Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7](Br)=[N:6]1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:21])=[N:6]1
Reactant: OB(O)c1ccccc1O
Reactant: COC(=O)Cn1nc(Br)n(Cc2cccc(F)c2)c1=O
Product: COC(=O)Cn1nc(-c2ccccc2O)n(Cc2cccc(F)c2)c1=O

Procedure:
By the method described for Example 147A, starting from 250 mg (0.73 mmol) of the compound from Example 146A and 138 mg of (1.02 mmol) 2-hydroxyphenylboronic acid, 22 mg (8% of theory) of the title compound and 222 mg (85% of theory) of the corresponding acid formed by hydrolysis (see also Example 150A) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:16]3[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c1CCN=C2c1ccc(Br)cc1

Procedure:
Forty-four (44) grams of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane was heated with stirring at 140° C. for 4 hours together with 300 ml of xylene, 100 ml of phosphorus oxychloride and 100 g of phosphorus pentoxide. The reaction mixture was decanted to remove the solvent. The residue was carefully decomposed with ice water, and made weakly alkaline with an aqueous solution of sodium hydroxide. The crystals precipitated were extracted with benzene, and dried, followed by distilling off the solvent. Recrystallization of the residue from hexane afforded 35 g of 1-(4-bromophenyl)-5-methyl-3,4-dihydroisoquinoline as colorless needles having a melting point of 60.0° to 61.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)ethynyl]-2-methylphenyl}-2,2,2-trifluoroacetamide (2.7 g, 8 mmol) in DMF (50 mL) was added N-aminopyridinium iodide (3.6 g, 16 mmol) and K2CO3 (3.3 g, 24 mmol). After 3 h, the reaction was diluted with water and extracted with DCM. The combined organic solutions were dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography. Fractions containing product were concentrated and the solid triturated with DCM and hexanes to give 1.92 g of the desired product (56%). 1H NMR (400 MHz, d6-DMSO) δ 11.07 (s, 1H), 8.89 (d, J=6.8 Hz, 1H), 8.45 (d, J=6.8 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 7.65-7.61 (m, 1H), 7.55 (s, 1H), 7.52-7.49 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.22-7.19 (m, 1H), 7.08 (d, J=5.6 Hz, 1H), 2.27 (s, 3H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:21]=O>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CNCC2c1cccc(Cl)c1
Reactant: C=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1cccc(Cl)c1

Procedure:
The free base isolated from 8.0 g. of rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is taken up in 150 ml. of methanol, 6 ml. of a 35% formaldehyde solution are added and the mixture is shaken until the precipitate formed again completely dissolves. The mixture is thereupon hydrogenated over 6 g. of Raney nickel, filtered and, after acidification with ethanolic hydrogen chloride, crystallized. Recrystallization from methanol-ether gives rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 250°-251°.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[SH:6][CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[C:8](=[O:10])[CH2:7][S:6][C:4]1=[S:5])[CH3:2]
Reactant: O=C(O)CS
Reactant: CCN=C=S
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCN1C(=O)CSC1=S

Procedure:
Ethylisothiocyanate (10 g, 0.115 moles), 7.9 g(0.086 moles) mercaptoacetic acid and 5 mL pyridine in C6H6 was refluxed, cooled and filtered yielding 3-ethylrhodanine, which was used in the next step without any further purification. Reaction of 3-ethylrodanine with piperonal in the presence of sodium acetate was performed in CH3OH under refluxing for 1 h. The yellow precipitate obtained after cooling and filtration, was washed several times with CH3OH on the filter and crystallizated from CH3OH to give 3-ethyl-5-piperilidenerodanine. 1H-NMR(DMSO-d6, 300 MHz):7.72 (s, 1H), 7.1–7.3 (m, 3H), 6.14 (s, 2H), 3.95–4.15 (q, 2H), 1.15–1.20 (t, 3H). 13C-NMR (75.48 MHz): 12.76, 40.28, 103.07, 110.21, 110.47, 120.68, 127.89, 128.07, 134.01, 149.23, 150.74, 167.57, 193.68. (2) 3-Ethyl-5-piperilidene-rodanine (1 g, 3.4 mmoles) was added to a stirred solution of 0.16 g (6.8 mmoles) in 8 mL abs. ethanol and the mixture was refluxed for 30 min. To the solution cooled to room temperature 5 mL H2O were added and the mixture was hydrolized with 10% HCl and extracted with ether. The ether phase was separated, dried (MgSO4) and evaporated to an oil. Since the investigation by TLC of the crude reaction mixture indicated the presence of piperonal, the reaction mixture was dissolved in CH2Cl2 and the obtained solution was washed with 1M NaOH. The aqueous phase was extracted twice with CH2Cl2 and then neutralized with dilute HCl. Free thiol was extracted with ethyl ether. After concentration, the product was purified by column cromatography eluating with hexane/ethyl ether:8/2. Yield 0.4 g (62.4%). 1H-NMR(CDCl3, 300 MHz):7.69 (s, 1H), 7.7.25–7.29 (d, 1H, J 1.46), 7.1–7.18 (m, 1H), 6.85–6.9 (d, 1H, J 8.13), 6.01 (s, 2H), 4.75 (s, 1H), 4.28–4.38 (q, 2H, J 7.12), 1.35–1.42 (t, 3H, J 7.13). 13C-NMR (75.48 MHz): 14.20, 62.5, 101.41, 108.37, 109.43, 121.06, 125.45, 129.20, 134.68, 147.80, 148.05, 165.43.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[H-].[Na+].[CH3:26][O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:40]=3)[CH:35]=2)=[CH:30][CH:29]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:40]=3)[CH:35]=2)[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:9]=2)=[CH:52][CH:53]=1
Reactant: COc1ccc(CNc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Reactant: COc1cccc(-c2cc(C(=O)O)ccc2OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Thionyl chloride (308 μl, 502 mg, 4.22 mmol) was added to 4-methoxy-3-(3-methoxyphenyl)-benzoic acid (365 mg, 1.41 mmol) in anhydrous THF (4.75 mL) at room temperature, and the resulting solution was heated at reflux for 4.5 hours. The solvent was removed and the resulting acid chloride was used without further purification. Sodium hydride (85 mg, 2.12 mmol) was added to 37 (378 mg, 1.02 mmol) in anhydrous THF (7.50 mL). After stirring for two hours at room temperature, a solution of the freshly-prepared acid chloride (1.41 mmol) in anhydrous THF (2.40 mL) was added and the reaction was heated to reflux for 18 hours. The reaction was cooled, partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (50 mL), then extracted with CH2Cl2 (3×100 mL). Combined organic extracts were washed with saturated aqueous NaCl solution (200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 4:1:1 Hexanes:EtOAc:CH2Cl2) to give 38 as a brown-yellow amorphous solid (515 mg, 83%): 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=9.0 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.50-7.45 (m, 3H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.29 (d, J=2.2 Hz, 1H), 7.25 (m, 2H), 7.21 (dd, J=8.9, 2.6 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09 (m, 1H), 7.01 (dd, J=8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (ddd, J=8.2, 2.7, 0.9 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.59-6.56 (m, 2H), 5.16 (s, 2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 159.3, 159.0, 157.6, 157.3, 139.9, 139.1, 136.8, 133.0, 132.4, 130.5, 130.1, 130.1 (2C), 129.6, 129.5, 129.1, 128.9, 128.9 (2C), 128.4, 128.2, 127.9, 127.7 (2C), 127.3, 125.8, 122.1, 120.0, 114.7, 114.0 (2C), 113.2, 110.4, 107.1, 70.3, 55.7, 55.4, 55.2, 53.9; IR (film) νmax 3059, 3032, 2999, 2934, 2835, 1636, 1601, 1506, 1456, 1389, 1248, 1209, 1026, 854, 818, 735, 698 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C40H35NO5, 610.2593; found, 610.2567.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COc1ccc(CCN)cc1
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH3:1][C:2]([CH:3]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[OH:4])=[CH:5][CH2:6][CH3:7]
Reactant: Cl[Mg]C1CCCC1
Reactant: CCC=C(C)C=O
Product: CCC=C(C)C(O)C1CCCC1
Reaction time: 1.5 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 800 ml of 2 M of cyclopentyl magnesium chloride was added and stirred. 139 g of 2-methyl-2-pentenal was added over the next 90 minutes. The reaction mixture was aged for another 90 minutes and the first sample was taken. 25 minutes later the reaction mixture was quenched with water, aged for 30 minutes and the organic layer was separated and washed with 2 one liter portions of water. The NMR spectrum of the Alpha-[1-Methyl-1-Butenyl]-Cyclopentanemetanol is as follows: 1.00 ppm (s, 3H); 1.1-1.2 ppm (s, 1H); 1.4-1.5 ppm (s, 2H); 1.5-1.7 ppm (m, 4H); 1.8 ppm (s, 1H); 2.1 ppm (m, 3H); 3.7 ppm (d, 1H); 5.4 ppm (t, 1H)
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][NH:29][CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][N:29]([CH2:2][CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
533 mg (1.84 mmol) of methyl 4-(2-iodoethyl)benzoate and 97 mg (0.92 mmol) of anhydrous sodium carbonate were added to a solution of 380 mg (0.61 mmol) of rac-ethyl 5-[(2-{5-fluoro-2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 159A) in 5 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 178 mg (0.23 mmol, 37% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].CS(C)=[O:22]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(F)cc1

Procedure:
Bis-(4-fluorophenyl) sulphone (100 g; 0.394 mole), potassium hydroxide solution (91.98 g; 0.787 mole KOH) and dimethyl sulphoxide (400 cm3) were stirred together in a stainless steel vessel under nitrogen at 57° C for 24 hours. Two liquid phases remained throughout the reaction. The reaction mixture was diluted with water and twice extracted with diethyl ether to recover non-phenolic material (9 g). The aqueous phase was then acidified and the phenolic component (86 g; m.p. 150°-154° C) was extracted with more ether. By subliming this product under a diffusion pump at 180° C, followed by recrystallisation from toluene (400 cm3), 4-(4-fluorophenylsulphonyl)phenol (72.5 g) was obtained, m.p. 158°-159° C. The potassium salt was obtained from this phenol as a very pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH:36]=[CH:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:35][CH:36]=[CH:37][CH3:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CC=CCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: CC=CCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.74 g, 1.41 mmol) and 4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.66 g, 1.40 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CCOCC.[I:22]N1C(=O)CCC1=O>C(#N)C>[I:22][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)c1ccc(O)c(I)c1
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a stirring solution of 4-hydroxy-benzoic acid (6.91 g, 50.03 mmol) in dry acetonitrile (250 mL) at −20° C. under an atmosphere of N2 was added HBF4.Et2O (10.50 g, 9.50 mL, 55.00 mmol) dropwise via syringe. The solution was stirred at 0° for 0.5 hours at which time solid N-iodosuccinimide (13.5 g, 60 mmol) was added at one time. The solution was left to stir for 16 hours and then filtered to remove precipitated succinimide. The solution was diluted with water (500 mL) and extracted with ethyl acetate (2×250 mL). The organic portions were combined and washed with 10% sodium bisulfite (250 mL), water (2×250 mL) and saturated aqueous NaCl (250 mL). The solvent was removed in vacuo to yield 8.76 g of crude solid. The crude solid was purified by column chromatography (6:4:0.1 hexane:ethyl acetate:formic acid) to yield 7.54 g (57%) of the desired product as white crystals. 1H NMR (DMSO-d6) δ 12.74 (br s, 1H), 11.18 (s, 1H), 8.20 (s, 8.20, 1H), 7.79 (d, 1H), 6.94 (d, 1H).
Reaction SMILES: OO.[F:3][C:4]([F:19])([F:18])[C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=1B(O)O.S([O-])(O)=[O:21].[Na+]>C1COCC1>[F:3][C:4]([F:19])([F:18])[C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=1[OH:21]
Reactant: O=S([O-])O
Reactant: CCOc1ccc(B(O)O)c(C(F)(F)F)c1F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.2 g (104.4 mmol) of an aqueous 30% hydrogen peroxide was dropped to 13.8 g (52.2 mmol) of the crude 2-trifluoromethyl-3-fluoro-4-ethoxyphenyl boronic acid obtained in the third step dissolved in 100 ml of THF, and further stirred at a room temperature for 2 hours. The solution was poured into 300 ml of an aqueous saturated sodium hydrogen sulfite solution and extracted with 200 ml of ethyl acetate. The organic layer was washed with 300 ml of an aqueous saturated sodium hydrogen sulfite solution, with 300 ml of water, and then with 200 ml an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The residue was purified by distillation and further recrystallized twice from a heptane/ethanol mixed solvent to obtain 5.67 g of pure 2-trifluoromethyl-3-fluoro-4-ethoxyphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][CH:11]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1cccc(NCc2cccnc2)c1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccccc2OC)c1

Procedure:
Using the method of Example 342 using N-(3-(2-methoxyphenoxy)phenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH gave the title compound. Anal Calcd for C21H22N2O4S: C, 63.30; H, 5.56; N, 7.03. Found: C, 63.16; H, 5.51; N, 6.64. MS found 398.9 [M+H]+
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:13][C:7](=[O:12])[CH2:8][C:9]1([CH3:11])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(C)OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 7.14 grams (0.055 moles) ethyl acetoacetate is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent by means of rotary evaporation. 9.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:15][C:9]2=[C:10]([CH3:14])[S:11][C:12]([CH3:13])=[C:8]2[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:14][C:10]1[S:11][C:12]([CH3:13])=[C:8]2[CH2:7][C:6]([NH:16][C:17]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:18])([C:4]([OH:5])=[O:3])[CH2:15][C:9]=12
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2c(C)sc(C)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(C)c2c1CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
The mixture of 1,3-dimethyl-5-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (74) (942 mg, 2.37 mmol) and KOH (3 g, 23 mmol) is dissolved in EtOH (20 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (75) as a pale brown solid (832 mg, 95%).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C(O)(CC(=O)OCC)c1ccccc1
Yield: 97 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.02 g (5 mmol) of trans-ethyl 3-benzoylacrylate in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.42 g of the desired product (yield 97%).