Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH:10]([N:6]2[C:5]3[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH3:11])[CH2:13]1
Reactant: [H][H]
Reactant: CC(c1cccnc1)n1c(=O)[nH]c2cc(Cl)ccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C1CCCNC1)n1c(=O)[nH]c2ccccc21
Yield: 100 %

Procedure:
A mixture of 24 parts of 5-chloro-1,3-dihydro-1-[1-(3-pyridinyl)ethyl]-2H-benzimidazol-2-one, 10 parts of sodium acetate and 400 parts of acetic acid is hydrogenated at normal pressure and at a temperature of 60° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with concentrated ammonium hydroxide. The product is extracted three times with 300 parts of trichloromethane. The combined extracts are dried, filtered and evaporated, yielding 22 parts (100%) of 1,3-dihydro-1-[1-(3-piperidinyl)ethyl]-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: FC1[CH:3]=[C:4](C=CC=1F)[C:5](O)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23](C(C3C=CC=CC=3)=O)=[CH:22][CH:21]=2)=[N:17][CH:18]=1>>[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25]=2[CH2:3][CH2:4][C:5]3=[O:6])=[N:17][CH:18]=1
Reactant: Nc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of {(4-[(5-amino-2-pyridinyl)oxy]phenyl}(phenyl)methanone obtained in Reference Example 25 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([CH:20](O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:30])=[CH:11][CH:10]=1.CO>C(O)(C(F)(F)F)=O>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:18]1[CH:17]=[CH:16][C:15](=[O:30])[N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:32][CH:31]=2)[CH:19]=1
Reactant: COc1cccc(C(O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Cc2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
According to Scheme 7 Method D: Triethylsilane (3 eq, 0.84 mmol, 0.10 g) was added to a solution of 1-(4-chlorobenzyl)-5-(hydroxy(3-methoxyphenyl)methyl)pyridin-2(1H)-one (1 eq, 0.28 mmol, 0.10 g, Example 41) in TFA (2 mL). The mixture was stirred 1 hour at room temperature. Upon completion, MeOH was added and the solution was evaporated. The crude residue was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic layers were successively washed with brine, dried over MgSO4 and concentrated under vacuum to afford the crude product. Purification by flash chromatography (AIT Flashsmart prepacked column 10 g SiO2) (CH2Cl2/AcOEt 95/5 to 90/10) of the crude product afford the title compound 5-(3-methoxybenzyl)-1-(4-chlorobenzyl)pyridin-2(1H)-one (0.20 mmol, 0.07 g, 71%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Br:10])[NH2:6].[C:11](Cl)(Cl)=[O:12].Cl>ClC1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([N:6]=[C:11]=[O:12])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(Br)c(Cl)c1
Yield: 113.2 %

Procedure:
600 g of 3-chlor-4-bromaniline hydrochloride were suspended in 2500 ml chlorobenzene and the entire mixture was heated to 150°C to 160°C with vigorous stirring. About 1.25 kg of phosgene was introduced at this temperature; after about 10 to 16 hours all the hydrochloride had disappeared. The solvent was distilled off and the residue was rectified in vacuo. In this way 650 g of 3-chloro-4-bromo-phenylisocyanate, boiling at 122°C to 123°C at 12 mm Hg, were obtained.
Reaction SMILES: [C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[O:14]CC(C)(C)N=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH2:21].[Na+].[Cl-]>O1CCOCC1>[C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([OH:14])=[O:21])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: CC1(C)COC(c2ccsc2C(=O)c2cccs2)=N1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccsc1C(=O)c1cccs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2.8 g of 2-(2-thenoyl)-3-(4,4-dimethyl-2-oxazoline-2-yl)thiophene was added to a solution of 30 ml of concentrated hydrochloric acid, 20 ml of water and 20 ml of dioxane, and the solution was stirred at 100° C. for 8 hours. After cooling the solution, an aqueous NaCl solution was added thereto. The resultant solution was extracted with chloroform and dried. After the solvent was distilled off, the residue was purified by silica gel chromatography to obtain 0.70 g of 2-(2-thenoyl)-3-thiophene carboxylic acid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12.C(N(CC)CC)C.NC(N)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>CC(C)=O>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12)=[O:44]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g. of p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 30 ml. of acetone containing 364 mg. (0.5 ml., 3.6 mmole) of triethylamine was added 962 mg. of urea. With stirring at room temperature, a solution of 730 mg. (4.4 mmole) of 2-thiophene acetyl chloride in 20 ml. of acetone was added dropwise to the mixture. After 2.5 hours the reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and the solution was washed successively with water, a 5% solution of sodium bicarbonate, 5% hydrochloric acid, and a saturated solution of sodium chloride. The washed solution was dried and then was concentrated by evaporation in vacuo to yield 1.2 g. of the reaction product as a crystalline residue. The product was recrystallized from ethyl acetate to yield pure p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3- cephem-4-carboxylate having the following spectral properties.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:13])[C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6](N)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>CN(C=O)C.O>[F:29][C:28]([F:30])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:1][N:2]2[C:6](=[O:7])[C:5]3[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:13])=[CH:23][CH:24]=1
Reactant: NC(=O)c1ccccc1C(=O)NO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirring solution of N-hydroxy phthalamide (5.25 g, 32.3 mmol) in DMF (30 mL) was added cesium carbonate (15.80 g, 48.5 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (5 ml, 32.3 mmol) at RT. Reaction mixture was stirred for 3 h. and then diluted with water. Precipitated product was filtered and dried to get titled compound in 87% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:14])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[C:2]1=2.[OH-].[Na+].[CH2:17]([CH:23]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C.O.[Zn]>[CH2:17]([CH:23]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][O:14][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:13][CH2:24][CH:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC(CCCCCC)COS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCCCCCCCC(CCCCCC)COc1c2ccsc2c(OCC(CCCCCC)CCCCCCCC)c2ccsc12
Temperature: 25 °C

Procedure:
Benzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.0 g, 4.54 mmol) and Zn powder (0.659 g, 10.1 mmol) were suspended in ethanol (10 mL). A solution of NaOH (3 g) in water (15 mL) was added. The resulting mixture was heated to reflux for 1 hour, after which 2-hexyldecyl(4-methylbenzenesulfonate) (3.86 g, 9.73 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and water (50 mL) was added. The reaction was extracted with ether, followed by separation and drying of the organic layer over MgSO4. Solvent was removed and the residue was purified by chromatography (10% dichloromethane in hexanes as eluent). The yield of the 4,8-bis[(2-hexyldecyl)oxy]-benzo[1,2-b:4,5-b′]dithiophene was 0.80 g (26%). 1H NMR (CDCl3, 500 MHz) δ=7.47 (d, J=2.75, 2H), 7.36 (d, J=2.75, 2H), 4.16 (m, 4H), 1.86 (m, 2H), 1.38-1.65 (m, 48H), 0.86 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=O>>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[N:1]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: Nc1cccc(C(=O)O)c1
Product: Nc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (674 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 84 mg (8%). 1H NMR (CDCl3) δ 7.97(bs, 1H), 7.70–7.57(m, 5H), 7.49(t, 1H), 7.45–7.35(m, 2H), 6.96(d, J=7.9 Hz, 1H). MS 287 m/z (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=O)C.[C:29](OCC)(=[O:31])[CH3:30]>>[C:29]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:1])(=[O:31])[CH3:30]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(C)=O)c2ccc(Cl)cc21
Product: CC(=O)N(C)c1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared from 3-acetylamino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (Example 31, step 1) according to the procedure described in Example 146. m.p.: 202-203° C. (ethyl acetate)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NC(=O)c1cc(Br)c(Br)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
10 g (0.034 mol) of 4,5-dibromo-thiophene-2-carbonyl chloride in 100 ml of toluene are treated dropwise at room temperature with 5.0 g (0.068 mol) of tert-butyl-amine in 20 ml of toluene. The reaction mixture is then stirred at 50° C. for one hour, cooled to room temperature and treated with water. The organic phase is separated off, rewashed with water and concentrated under reduced pressure. After treating the residue with hexane, the crystalline residue which is deposited is filtered off and dried at 50° C. under reduced pressure. 4.8 g (41.4% of theory) of 4,5-dibromo-thiophene-2-carboxylic acid t-butyl-amide of melting point 190° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[CH2:18]([S:25][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1cncc(SCc2ccccc2)c1
Yield: 25.7 %

Procedure:
In a similar fashion using route 38 general procedure 92, 3-bromo-5-(trifluoromethyl)pyridine (400 mg, 1.76 mmol), K2CO3 (366 mg, 2.65 mmol), benzylmercaptan (330 mg, 2.65 mmol) and DMSO (3.2 ml) at 150° C. for 4 h in sealed tube gave the title compound (122 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (99:1) as the eluent.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:40])[C:29]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:30]=3[N:31]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:40])[C:29]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
H2O2 (70%, 0.36 mL, ca. 6.0 mmol) was added dropwise to a stirred solution of TFAA (0.96 mL, 6.0 mmol) in DCM (5 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then added to a stirred solution of 1-oxide 179 (204 mg, 0.60 mmol) and TFA (0.24 mL, 3.0 mmol) in DCM (5 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1,4-dioxide 180 (28 mg, 13%) as a red solid which was converted to the hydrochloride salt: mp (MeOH/DCM) 182-185° C.; 1H NMR [(CD3)2SO] δ 10.29 (s, 1H, HCl), 8.35 (br s, 1H, NH), 7.95 (s, 1H, H-10), 7.87 (s, 1H, H-5), 3.92-4.01 (m, 2H, CH2O), 3.37 (m, 4H, CH2N, CH2O), 2.88-3.22 (m, 8H, 2×CH2N, H-6, H-9), 2.53 (t, J=5.6 Hz, 2H, CH2N), 2.00-2.09 (m, 2H, CH2N), 1.74-1.83 (m, 4H, H-7, H-8); 13C NMR [(CD3)2SO] δ 149.2, 147.8, 138.0, 136.1, 128.5, 119.4, 115.0, 63.0 (2), 53.5, 50.9 (2), 37.9, 29.4, 28.5, 22.7, 21.7, 21.6. Anal. calcd for C18H25N5O3.2HCl.2H2O: C, 46.2; H, 6.7; N, 15.0. Found: C, 46.3; H, 6.4; N, 15.0%.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])[CH2:3]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[N:45]1C(=O)CC[C:46]1=O>C1COCC1>[CH3:46][NH:45][CH2:3][C:2]([CH3:1])=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene-1-ol (3.2 g, 10 mmol) and triphenylphosphine (2.88 g, 11 mmol) in 20 ml of THF is stirred in an ice bath and 1.78 g (10 mmol) of N-bromosuccinimide is added in small portions over a period of one hour. After addition, the cooling bath is removed and the temperature of the reaction mixture is allowed to rise slowly to room temperature. The mixture is concentrated in vacuo and then diluted with a mixture of ether/petroleum ether. After sitting in refrigerator for several hours, white crystals of triphenylphosphine oxide occur, which is collected by filtration. The filtrate is concentrated and dissolved in 10 ml of dry DMF. To this solution is added 2 g of triethylamine and 0.68 g of methylamine hydrochloride. The resulting mixture is stirred at room temperature for 18 hours and poured into 500 ml of ice-water. The crude product is extracted into ethylacetate and washed with water. After drying over magnesium sulfate, the solvent is removed in vacuo to give the crude product as an oil. This substance is purified on HPLC (2% ethyl acetate in hexane, silica gel column) to give 1-methylamino-2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41](O)=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([O:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=2)=[O:42])[CH:29]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]=1[OH:34])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(CCC(=O)NCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1cc(CCC(=O)NCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 32 g (0.1 mole) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-hydroxyethyl)propionamide, 27 g (0.1 mole) of 3(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 1 g Tyzor TBT catalyst and 100 ml xylene was refluxed at 150° until evolution of water ceased. In the course of four hours, two ml water was collected in the Stark & Dean trap. The xylene was removed by vacuum stripping. The title compound (54 g) was recrystallized from a toluene/hexane mixture. It melted at 151°-154° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([O:27]CC)=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37].[OH-].[Na+].Cl>O1CCCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(O)ccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(O)cc12
Temperature: 70 °C

Procedure:
To a solution of EXAMPLE 149B (22 mg) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 10% NaOH 0.3 ml. The reaction was heated at 70° C. for 24 hours, cooled, acidified with diluted aqueous HCl and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.83 (s, 1H), 8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45-7.55 (m, 5H), 7.34-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7.17 (td, J=7.36, 1.23 Hz, 1H), 7.04 (dd, J=7.52, 1.38 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.75 (dd, J=8.90, 2.45 Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.84 (t, J=7.52 Hz, 2H), 4.15 (t, J=5.68 Hz, 2H), 2.63-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J=6.75 Hz, 3H), 0.96 (d, J=7.06 Hz, 3H).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH:8]=[CH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: Oc1c(-c2ccccc2)sc2c3sccc3cc[n+]12
Reactant: C#CC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Reaction time: 1 h

Procedure:
(ca) 22.9 g of 3-hydroxy-2-phenylthiazolo[3,2-a]thieno-[2,3-c]pyridinium hydroxide (internal salt) and 13.6 ml of methyl propiolate were heated together under argon in 1000 ml of toluene until the starting material was completely taken up. The solvent was removed in vacuo and the residue was stirred in 500 ml of ether/methanol (9:1) for 1 hour. The yellow crystals obtained were removed by filtration under suction. There was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 153°-154° (dec.). An additional portion of product of m.p. 151°-152° (dec.) can be obtained by chromatography of the filtrate on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][O:22]C)=[N:17][O:16][N:15]=2)[O:5][CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][OH:22])=[N:17][O:16][N:15]=2)[O:5][CH:6]=1
Reactant: COCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1onc(-c2nonc2NCCO)n1Cc1cc(Br)co1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
In a round bottom flask under nitrogen atmosphere, 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (8.2 g, 21 mmol) was stirred in dichloromethane (68 mL). The temperature was brought to −78° C. and a solution of 1.0 M boron tribromide in dichloromethane (43 mL, 43 mmol) was added dropwise over 45 minutes. The reaction stirred at −78° C. for 45 minutes and continued to stir at 0° C. for an additional 30 minutes. While remaining at 0° C., a saturated solution of sodium bicarbonate in water (120 mL) was added dropwise over 25 minutes. After warming to room temperature, the organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (7.7 g, 97%) along with a small amount of 3-{4-[(2-bromoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one. LCMS calculated for C11H11BrN5O5 (M+H)+: m/z=371.7, 374.0. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1 H), 6.68 (s, 1 H), 6.31 (t, J=5.8 Hz, 1 H), 5.08 (s, 2 H), 4.85 (br s, 1 H), 3.56 (m, 2 H), 3.30 (q, J=5.6 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:34]=2)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1coc(-c2cccc(OCc3ccccc3)c2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(COc2cccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)c2)cc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(3-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(3-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 112-113° C.