Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21](C(O)=O)[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:8][CH2:7]1.Cl>O1CCOCC1>[F:31][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCN(CC4CC4(F)F)CC3)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: FC1(F)CC1CN1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.3 g of tert-butyl ester of 4-{5-[4-(2,2-difluoro-cyclopropylmethyl)-piperazin-1-yl]-pyridin-2-yl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in 5 mL of dioxane, to which 2.32 ml of 4N HCl in dioxane is added. The reaction mixture is stirred at room temperature in a closed environment for 18 h. Once again, 2.32 mL of 4N HCl in dioxane is added, and the reaction mixture is stirred for a further 18 h at room temperature. 2.32 ml of 4N HCl in dioxane is added once again, and the reaction mixture is stirred for a further 18 h at room temperature. After concentration to dryness, the reaction mixture is diluted with a solution of 50 ml of 1N HCl in water and extracted with 100 ml of diethyl ether. The organic phase is washed again with 50 ml of 1N HCl in water. The aqueous phases are then combined, basified with K2CO3 in powder form to pH 10, and extracted 3 times with 50 ml of dichloromethane. The resultant organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated to dryness. 0.24 g of 1-{5-[4-(2,2-difluoro-cyclopropylmethyl)-piperazin-1-yl]-pyridin-2-yl}-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: C([NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])(C1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]
Reactant: CC(CCC(C)(C)O)NC(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(N)CCC(C)(C)O
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
The obtained 5-benzhydrylamino-2-methylhexan-2-ol (5.20 g) was dissolved in methanol (250 ml), and thereafter, palladium hydroxide (2.00 g) was added to this solution. The mixture was then stirred in an autoclave under a hydrogen pressure of 9 kg/cm for 2.5 hours. The reaction solution was filtrated using a filter medium (Celite), and the filtrate was then concentrated under a reduced pressure. Thereafter, distilled water (50 ml) was added to the residue, and the liquid was then adjusted to be pH 2.0 by addition of 1 M hydrochloric acid. Thereafter, the solution was washed with diethyl ether (100 ml×3). The water layer was adjusted to be pH 12 by addition of an aqueous 6 M sodium hydroxide solution, followed by extraction with chloroform (100 ml×3). The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure to obtain 5-amino-2-methyl-2-hexanol (2.01 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
A solution of 6-bromohexan-1-ol (3.64 g, 0.020 mol) from step 1 in butanone (80 ml) was added at room temperature to a stirred mixture of 4-bromo-4-′-hydroxybiphenyl (5.00 g, 0.020 mol) and potassium carbonate (5.50 g, 0.040 mol) in butanone (70 ml). The reaction mixture was heated under reflux for 48 h. The potassium carbonate was filtered off and the solvent was removed in vacuo, the residue was dissolved in diethyl ether (250 ml) and washed with water (2×150 ml) and dried (MgSO4). The solvent was removed in vacuo and the crude solid was then recrystallised from ethanol to give white crystals.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:16][CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.C[O-].[Na+].[C:31]1([CH3:38])[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.[Cl-].[NH4+]>CN(C=O)C.CO>[C:31]1([CH3:38])[CH:36]=[CH:35][C:34]([S:37][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:18][CH:19]=2)[C:12]#[N:13])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2ccc(C(=O)c3cccs3)cc2)cc1
Reactant: Cc1ccc(S)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(SC(C#N)c2ccc(C(=O)c3cccs3)cc2)cc1
Temperature: -15 °C
Yield: 55.4 %

Procedure:
795 mg of O-(p-toluenesulfonyl)-p-(2-thienylcarbonyl)mandelonitrile was dissolved in 3 ml of anhydrous DMF, and the solution was stirred at -15° C. in an argon atmosphere. A solution prepared by adding 0.80 ml of a 2.5 M methanol solution of sodium methoxide at room temperature to 2 ml of an anhydrous methanol solution containing 250 mg of p-toluenethiol was added dropwise over the course of 10 minutes. After the addition, the mixture was further stirred, and its temperature was gradually raised to bring it to -5° C. in 20 minutes. At this time, an aqueous solution of ammonium chloride (1 g/30 ml) was added to the reaction mixture, and the mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 387 mg of alpha-[p-tolylthio)[p-(2-thienylcarbonyl)phenyl]acetonitrile as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was separated by column chromatography (silica gel; methylene chloride) to afford 95 mg of alpha(p-tolylthio)[p-(2-thienylcarbonyl)phenyl]acetonitrile. The total amount of the products yielded was 482 mg, and the yield was 69%.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O.[CH:56]([NH2:59])([CH3:58])[CH3:57]>C1COCC1.C(Cl)(Cl)Cl>[CH:56]([NH:59][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)([CH3:58])[CH3:57]
Reactant: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2cc(CO)ccc21
Reactant: CC(C)N
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)NCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
N-(7-Hydroxymethyl-chroman-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step A) (0.050 g, 0.010 mmol) and DIEA (0.038 g, 0.030 mmol) were dissolved in THF (1.5 mL). The solution was cooled to 0° C. and methanesulfonic anhydride (0.023 g, 0.014 mmol) was added. After the reaction was stirred for 3.5 h, isopropylamine (0.14 g, 2.3 mmol) was added and the solution was stirred at RT overnight. The reaction was diluted with CHCl3 and washed with brine. The aqueous phase was extracted once with CHCl3. The organic phases were combined, dried over MgSO4, filtered, and concentrated in vacuo to provide a residue which was purified by column chromatography (silica, 0.2% TEA in acetone) to provide the title compound. MS (ESI) m/z 558 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C1(=O)O[CH2:28][CH2:27][O:26]1>[I-].C([N+](CC)(CC)CC)C.CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:28][CH2:27][OH:26])=[O:11]
Reactant: O=C1OCCO1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CCOCC
Product: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (7.24 g, 0.02 mole), ethylene carbonate (2.0 g, 0.023 mole) and tetraethylammonium iodide (1.0 g) was heated in an oil bath at 105°-110° C. for 10 hrs. The reaction was completed and the resulting gummy material was taken into 300 ml of ether. The ethereal solution was washed three times with water and dried over CaSO4. After the solvent had been removed, the product was crystallized from toluene/hexane and an almost quantitative yield (>95%) of the desired ester was obtained as a light brown crystalline solid; m.p. 71°-74° C., NMR (CDCl3) 3.33 (S, 1H), 3.67-4.12 (m, 2H), 4.15-4.63 (m, 2H), 7.02-8.25 (m, 6H); ir (CHCl3) 1749 cm-1. No by-product was detected by NMR analysis.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][NH2:34]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][NH2:35])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: NCCCN
Product: NCCCNc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 31 %

Procedure:
Following the procedures in Example 271, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and propane-1,3-diamine were reacted and the product was deprotected to give 280 as a yellow solid (20 mg, 31%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H) 8.43-8.44 (m, 1H), 7.53-7.57 (m, 2H), 7.38-7.40 (m, 1H), 7.03 (s, 1H), 6.53 (d, J=6.4 Hz, 1H), 4.01 (t, J=1.2 Hz, 2H), 2.92 (m, 2H), 2.50 (t, J=1.2 Hz, 2). ESI MS m/z=346 (M+1)
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:8]1=[O:23].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:8](=[O:23])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2n(CC2OCCO2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2ccc(OC)cc2n(CC=O)c1=O
Reaction time: 4 h
Yield: 138 %

Procedure:
To 0.37 g of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 4 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.44 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-3-carboxylate. (2) To 5 mL of a dichloromethane solution containing 0.44 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-3-carboxylate, 0.46 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 60 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 0.37 g of sodium triacetoxyborohydride was added and stirred for 2 hours. Chloroform and water were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.31 g of methyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(Br)ccc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Yield: 66.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 4-bromo-1-fluoro-2-methoxy-benzene (191 mg, 0.9315 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3) afforded 170 mg of the product (66.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23].[CH3:28][NH:29][CH:30]([CH3:32])[CH3:31]>ClCCCl>[Cl:1][C:2]1[C:3]([S:22]([NH:25][C:26]([N:29]([CH:30]([CH3:32])[CH3:31])[CH3:28])=[O:27])(=[O:24])=[O:23])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)N=C=O)c(Cl)cc2F)c1=O
Reactant: CNC(C)C
Solvent: ClCCCl
Product: CC(C)N(C)C(=O)NS(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
With stirring, 1.0 g (2.34 mmol) of 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]benzenesulfonyl isocyanate in 1,2-dichloroethane was added to a solution of 0.34 g (4.68 mmol) of N-methylisopropylamine in 1,2-dichloroethane, and the mixture was stirred overnight. The reaction mixture was concentrated, the residue was taken up in methylene chloride and 0.5N hydrochloric acid was added. The organic phase was then dried and the solvent was removed. This gave 0.5 g (42% of theory) of the title compound as a colorless solid (m.p.: 145° C.).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]C)=[O:4].[OH-].[Na+].[Cl:9][CH2:10][CH2:11][N:12]([CH2:36][CH2:37][Cl:38])[P:13]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])(=[O:28])[O:14][CH2:15][CH2:16]OS(C1C=CC(Br)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[Cl:35][CH2:34][CH2:33][N:29]([P:13]([N:12]([CH2:11][CH2:10][Cl:9])[CH2:36][CH2:37][Cl:38])([O:14][CH2:15][CH2:16][S:1][CH2:2][C:3]([OH:5])=[O:4])=[O:28])[CH2:30][CH2:31][Cl:32]
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: COC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl

Procedure:
Methyl 2-mercapto-acetate, 2.6 mL (28.5 mmol), was dissolved in 10 mL dry methanol, and sodium hydroxide, 2.24 mL of 25 M solution (56 mmol), and 10 mL methanol were added, followed by 2-(4-bromobenzene-sulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 26 mL of 1 M solution in toluene (26 mmol) with stirring, and a further 20 mL methanol. A white precipitate formed immediately, and a further 30 mL methanol was added to enable easy stirring overnight. The solid was filtered, and an additional 2 mL of the sodium hydroxide solution added to the filtrate and stirred for 2 hours. The basic solution was washed with ethyl acetate, then hydrochloric acid added until the solution became cloudy. This solution was extracted three times with ethyl acetate, and the combined ethyl acetate extracts backwashed with water, dilute hydrochloric acid, water, and brine, and then dried over Na2SO4 and concentrated, to give 7.31 g of 2-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]acetic acid as an oil that solidified on standing. The identity was verified by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.CC([O-])(C)C.[K+]>C1COCC1.CC(O)(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:20]=[CH:1]/[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(C)nc12
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(/C=C/c3ccc(OC)c(OC)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A solution of methyl 2-methylbenzo[d]oxazole-4-carboxylate (0.63 g, 4.12 mmol) and 3,4-dimethoxybenzaldehyde (0.68 g, 4.12 mmol) in THF (25 mL) and t-BuOH (5 mL) was cooled to −50° C. under nitrogen and treated with a solution of t-BuOK in THF (1.0 mol/L, 4.94 mL, 4.94 mmol) at such a rate that the internal reaction temperature did not exceed −46° C. After 2 hours at −50° C., the cooling bath was removed and the mixture was stirred at room temperature for 12 h in the dark. Water was added and the mixture was made slightly acidic by addition of a 1N HCl solution then extracted with DCM. The organic layers were combined, washed with water and brine then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether: ethyl acetate 2:1 (v:v) as eluent to give (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (0.30 g, 27%). LC-MS (ES-API); rt 9.25 min; m/z calculated for C19H17NO5 [M+H]+ 340.1, found 340.1.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>CO>[CH:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC#CC=CC#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC=CC#CCCCC
Yield: 80 %

Procedure:
Compound (a5) (3.02 g, 14.80 mmol) was dissolved in dry methanol (10 ml), and the solution was stirred with K2CO3 (1.0 g) at room temp. for 1.5 hrs. After the evaporation of methanol in vacuo, the reaction was quenched with saturated aqueous NaHCO3 solution and the resultant solution was extracted with EtOAc. The organic layer was separated and dried over MgSO4. After filtration, the solvent was evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as an oil in 80% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:23])([F:22])[F:24])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:54][CH:55]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 352.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 155A, 73 mg, 0.07 mmol) and triphenylphosphine (79 mg, 0.08 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. At this time, reaction mixture was treated with 2-amino-5-bromopyridine (52 mg, 0.30 mmol) and a few drops of pyridine. The resulting reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic phase was washed with water (1×35 mL) and a saturated aqueous sodium chloride solution (3×35 mL), dried over magnesium sulfate and sodium sulfate, treated with charcoal, filtered through a pad of celite, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70/30 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (128.3 mg, quant) as a white solid: mp 81-85° C.; EI-HRMS m/e calcd for C21H22BrF3N2O3S (M+) 518.0486, found 518.0489.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([O:9][Si](C)(C)C)=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][Si](C)(C)C)[C@H:4]2[S:3]1.C1OC1C.ClC(Cl)C([O:31][N:32]=[C:33]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:34](Cl)=[O:35])=O.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([OH:9])=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][C:34](=[O:35])[C:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[N:32][OH:31])[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@H](N[Si](C)(C)C)C(=O)N2[C@H]1C(=O)O[Si](C)(C)C
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Agent: CC1CO1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(=NO)c3cccs3)C(=O)N2[C@H]1C(=O)O

Procedure:
A solution of trimethylsilyl 2,2-dimethyl-6β-trimethylsilylaminopenam-3α-carboxylate [prepared from the corresponding amino-acid (0.864 g.)] and propylene oxide (1 ml.) in dichloromethane (20 ml.) was cooled to 0° and treated dropwise with a solution of 2-dichloroacetoxyimino(thien-2-yl)acetyl chloride syn-isomer; [prepared from the corresponding acid (0.753 g.)] in dichloromethane (12 ml.). The resulting solution was maintained at 0° for 1 hour and was then evaporated to a small bulk and partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N-hydrochloric acid, and extracted with ethyl acetate. The dried organic solution was evaporated to a small bulk and added dropwise to stirred petroleum spirit (b.p. 40°-60°). The resulting precipitate was collected, washed, and dried to afford the title acid (0.337 g., 24% based on amine), [α]D + 224° (c 0.57, DMSO), λmax. (pH 6 buffer) 288 nm (ε 6,400), λ inf. 270 nm (ε 5,800), νmax. (Nujol), 2600 and 1730 (CO2H), 1776 (β-lactam), 1670 and 1526 cm.-1 (CONH), τ (d6 -DMSO) values include 0.44 (d, J 6 Hz; NH), 2.45 and 2.9 (multiplets, aromatic protons), 5.78 (s; C-3H), 8.46 and 8.55 (2 s; CH3 groups).
Reaction SMILES: [CH2:1]=C1CCN(C2C([N+]([O-])=O)=CC=CN=2)CC1.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=O)[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[CH2:1]=[C:26]1[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:25]1
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: C=C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was synthesised following the method described here for Compound 2a using 1-Boc-3-pyrrolidinone instead of 1-(3-nitro-2-pyridyl)-4-oxopiperidine. After the usual work-up procedure, the crude product was purified by automated flash chromatography (Horizon®TM-Biotage) eluting with a Petroleum Ether-EtOAc gradient from 95:5 to 7:3, yielding the title compound as brownish oil. Yield: 75.8%.