Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:23]([O:22][C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[NH4+].[C:14]([NH:17][CH2:18][C:19]1[N:24]=[C:23]([C:25]2[N:26]=[C:27]([NH2:30])[S:28][CH:29]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH3:15]>CC(C)=O>[C:14]([NH:17][CH2:18][C:19]1[N:24]=[C:23]([C:25]2[N:26]=[C:27]([NH:30][C:11]([NH:12][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:10])[S:28][CH:29]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)n1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1

Procedure:
Benzoyl chloride (15.7 ml) was dropped to a refluxing solution of ammonium thiocyanate (11.3 g) in acetone (640 ml) and the mixture was refluxed for 20 minutes. 4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole (32.0 g) was added portionwise to the refluxing mixture. After the mixture was refluxed for 3 hours, the solvent was evaporated in vacuo and the residue was mixed with ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and resulting precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-benzoylthioureido)thiazole (15.11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[C:11]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)cc(S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)O)cc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2′,4′-difluoro-5-(methylsulfonyl)biphenyl-3-carboxylate (77 mg, 0.21 mmol) in dichloromethane (1.05 mL) was added trifluoroacetic acid (1.05 mL). The mixture was stirred at ambient temperature for 30 min. The mixture was concentrated to dryness to give the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(Cl)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 79.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0344 g, 0.058 mmol) and LiOH (0.014 g, 0.580 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0258 g, 0.046 mmol, 79% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.38-7.44 (m, 4H), 7.15-7.20 (m, 1H), 7.01-7.10 (m, 3H), 5.99 (br. s., 1H), 5.08-5.16 (m, 2H), 3.57 (br. s., 1H), 2.90 (br. s., 1H), 2.64 (s, 3H), 2.24-2.32 (m, 1H), 2.22 (s, 3H), 1.97-2.13 (m, 1H), 1.25 (s, 9H), 0.88 (br.s., 3H), 0.64 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=565.3.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:29][CH3:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]4[C:18]=3[C:13](=[CH:14][CH:15]=[CH:16]4)[C:12]2=[O:28])=[CH:7][CH:6]=1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>C(#N)C>[Br-:1].[CH2:29]([N:4]([CH2:3][CH2:2][N+:34]1[CH:35]=[CH:36][N:32]([CH3:31])[CH:33]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]4[C:18]=3[C:13](=[CH:14][CH:15]=[CH:16]4)[C:12]2=[O:28])=[CH:7][CH:6]=1)[CH3:30]
Reactant: CCN(CCBr)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Reactant: Cn1ccnc1
Solvent: CC#N
Product: CCN(CC[n+]1ccn(C)c1)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Product: [Br-]
Reaction time: 2 h

Procedure:
0.5 g (1.07 mmol) of 2-{4-[(2-bromoethyl)(ethyl)amino]phenyl}-6-nitro-1H-benzo[de]isoquinolin-1,3-(2H)-dione was dissolved in 40 mL of acetonitrile. After the addition of 0.44 g (5.35 mmol) of N-methylimidazole, the mixture was stirred for 2 hours at reflux. Following removal of the solvent under vacuum, the precipitate was filtered off, washed with ethyl acetate and dried. Yield: 0.32 g (54% of the theoretical), red-brown powder. UV/Vis (DMSO): λmax: 409, 520 nm
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])C.[C:10](O)(=[O:12])C>>[C:1]([OH:3])(=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:10]=[O:12]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)O
Product: C=O
Product: O=C(O)c1ccccc1

Procedure:
Khandual et al., J. Indian Chem. Soc., 49, 557-560 (Eng.) (1972) as abstracted in C.A. (1972), 77, 125628g, show the oxidation of acetophenone in 95% acetic acid by manganic acetate to form benzoic acid, and formaldehyde. The oxidation of acetophenone containing ring substituents, e.g., methoxy, is also taught.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:10])([F:9])[C:6]([OH:8])=[O:7]>O>[O-:8][C:6]([C:5]([F:10])([F:9])[F:4])=[O:7].[NH3+:2][NH2:3]
Reactant: NN
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: N[NH3+]
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (4.41 ml, 90.9 mmol) was added via syringe to a 250-ml round-bottom flask containing 50 ml of distilled water with stirring at room temperature. Trifluoroacetic acid (7.0 ml, 90.9 mmol) was added via syringe and the reaction was stirred at room temperature overnight. The water was removed in vacuo with heating to 80° C., yielding product as a colorless liquid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-methylimidazole
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=1/[CH:6]=[N:7]/[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=1[CH:6]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][NH:7]1)[CH3:2]
Reactant: CCOC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SCC
Reaction time: 3 h

Procedure:
To 35B (23.4 mmol) in CH2Cl2 (200 mL) at −15° C. was added Et3N (5.7 mL, 41 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 41 mL, 41 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (200 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet Celite®, extracted with CH2Cl2 (3×60 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio, LC-MS 325 (M+H). To the above ethyl 2-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate in THF (100 mL) was added Et3N (3.3 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 24 mL, 24 mmol). The mixture was stirred at rt for 3.0 h before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was first triturated with EtOAc, the precipitate was collected by filtration and washed with EtOAc to give the trans 35C (1.7 g). The filtrate was concentrated and further purified by flash silica gel column chromatography using gradient EtOAc in hexane to give predominantly cis isomer 35D (1H NMR indicated presence of 30% trans isomer). To this cis isomer was added mixture of EtOAc/hexane (1:3), the precipitate was collected and washed with the same mixture of EtOAc/hexanes (1:3) to give a second crop of the trans 35C (0.8 g, total 2.5 g, 25% yield). The filtrate was concentrated to give enriched cis isomer 35D (3.0 g, >92% purity, 30% yield). 35C: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 1.20 and 1.23 (m, 12H) 1.33 (t, J=7.42 Hz, 3H) 2.08-2.19 (m, 2H) 2.90 (br s, 1H) 3.15 (q, J=7.15 Hz, 2H) 3.48-3.58 (m, 1H) 3.70 (m, 1H) 4.10-4.19 (m, 2H) 5.31 (br s, 1H) 7.58 (d, J=8.79 Hz, 1H) 7.84 (s, 1H) 8.02-8.09 (m, 1H). LC-MS 425 (M+H). 35D: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 0.86 (t, J=6.87 Hz, 3H) 1.18 (s, 9H) 1.34 (t, J=7.15 Hz, 3H) 2.12-2.22 (m, 2H) 3.09-3.17 (m, 2H) 3.56-3.67 (m, 3H) 3.69-3.83 (m, 2H) 5.43 (d, J=8.79 Hz, 1H) 7.50-7.58 (m, 1H) 7.81 (s, 1H) 8.03 (d, J=8.79 Hz, 1H); LC-MS 425 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]3[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:23]CCC.C[Si](C)(C)[O:29][C@@H:30]1[C@@H:35]([O:36][Si](C)(C)C)[C@H:34]([O:41][Si](C)(C)C)[C@@H:33]([CH2:46][O:47][Si](C)(C)C)[O:32][C:31]1=[O:52].CS(O)(=O)=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2([O:52][CH3:23])[C@H:30]([OH:29])[C@@H:35]([OH:36])[C@H:34]([OH:41])[C@@H:33]([CH2:46][OH:47])[O:32]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]2[CH2:21][CH2:20]2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: Clc1ccc(Br)cc1Cc1ccc(CCOC2CC2)cc1
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)c(Cc3ccc(CCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethyl)benzyl)benzene (105 mg, 0.29 mmol) in anhydrous toluene/THF (1.2 mL, v/v=2:1) was added dropwise n-BuLi (2.5 M in hexane, 0.14 mL) at −65° C., and the mixture was stirred for 30 min at −65° C. Then a −65° C. solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (148 mg, 0.32 mmol) in toluene (1.2 mL) was added dropwise over 15 min. The mixture was stirred at −65° C. for 3 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.04 mL, 0.60 mmol) in methanol (1 mL), and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated bicarbonate, then with water, and then with brine, and dried over sodium sulfate. Removal of the volatiles afforded a residue (134 mg), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11](OC(C)=O)=[CH:12][C:7]=2[O:6][C:4](=[O:5])[CH:3]=1.CC1C2C=CC([O:29][CH:30]3[O:35][CH:34]([CH2:36][OH:37])[CH:33]([OH:38])[CH:32]([OH:39])[CH:31]3[NH:40][C:41]([CH3:43])=[O:42])=CC=2OC(=O)C=1>>[CH3:1][C:2]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:4](=[O:5])[CH:3]=1.[CH3:43][C:41]([NH:40][C@H:31]1[CH:30]([OH:29])[O:35][C@@H:34]2[CH2:36][O:37][CH:2]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=3)[O:38][C@H:33]2[C@@H:32]1[OH:39])=[O:42]
Reactant: CC(=O)NC1C(Oc2ccc3c(C)cc(=O)oc3c2)OC(CO)C(O)C1O
Reactant: CC(=O)Oc1ccc2c(C)cc(=O)oc2c1
Product: CC(=O)N[C@H]1C(O)O[C@@H]2COC(c3ccccc3)O[C@H]2[C@@H]1O
Product: Cc1cc(=O)oc2ccccc12

Procedure:
4-methylumbelliferyl acetate; 4-methylumbelliferyl-N-acetyl-β-D-galactosaminide;
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]([NH:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:14])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[NH2:18][CH2:17][CH2:16][NH:15][C:13]([C:9]1[N:10]=[CH:11][S:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)=[O:14]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1cccc(I)c1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1ncsc1-c1cccc(I)c1
Yield: 88 %

Procedure:
6.3 g (13.3 mmol) of t-butyl [2-[5-(3-iodophenyl)-4-thiazolecarboxamido]ethyl]carbamate were dissolved in 70 ml of methylene chloride, treated with 5.1 ml of trifluoroacetic acid and stirred under reflux for 2 hours. Subsequently, the mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of methanol and treated with 5.2 ml of 2.7N ethanolic hydrochloric acid, whereby 4.8 g (88%) of N-(2-aminoethyl)-5-(3-iodophenyl)-4-thiazolecarboxamide hydrochloride were obtained as white crystals, melting point 272°-273°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH:15]1([S:12]([C:10]2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:11]=2)(=[O:14])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(S(=O)(=O)C2CCCC2)c1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(=O)(=O)C2CCCC2)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-(cyclopentylsulfonyl)benzoate (0.50 g, 1.44 mmol), p-tolylboronic acid (0.44 g, 3.25 mmol), toluene (7 mL), and a solution of cesium carbonate (1.06 g, 3.26 mmol) in water (0.3 mL). The vial was degassed and purged with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added. The reaction mixture was subjected to microwave irradiation at 100° C. for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash column (0-25% EtOAc/hexane) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(O)cc2)cc1
Yield: 73.5 %

Procedure:
A mixture of α-methyl-4'-(hydroxy)[1,1'-biphenyl]-4-acetic acid (22.0 g, 90.8 mmol) in ethanol (500 mL) and concentrated sulfuric acid (5.0 mL) is refluxed for 30 hours. The solution is concentrated under reduced pressure, is diluted with water (300 mL) and is extracted with ethyl acetate (3×300 mL). The combined ethyl acetate extract is washed with water (400 mL) and brine (400 mL), dried over MgSO4 and is concentrated under reduced pressure to give 20 g of crude product. Purification of this material by column chromatography (25% ethyl acetate in hexane) followed by crystallization from ethyl acetate and hexane gives 18.0 g (73.5%) of crystalline product, m.p. 124°-125° C., MS(CI+ m/z): 271[M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]>C1(C)C=CC=CC=1.[OH-].[Na+]>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
50.0 g of p-toluenesulfonyl chloride was added to 100 ml of 90° C. toluene with stirring. The p-toluenesulfonyl chloride solution in toluene was slowly added to 25.0 g of L-alanine dissolved in 500 ml of 1N NaOH cooled to 5° C. and stirred for 24 hours. The resulting aqueous layer is separated and cooled to below 5° C. and with the addition of concentrated hydrochloric acid, pH was adjusted to 1.5. After standing in the refrigerator for 3 to 4 hours, the white solid crystals, so formed, were filtered, twice washed with water, and dried.
Reaction SMILES: [SH:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][O:14][C:15](=[O:22])[N:16]=[C:17](SC)SC>C(O)C>[CH3:13][O:14][C:15](=[O:22])[NH:16][C:17]1[S:1][C:2]2[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: CCCOc1ccc(N)c(S)c1
Reactant: COC(=O)N=C(SC)SC
Solvent: CCO
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Reaction time: 12 h

Procedure:
In a round bottom 1 liter flask equipped with a reflux condenser, a magnetic stirrer and a heating mantle is placed 45.75 g. of 2-mercapto-4-propoxyaniline; 48.25 g. of methyl-N-[di(methylthio)-methylene]carbamate, and 250 ml absolute ethanol. This mixture is heated to boiling under an inert atmosphere of nitrogen for 12 hrs. It is then chilled and the white crystalline solid which is formed is isolated by filtration, washed with cold ethanol and dried. m.p. 178°-180° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[NH2-].[Na+].[OH:26][C:27]1[CH:44]=[CH:43][C:42]2[C@:41]3([CH:45]=O)[C@H:32]([C@H:33]4[C@@:37]([CH2:39][CH2:40]3)([CH3:38])[CH2:36][C@H:35]([OH:47])[CH2:34]4)[CH2:31][CH2:30][C:29]=2[CH:28]=1.CS(C)=O.O>C(OCC)(=O)C>[CH:45]([C@:41]12[CH2:40][CH2:39][C@@:37]3([CH3:38])[C@@H:33]([CH2:34][C@@H:35]([OH:47])[CH2:36]3)[C@@H:32]1[CH2:31][CH2:30][C:29]1[CH:28]=[C:27]([OH:26])[CH:44]=[CH:43][C:42]2=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12

Procedure:
8.68 g (20 mmol) of propyltriphenyl-phosphonium bromide+sodium amide (1 g contains 2.3 mmol of propyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 ml of DMSO are introduced into a reaction flask that was rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at 60° C. After the reaction is completed, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing of the organic phase with water, and concentration by evaporation until a dry state is reached.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH3:16]>C1COCC1>[Br-:1].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-n2ccnc2)cc1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc(Br)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 4.48 mmol (1.00 g) 1-(4-bromophenyl)imidazole and 5.40 mmol (0.660 g, 0.49 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 20 h to 90° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:34][C:35]([F:51])([F:50])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45](C=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[B-]C#N.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:45]3[CH:44]=[CH:43][C:42]([C:39]4[CH:40]=[CH:41][C:36]([C:35]([F:34])([F:50])[F:51])=[CH:37][CH:38]=4)=[CH:47][CH:46]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CN2CCN(Cc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.7 g, 4.6 mmol), trifluoroacetic acid (10 ml) and methylene chloride (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). To the solution, 4′-trifluoromethylbiphenyl-4-carboaldehyde (2.3 g, 9.19 mmol), sodium cyanotrihydroborate (580 mg, 9.23 mmol) and acetic acid (0.55 ml, 9.62 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-methyl-6-nitro-2-[4-(4′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (1.47 g, yield 63%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[OH:8][C:7]1[C:2]2[NH:1][C:10](=[O:11])[O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(O)cccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(O)cccc2o1

Procedure:
A mixture of 2-amino-benzene-1,3-diol (K-68, 2.03 g, 16.2 mmole) and 1,1′-carbonyldiimidazole (2.63 g, 16.2 mmole) in THF (200 ml) was refluxed over night. After removal of THF under vacuum, residue was dissolved in ethyl acetate and washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, solid was washed with ether to give 1.9 g of compound K-72. 1H-NMR (500 MHz, DMSO-d6).