Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].C([O-])([O-])=O.[K+].[K+].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].C(O)CO>C(OCC)(=O)C.CC(O)C>[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])=[O:5])=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: COc1ccccc1NC(=O)c1ccccc1I
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: COc1ccccc1NC(=O)c1ccccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
2-Iodo-N-(2-methoxyphenyl)benzamide 3 (0.355 g, 1.0 mmol), Cu(I) iodide (20 mg, 0.1 mmol), K2CO3 (0.276 g, 2.0 mmol), and 4-nitrothiophenol (0.155 g, 1 mmol) were added to a 10 mL reaction vessel with Teflon-lined septum. The tube was evacuated and backfilled with dry N2 (3 cycles). Ethylene glycol (0.1 mL, 2.0 mmol) and 2-propanol (1 mL) were added by syringe at room temperature. The reaction vessel was heated in a microwave reactor (CEM, Explorer) at 80° C. and 150 W power for 30 min (2×). The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 10 mL) was added; the reaction mixture was filtered and concentrated. The crude product was purified by flash column chromatography on silica, eluting with 20% EtOAc in hexanes. This procedure provided 2-(4-nitrophenylthio)-N-(2-methoxyphenyl)benzamide 1 as pale yellow crystalline solid (0.24 g, 63%); 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.0 Hz, 1H), 8.39 (s, 1H, overlapping signal), 8.05 (ddd, J=9.2, 2.4, 1.6 Hz, 2H), 7.77 (dd, J=6.4, 2.4 Hz, 1H), 7.56-7.49 (m, 3H), 7.29-7.25 (m, 2H), 7.06 (ddd, J=9.2, 7.6, 1.6 Hz, 1H), 6.95 (dt, J=8.8, 0.8, 1.2 Hz, 1H), 6.85 (dd, J=8.0, 0.8 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.44, 148.22, 146.87, 146.15, 140.63, 135.76, 131.66, 130.09, 129.87, 129.49, 128.79 (2C), 127.54, 124.54, 124.35 (2C), 121.37, 120.05, 110.19, 55.88; MS (ESI): m/z 402.99 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18](B(O)O)=[C:17]([O:25][CH3:26])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[C:20]([F:21])[C:15]([F:14])=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: COC(=O)CNc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (82%). MS (ESI): m/z=309.104 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
Dichloromethane (80 mL) was added to serine methyl ester hydrochloride (2.64 g, 17 mmol), 3-methoxy-4-nitrobenzoic acid (3 g, 15.2 mmol), WSC hydrochloride (3.83 g, 20 mmol), DMAP (0.18 g, 1.5 mmol) and N,N-diisopropylethylamine (2.58 g, 20 mmol), and the mixture was stirred at room temperature for one day. The reaction solution was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0) to obtain 3.11 g of the title compound as a colorless solid (69%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][CH2:8][C:9]1[C:10]([Cl:20])=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>>[Br:7][CH2:8][C:9]1[C:10]([Cl:20])=[C:11]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(CBr)c1Cl
Product: O=S(=O)(c1ccc(Cl)c(CBr)c1Cl)N1CCOCC1

Procedure:
Working analogously to Preparation VII, starting from morpholine and 3-bromomethyl-2,4-dichlorobenzenesulphonyl chloride, the expected product is obtained in the form of a yellow solid (Yield=85%) (the product contains the chloromethylated analogue in part).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([C:24](=[CH2:26])C)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:30]CC1.O>C(OCC)(=O)C.O=[Os](=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH:26]=[O:30])[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C(C)N1CCCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCCN(CC=O)S2(=O)=O)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 89 (0.50 g, 1.29 mmol), THF (16 mL), H2O (12 mL), and NaIO4 (0.69 g, 3.2 mmol) was added OsO4 (1 mL, 0.1 mmol; 2.5 %/tertbutanol) to effect a white precipitate. After 3.0 h, the reaction mixture was diluted with ethyl acetate and washed with H2O, 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give aldehyde 90 as an oil. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.08 (m, 2H), 4.00 (d, J=17 Hz, 1H), 3.89 (d, J=17 Hz, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.66 (m, 2H), 2.20 (m, 1H), 2.08 (m, 1H), 2.00-1.35 (m, 9H), 1.10 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2N)[CH:24]=[N:23]1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[NH:22][N:23]=[CH:24]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2cn[nH]c12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3cn[nH]c23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 1H-indazol-7-amine (56 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (90 mg, 86.5% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.N1C=CC=CC=1>O1CCCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:30]([C:25]4[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=4)(=[O:32])=[O:31])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)cc(F)c2)c1F)c1c[nH]c2ncc(Cl)cc12
Temperature: 130 °C

Procedure:
Into a microwave reaction vessel were combined (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (56, 50 mg, 0.16 mmol), 3,5-difluorobenzenesulfonyl chloride (57, 103 mg, 0.49 mmol), pyridine (0.5 mL, 6.1820 mol) and tetrahydrofuran (3.0 mL). The reaction was warmed in the CEM microwave at 300 watts, 130° C. for 10 minutes. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The compound (58) was isolated using column chromatography (silica, hexane:ethyl acetate 70:30) to obtain 36 mg (46%) compound. MS=482.0.
Reaction SMILES: CC(C)(C)C(OC[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][C:14]=2[OH:18])[N:9]=[CH:8]1)=O.[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:24]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.CO>C(Cl)Cl.N>[CH2:23]([O:18][C:14]1[CH:13]=[C:12]([O:19][CH3:20])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:7]=[CH:8][NH:9]2)[CH3:24]
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1cc(OC)cc2[nH]cnc(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of [5-hydroxy-7-(methyloxy)-4-oxo-3(4H)-quinazolinyl]methyl 2,2-dimethylpropanoate (1 g, 3.26 mmol, prepared according to J. Med. Chem. (2006) 49 6465), triphenylphosphine (1.370 g, 5.22 mmol), and ethanol (0.210 mL, 3.59 mmol) in DCM (10 mL) at 0° C. was treated dropwise over 2 minutes with a 40% solution of DEAD in toluene (2.379 mL, 5.22 mmol). After addition, the mixture was warmed to room temperature and stirred for 3 hours before being concentrated. The residue was dissolved in 7 M ammonia in methanol (10 mL, 70.0 mmol) and the mixture was stirred for 3 days. The solid was collected by filtration and washed with MeOH and CH2Cl2 to give 5-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (286 mg, 40%) as a white solid. MS (m/z) 221.1 (M+H+).
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:30])=[CH2:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=N.[OH-:42].[Na+]>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:16]2[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:4]([OH:42])=[O:3])[CH:11]=3)[N:17]=2)(=[O:20])=[O:21])=[N:23][CH:24]=1)([CH3:30])=[CH2:29]
Reactant: [OH-]
Reactant: C=C(C)c1ccc(S(=O)(=O)Nc2nc(-c3ccnc(C(=N)OC)c3)nc(OC)c2Oc2ccccc2OC)nc1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C=C(C)c1ccc(S(=O)(=O)Nc2nc(-c3ccnc(C(=O)O)c3)nc(OC)c2Oc2ccccc2OC)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
0.1 g of 4-[4-(5-isopropenyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt, product of example 66 b), in MeOH (10 ml) were treated at RT with 1.8 ml 1N NaOH and the solution was stirred for 26 h at RT. After this time further 1.8 ml 1N NaOH were added and stirring was continued for further 20 h until the reaction was complete according to HPLC analysis. The solution was concentrated then poured into diluted aqueous HCl, the product was extracted into AcOEt. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo. The crystalline precipitate that had formed was collected under suction and washed with ether to give 4-[4-(5-isopropenyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid as light yellow crystals. ISN mass spectrum, m/e 548 (M−1 calculated for C26H23N5O7S: 548).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([Mg]Br)[CH:13]=[CH2:14].[Cl-].[NH4+]>C(OCC)C>[C:1]1([CH2:7][O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH:13]=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCOCc1ccccc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring 0° C. solution of 59.0 g of product from Example 1 in 375 ml of diethyl ether is added, dropwise, 432.24 ml of 1M allylmagnesium bromide in ether. The reaction is stirred at 0° C. for 1 hour, followed by overnight stirring at room temperature. The reaction is cooled to 0° C., hydrolyzed with saturated ammonium chloride, and the layers are separated. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 61.5 g of the desired product as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.C(O)C.Cl.[N-:25]=[C:26]=[O:27].[K+]>O>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:25][C:26](=[O:27])[NH:2][CH:3]=2)[CH:11]=[C:10]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:9]=1[OH:16])([CH3:19])([CH3:20])[CH3:18]
Reactant: [N-]=C=O
Reactant: CC(C)(C)c1cc(C(=O)CN)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(-c2c[nH]c(=O)[nH]2)cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 43.3 %

Procedure:
To a mixed solution of 1.2 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride, 10 ml of ethanol, and 0.3 ml of concentrated hydrochloric acid was added a solution of 0.64 g of potassium isocyanate in 3 ml of water at room temperature. After stirring the mixture for 2 hours, 0.3 ml of concentrated hydrochloric acid was added thereto and the resultant mixture was refluxed for 2 hours. The reaction mixture thus obtained was poured into water and the precipitates formed were recovered by filtration. The reaction product was then recrystallized from aqueous ethanol to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:30]([C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[C:3]1=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.315 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 0.256 g of 2,4-dimethoxybenzenesulfonyl chloride. This gives the expected product after crystallization from a DCM/iso ether mixture. m=0.300 g. M.p.=179°-180° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:16][C:15]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:17]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and aluminium chloride in nitrobenzene to give (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone. Reduction of this ketone with lithium aluminium hydride in ether yields 5,6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalene-methanol which is converted by treatment with phosphorus tribromide in ether/hexane in the presence of a small amount of pyridine into 2-bromoethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. This bromoethyl compound is converted by treatment with triphenylphosphine in xylene while heating for 12 hours into [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide which, in a Wittig reaction with 4-ethoxycarbonyl-benzaldehyde, yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester of melting point 90°-91° C. This ester is reduced with lithium aluminum hydride in ether/tetrahydrofuran to give p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol of melting point 123°-124° C. (from methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]3=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]3=[S:32])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=O
Solvent: Cc1ccccc1
Product: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=S
Yield: 124.9 %

Procedure:
Reaction of 146i (0.13 g, 0.45 mmol) and Lawesson's reagent (0.11 g, 0.27 mmol) in toluene according to method described for synthesis of 147a afforded 104 mg of 147i (76%) as yellow solid with greenish tinge. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.39 (m, 5H), 6.67 (dd, J=7.8, 1.1 Hz, 1H), 6.58 (dd, J=73, 6.7 Hz, 1H), 5.95 (s, 2H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.29, 159.15, 150.11, 147.43, 137.67, 136.17, 131.78, 128.58, 127.28, 121.35, 111.72, 109.67, 58.54, 56.66. HRMS (EI) calcd for C18H16N2OS [M]+ 308.0983. found 308.0975.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C#N)cc1
Yield: 87.3 %

Procedure:
A suspension of [4-(4-cyanophenyl)but-3-ynyl]carbamic acid tert-butyl ester 56 (5.2 g, 19.2 mmol) and 10% palladium on carbon (2.5 g, wet) in ethanol/THE (30 mL, 1:1) was stirred overnight under 1 atmosphere of hydrogen. After purging with nitrogen, the reaction mixture was suction filtered through a pad of Celite. The solvent was removed from the filtrate by evaporation. The residue was chromatographed on silica gel, eluting with methylene chloride/ethyl acetate (30:1), to afford the pure product 57 (4.6 g, 87%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.51 (m, 2H), 1.65 (m, 2H), 2.69 (t, 2H), 3.14 (m, 2H), 4.52 (br s, 1H), 7.27 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([NH:13][C:14](=[O:35])[C:15](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[CH2:16][CH2:17][CH2:18]Cl)([CH3:12])[CH3:11].O.C(OCC)(=O)C>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:13]1[CH2:18][CH2:17][CH2:16][C:15](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[C:14]1=[O:35])([CH3:12])[CH3:11]
Reactant: COc1cc(C=C(CCCCl)C(=O)NC(C)(C)c2ccccc2F)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=C2CCCN(C(C)(C)c3ccccc3F)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
IPEA (0.5 mL), EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(2-fluorophenyl)-1-methylethylamine (102 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 70 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.[Fe]>[Br:17][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1O
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(Br)c1O
Yield: 78.2 %

Procedure:
To a stirred suspension of isovanillin (10 g, 66 mmol), powdered anhydrous sodium acetate (10.82 g, 0.132 mol) and iron powder (0.3 g, 5.4 mmol) in glacial acetic acid (60 mL) under argon, was added drop-wise over 15 min a solution of Br2 (3.7 mL, 0.0726 mol) in acetic acid (12.5 mL). The reaction temperature rose during the course of addition, and the mixture became viscous. After all the starting material was consumed, as determined by TLC, the mixture was poured onto ice cold water, and the resulting precipitate filtered under vacuum. The precipitate was washed several times with cold water and air-dried. Crystallization from boiling ethanol gave 8 (11.93 g, 79% yield) as a gray powder. Rf=0.10 (1:5 EtOAc/hexanes). M.p. 196-200° C. IR (thin film) 3215, 1662, 1588, 1561, 1491, 1273 cm−1. 1H NMR (300 MHz, CDCl3) δ 10.27 (1H, s), 7.59 (1H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz), 6.02 (1H, bs), 4.00 (3H, s). 13C NMR (75 MHz, CDCl3) δ 56.58, 109.24, 112.84, 113.84, 122.74, 143.25, 151.65, 190.87. HRMS calcd. for C8H8O3Br (MH+) 230.9657. Found 230.9652.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:22][CH3:23])=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)[CH:7]=1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Cl)cc(Br)c1
Product: CCc1ccc(-c2ccc(-c3cc(Cl)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-chloro-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 36 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.