Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][C:16]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:8]([NH:15][C:16]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:10])[CH3:9]
Reactant: NC1(CC(=O)O)CCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1(CC(=O)O)CCCC1

Procedure:
Triethylamine (1.2 mL, 8.4 mmol), acetic anhydride (0.8 mL, 8.4 mL) and DMAP (10 mg, 0.09 mmol) are subsequentially added to a suspension of (1-amino-cyclopentyl)-acetic acid (1.00 g, 5.6 mmol) in THF (30 mL). After heating at 60° C. for 2 h AcOEt is added and the organic phase is washed with 1N HCl. Drying (Na2SO4), filtration and evaporation of the solvent yields the desired product. MS (LC-MS): [M+H]+=186.1. tR (HPLC, Waters Symmetry C18 column, 80-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.53 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:18](=[O:19])[CH2:17][C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:10][C:9]2=[O:20])[CH:7]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([F:31])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]3[C:18](=[O:19])[CH2:17][C:11]4([CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH2:10][C:9]3=[O:20])[CH:7]=2)=[C:26]([F:31])[CH:25]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)CC2(CCOCC2)CC1=O
Reactant: Oc1ccc(Br)cc1F
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc(Br)cc2F)cc1C1C(=O)CC2(CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-(5-bromo-2-ethylphenyl)-3-oxaspiro[5.5]undecane-8,10-dione (360 mg, 0.99 mmol), 4-bromo-2-fluorophenol (227 mg, 1.19 mmol), cesium carbonate (645 mg, 1.98 mmol), copper(II) trifluoromethanesulfonate (18 mg, 0.05 mmol) and ethyl acetate (50 μl) in toluene (10 ml) is heated under reflux for 19 hours. The mixture is cooled to room temperature, N,N-dimethylformamide (2 ml) and 2M aqueous hydrochloric acid (10 ml) are added, and the mixture is stirred vigorously for 45 minutes. The mixture is extracted with ethyl acetate, and the organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 9-[5-(4-bromo-2-fluorophenoxy)-2-ethylphenyl]-3-oxaspiro[5.5]undecane-8,10-dione.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.[Cl-].[Na+]>CN(C=O)C>[O:9]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:3]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCCCN1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
60% sodium hydride (600 mg, 15.0 mmol) was suspended in DMF (30 mL), 2-piperidone (1.49 g, 15.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of methyl 4-bromomethylbenzoate (2.29 g, 10.0 mmol) in DMF (10 mL) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate:methanol=9:1) to afford methyl 4-[(2-oxopiperidino)methyl]benzoate (2.47 g 100%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([O:22][CH3:23])[CH:15]=1.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=BOB=O
Solvent: CCCCN
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: COc1cc(O)ccc1C=CC(=O)CC(C)=O
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Ethyl acetate (7 mL), 2,4-pentanedione (9.6 mL, 94 mmol) and boron trioxide (5.9 g, 85 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 4-hydroxy-2-methoxybenzaldehyde (2.16 g, 14.2 mmol) and trimethyl orthoformate (1.6 mL, 14 mmol) in 14 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (7.0 mL, 71 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (33 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a pale yellow crystal (1.07 g, 33%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29]C=O)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][OH:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCO)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.), conc. hydrochloric acid (1.8 ml.), methanol (15 ml.) and tetrahydrofuran (15 ml.) was stirred at room temperature for 5 hours. After removing the solvent in vacuo, water was added to the residue and adjusted to pH 4.0 with an aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% isopropyl alcohol. The eluate was concentrated in vacuo and the residue was lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.56 g.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=O)[O:14]C(C)(C)C)([CH3:11])([CH3:10])[CH3:9]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 10 g of 4-hydroxypiperidine in 300 ml of chloroform, 20 g of di-t-butylcarbonate was added under cooling with ice, followed by 2 hours' stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 18 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3].O.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 58 %

Procedure:
A portion of the benzhydrylpiperazine from above (0.36 g, 0.44 mmol) was stirred with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 hr. The solvent was removed and the residue purified by chromatography on silica gel with dichloromethane:ethanol to give 0.180 g (58%) of tert-butyl N-(4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH3:11][O:12][C:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19](C)([CH2:24]O)[NH:20][NH:21]2)=[CH:17][CH:16]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH3:24])=[N:20][NH:21]2)=[CH:17][CH:16]=1)=[O:14]
Reactant: COC(=O)c1ccc2c(c1)NNC2(C)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Yield: 87 %

Procedure:
6-(Methoxycarbonyl)-3-methyl-1H-indazole methanol (50 ml), and concentrated sulfuric acid (0.1 ml) was added. The mixture was heated under reflux for 22 hr. After cooling, a saturated aqueous sodium hydrogencarbonate solution was added and the methanol was distilled away under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (340 mg, 87%) as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[C:12]([C:16]4[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=4)[CH:13]=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH2:34])[CH2:31][O:32][CH3:33]>>[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH:34][C:21]([C:19]1[O:18][N:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH:11]=2)[CH:20]=1)=[O:22])[CH2:31][O:32][CH3:33]
Reactant: O=C(O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1
Reactant: COC[C@H](N)C(=O)OC
Agent: Cl
Product: COC[C@H](NC(=O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1)C(=O)OC
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure as set forth in Example 5, except that 3-[3-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid was used instead of the compound of Example 2 and (S)-2-amino-3-methoxy-propionic acid methyl ester hydrochloride was used instead of (S)-Val-OMe.HCl to yield 68% of the title compound. Mass (ES+): 471 (M++1), 493 (M++Na); IR (KBr): 3319, 2929, 1740, 1670, 1571, 1474; 1H NMR (DMSO-d6) δ: 3.29 (s, 3H), 3.67 (s, 3H), 3.74 (m, 2H), 4.74 (m, 1H), 7.18 (m, 1H), 7.53 (m, 2H), 7.62 (dd, 1H), 7.72 (s, 1H), 7.76 (dd, 1H), 7.95 (m, 1H), 8.32 (s, 1H), 9.39 (d, 1H), 10.70 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:26]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[C:10]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.0 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.61 (dd, J=7.8, 2.9 Hz, 3H), 7.48-7.30 (m, 4H), 7.24-7.10 (m, 5H), 6.73-6.68 (m, 2H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.81 (s, 4H), 2.36 (s, 3H), 1.50 (s, 9H), MS (ES) m/e 562 M+1).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11](O)[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)[S:28](Cl)(=O)=O>CC(C)=O>[CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([SH:28])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
To a solution of 600 mg of (2RS)-2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloroindan-1-one (prepared by the method described in European Patent Publication No. 47011) in 6 ml of dry acetone was added 690 mg of potassium carbonate at a time and the mixture was stirred for twenty minutes. The reaction mixture was cooled to 0° C., 0.23 ml of trifluoromethanesulfonyl chloride was dropped thereto and the mixture was stirred for 10 minutes at the same temperature. The solid was filtered out from the reaction mixture and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride and the solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 860 mg of the title compound as crude product having the following physical data.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)=[CH:29][C:30](=[O:34])[O:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1>[F:41][C:37]1[CH:36]=[C:35]([C:28]2[C:27]3[C:32](=[CH:33][C:24]([CH2:23][N:21]4[CH:22]=[C:18]([C@:11]([OH:10])([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])[N:19]=[N:20]4)=[CH:25][CH:26]=3)[O:31][C:30](=[O:34])[CH:29]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-1-(1-{[4-(3-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (15 mg, 0.025 mmol) in THF (2 mL), lithium hydroxide (0.125 mL of 1M solution, 0.125 mmol) was added. After 45 minutes stirring at room temperature, the reaction was quenched by the addition of 0.150 mL of a 2N HCl solution. The mixture was stirred 3 h at room temp and then heated 2 h at 40° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.21 (s, 1H), 7.7-7.6 (m, 1H), 7.53 (d, 1H), 7.42-7.3 (m, 5H), 6.41 (s, 1H), 5.87 (s, 2H), 5.48 (s, 1H), 2.4-2.3 (m, 1H), 2.1-2.0 (m, 1H), 0.87 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CO)cc1
Temperature: 5 °C

Procedure:
A stirred suspension of 4-formylbenzonitrile (10.0 g; 0.0763 moles) in methanol (100 mL) under nitrogen was cooled to 5° C. Sodium borohydride (1.45 g; 0.0382 moles) was added. After 30 minutes the mixture was added to water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined extracts were washed with aqueous sodium chloride solution (50 mL) and dried over sodium sulfate. Following filtration and removal of solvent under vacuum the product, 4-(hydroxymethyl)benzonitrile, (9.44 g; 93%) was obtained as a white solid. 1H NMR (400 MHz) CDCl3 δ 7.61-7.66 (2H, m), 7.45-7.50 (2H, m), 4.78 (2H, d, J=5.5 Hz), 2.27 (1H, t, J=5.5 Hz).
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:33]([CH2:34][CH2:35][C@:17]12[CH3:18])[C@:30]1([CH2:31][OH:32])[C:25]([CH2:26][C:27](=[O:36])[CH2:28][CH2:29]1)=[CH:24][C@H:23]3[CH3:37].[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:37][C@@H:23]1[CH:24]=[C:25]2[C@:30]([CH2:31][OH:32])([CH2:29][CH2:28][C@@H:27]([OH:36])[CH2:26]2)[C@@H:33]2[C@@H:22]1[C@H:19]1[C@@:17]([CH2:35][CH2:34]2)([CH3:18])[C@@H:16]([OH:15])[CH2:21][CH2:20]1
Reactant: C[C@@H]1C=C2CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: C[C@@H]1C=C2C[C@H](O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An 0.5 M solution of potassium tri-sec-butylborohydride in tetrahydrofuran under nitrogen is cooled to -78° C. in a dry ice-acetone bath. 17β,19-Dihydroxy-7α-methyl-5-androsten-3-one in tetrahydrofuran is slowly added. The reaction mixture is stirred for a period of two hours at this temperature, warmed to 0° C., and stirred for an additional two hours. The reaction mixture is decomposed by the addition of a 3 N sodium hydroxide solution followed by a 30% hydrogen peroxide solution. Solid potassium carbonate is added and the tetrahydrofuran solution decanted. The solid residue is washed with fresh tetrahydrofuran and the combined tetrahydrofuran solutions are dried over anhydrous sodium sulfate, filtered and the filtrate removed by evaporation. The residue is crystallized from acetone to yield 7α-methyl-5-androstene-3α,17β,19-triol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, methyl bromoacetate (1.5 eq), and Cs2CO3 (1.5 eq): MS (ES) m/z 295 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[NH:8][CH:7]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O[Si](C)(C)C(C)(C)C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a solution of Example 400A (1.20 g, 3.59 mmol) in DMF (20 mL) was added t-butyldimethylsilyl chloride (649 mg, 4.3 mmol), imidazole (293 mg, 4.3 mmol) and DMAP (50 mg) at rt. The reaction mixture was stirred at rt for 16 hours. EtOAc (100 mL) was added and the mixture was washed with brine (100 mL) and water (100 mL). The organic phase was concentrated and the residual oil was purified by flash chromatography (10-40% EtOAc in hexane) to give the desire product (1.6 g, 100%). MS (DCI) m/z 466 (M+18)+.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:11]([C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(Nc2ccncc2)c2occc2c1
Temperature: 120 °C
Yield: 58.9 %

Procedure:
A mixture of 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), 4-aminopyridine (0.39 g, 4.15 mmol), Xantphos (0.20 g, 0.36 mmol), Pd2(dba)3 (0.08 g, 0.09 mmol), NaOtBu (0.47 g, 4.84 mmol) in xylene (200 mL) was heated at 120° C. overnight. The reaction mixture was filtered through Celite and a yellow precipitate was formed which was collected by filtration to yield 0.52 g (60%) of the title product. HPLC 96%, RT: 1.344 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 6.91-7.12 (m, 4H) 8.00 (d, J=2.23 Hz, 1H) 8.15-8.24 (m, 2H) 8.37 (d, J=2.23 Hz, 1H). LC-MS 256 (M+H)+.
Reaction SMILES: [CH2:1]=[O:2].CO.[CH2:5]([PH:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C(N(CC)CC)C>[CH2:5]([P:8](=[O:12])([CH2:9][CH2:10][CH3:11])[CH2:1][OH:2])[CH2:6][CH3:7]
Reactant: C=O
Reactant: CCC[PH](=O)CCC
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCP(=O)(CO)CCC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 37% of formaldehyde solution, 16.2 g, was added in small portions over a five minute period to solution of 40 ml of methanol, 21.78 g of di-n-propyl phosphine oxide, (Example 16), and 1.5 ml of triethylamine. The reaction exothermed to 30° C. and was allowed to stir for ten minutes before it was warmed to 70° C. for three hours. The reaction was then allowed to cool to room temperature and stand overnight. The reaction was concentrated, the concentrate dissolved in 70 ml of THF, filtered and reconcentrated. The concentrate was diluted with 60 ml of 1,4-dioxane which was distilled off to yield 19.8 g of the desired phosphine oxide as an oil.