bicyclo[2.2.1]hept-2-ene (17 g, 90.8 mmol, 1.03 eq.) that is dissolved in tetrahydrofuran (25 ml) is added dropwise. After stirring for one hour the excess of magnesium turnings is filtered off. The solution is added dropwise to a mixture of 1,3-dibromopropan (17.9 g, 88 mmol, 1 eq.), Li2CuCl4 (0.1 M in THF) (9 ml, 0.9 mmol, 0.01 eq.) and tetrahydrofuran (35 ml). After complete addition of the Grignard reagent, the black solution is stirred for one hour more. The reaction mixture is hydrolyzed with acetic acid (20%). Diethylether (40 ml) is added and the organic phase is washed with saturated sodium hydrogencarbonate solution (30 ml) and distilled water (30 ml). The organic layer is dried over magnesium sulfate and the solvent evaporated in vacuo at room temperature. The product is distilled at 20 mbar and 140° C. A colourless oil is obtained (Yield: 10.31 g, 45 mmol, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12](Cl)Cl.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][NH2:19]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]1[NH:20][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C(Cl)Cl)c1
Reactant: NCCCCN
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCCN2)c1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
(2-Chloro-5-nitrophenyl)carbonimidic dichloride (17.8 g, 70.0 mmol) was dissolved in tetrahydrofuran (68 mL). The solution was added dropwise within 30 min to a solution of 1,4-butanediamine (30.9 g, 350 mmol) in tetrahydrofuran (168 mL) which was kept at 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. another 2 hr at room temperature. The suspension was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The residue was taken up in water, filtered, and washed with water and disopropyl ether. After drying at 50° C. under vacuum, the title compound (8.9 g, 33.4 mmol, 48%) was obtained as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:15])=[CH:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: COc1ccc(C(=O)NC2CCCC2)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and cyclopentylamine in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[O:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[O:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1noc(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
7.13 g (26.7 mmol) (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate and 2.33 g (56.7 mmol) lithium hydroxide monohydrate were mixed with 1:1 THF/Water (100 mL) and stirred for 18 h. Reducing the volume of the mixture in vacuo to about ½, followed by dilution with brine and extraction with ethyl acetate. 5.8 g (97%) of the title compound was obtained after evaporation and drying. 1H NMR: 8.14 (s, 1 H), 8.02 (d, 1 H), 7.57 (d, 1 H), 7.47 (t, 1 H), 5.04-5.14 (m, 1 H), 2.42 (br s, 1 H), 1.67 (d, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH:5]2[OH:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[CH2:7][CH2:6][CH:5]2[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)CCC(O)c2cc(Br)ccc21
Product: CC1(C)CCC(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc21

Procedure:
Continuing on with the description of Reaction Scheme 6, 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene is reacted in the presence of base with t-butyldimethylsilyl chloride to provide 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldirnethylsilyloxy)naphthalene (Compound B15). The starting 6-bromo-1,2,3,4-tetrahydro-1,1-dinethyl-4-hydroxynaphthalene can be obtained by reduction of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Under conditions similar to the ones described above Compound B15 is converted to the boronic acid derivative (5,5-dimethyl-8-(t-butyldimethylsilyloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronic acid (Compound B14). Compound B14 is then coupled with ethyl 6-bromo-naphthalene-2-carboxylate to yield ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-2-yl]naphth-2-oate (Compound B3). Compound B3 is then reacted with tetrabutylammonium fluoride to remove the t-butyldimethylsilyl blocking group and to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-2-yl]naphth-2-oate (Compound B4). Compound B4 can be acylated to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-2-yl]naphth-2-oate (Compound B10), or methoxymethylated with methoxymethyl chloride in the presence of base (preferably ethyl N,N-diisopropylamine, Hunig's base) to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-2-yl]naphth-2-oate (Compound B8), and oxidized with N-methyl morpholine N-oxide to provide ethyl-6-[5,5-dimethyl-5,6-dihydro--naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate (Compound B6). Compounds B8 and B10 of the invention are within the scope of Formula 1, whereas Compound B6 is within the scope of Formula 2. Compound B6 can be converted into the O-methyloxime (ethyl 6-[5,5-dimethyl-5,6-dihydro--naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate (Compound B11) not shown in the scheme) and into other derivatives such as oximes, imines, hydrazones and the like, as is described above in connection with Reaction Scheme 2. Further derivatives of Compound B6 (and of analogous compounds) wherein the 8-oxo function of the molecule is modified can be obtained in accordance with the general synthetic methodology descnred in this specification. For example the trifluoromethylsulfonyl (triflate) derivative can be obtained in analogy to the reaction leading to Compound A9 as described in Reaction Scheme 2 , and the trifluoromethylsulfonyl (triflate) derivative is reacted with the reagents R14Me to provide compounds of Formula 6. ##STR28##
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>CCOCC.CO>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(Oc2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(Oc2cccc([C@H](C)N)c2)cn1
Yield: 141.6 %

Procedure:
(S)-{1-[3-(6-Methyl-pyridin-3-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.45 g, 10.52 mmol), hydrogen chloride in ether (36.8 mL, 1.0M) and methanol (5 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo to provide the title compound (3.4 g, quantitative yield) as yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[C:33]2[C:38]([C:39]([Br:46])=[C:40]3[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:37][CH:36]=[CH:35][CH:34]=2.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:46][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:20]2[CH:21]=[C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH:17]=[CH:18][CH:19]=2)=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[CH:44]2
Reactant: CC1(C)OB(c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)OC1(C)C
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
Temperature: 85 °C
Yield: 75.1 %

Procedure:
Compound 5 (see WO 2007046658 A1, US 20070205412 A1 and WO 2007086695 A1, which are incorporated by reference herein for their relevant teachings) was prepared as follows: a mixture of Compound 2 (5.270 g, 13.30 mmol), 9,10-dibromoanthracene (13.41 g, 39.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.922 g, 0.798 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and tetrahydrofuran (THF) (150 mL) was degassed with argon for 1.5 h. while stirring. The reaction mixture was then maintained under argon at 85° C. while stirring for 46 h. Upon completion, the reaction was cooled to RT and poured over dichloromethane (about 500 mL). The soluble organics were then washed with H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% dichloromethane) to provide Compound 5 (5.25 g, 75%) as a light yellow solid.