Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([C:1]2([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
To a solution of delta-valerolactone (1.854 mL, 19.98 mmol) in THF (20 mL) was added 1M phenylmagnesium bromide (19.98 mL, 19.98 mmol) dropwise at room temperature (exothermic), and the mixture was stirred at room temperature for 5 hrs. Then the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 4:6 followed by 1:1 EtOAc-hexane to give 1.97 g of 2-phenyltetrahydro-2H-pyran-2-ol as oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.92-8.00 (1H, m), 7.17-7.60 (5H, m), 3.67 (1H, t, J=6.15 Hz), 3.03 (1H, t, J=7.14 Hz), 2.25-2.37 (1H, m), 1.75-1.92 (2H, m), 1.54-1.71 (2H, m), 1.30-1.43 (1H, m).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Yield: 100.6 %

Procedure:
The product from Example 21A (50 mg, 0.14 mmol) in THF (10 mL) was treated with sodium borohydride (21 mg, 0.57 mmol) at −40° C. for 1 hr, quenched with saturated NH4Cl, extracted with EtOAc (2×), dried over MgSO4, filtered and concentrated to afford 50 mg of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.67 (s, 9 H) 3.93 (s, 3 H) 4.88 (s, 2 H) 6.94 (d, J=8.85 Hz, 1 H) 7.37 (dd, J=8.85, 3.05 Hz, 1 H) 8.05 (s, 1 H) 8.08 (d, J=2.75 Hz, 1 H); MS (DCI/NH4+) m/z 355 (M+H)+.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12](CO)[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24]([O-])(=[O:26])C.[N+](C1C([N+]([O-])=O)=C(O)C(=CC=1)C([O-])=O)([O-])=O.[Na+]>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:10]([OH:17])[C@@H:11]([OH:16])[C@H:12]([OH:13])[O:19][C@@H:18]2[CH2:24][OH:26])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)[O-]
Agent: O=C([O-])c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1O
Agent: [Na+]
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The fourth test is practised on 0.1 to 0.4 mg of dry yeast matter which are placed in the presence of saccharose at a final concentration of 0.1 Molar, in a test tube in a buffered medium with acetate buffer at pH 4.7, placed in a water bath at 30° C. At the end of 5 minutes, the saccharose inversion reaction is blocked by the addition of the reactant with sodium dinitrosalicylate which serves to determine reducing sugars formed, by colorimetric reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a stirred and cooled (ice-bath) solution of 27 parts of 4-fluorobenzeneacetonitrile in 180 parts of N,N-dimethylformamide are added 6.2 parts of sodium hydride dispersion 78% and the whole is stirred for 1 hour while cooling. Then there are added dropwise 31 parts of 1-bromopentane. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding 21 parts of 4-fluoro-α-pentylbenzeneacetonitrile; bp. 85°-93° C at 0.1 mm. pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19]([NH2:21])=[O:20])[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19](=[NH:21])[O:20][CH3:27])[CH:9]3[CH2:17][CH:13]4[CH2:12][CH:11]([CH2:16][CH:15]2[CH2:14]4)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: NC(=O)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=N)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A solution of 6-1a (30 mg, 0.1 mmol) in 0.5 mL of anhydrous methylene chloride was treated with trimethyloxonium tetrafloroborate (30 mg, 0.2 mmol). The mixture was stirred under nitrogen for 18 h, then added to a separatory funnel containing 25 mL of methylene chloride and saturated aqueous sodium bicarbonate solution. The layers were mixed and separated and the organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 32 mg of title compound, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[NH:9][N:8]=2)[N:6]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[N:6]=1
Reactant: COC(=O)c1cc(-c2csc(C)n2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2cc(C(=O)O)[nH]n2)cs1
Yield: 123.2 %

Procedure:
A solution of methyl 3-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate (0.586 mmol) in 5 ml of THF and 1 ml of MeOH was treated with 2 ml of 1 M NaOH-solution at RT over three nights. Solvent was evaporated and the residue was taken up in water and washed with DCM. 1 M HCl was added to the water phase until pH was 5. The water phase was washed twice with DCM and neutralized by 1 M sodiumbicarbonate solution. The water phase was evaporated from toluene and the evaporation residual suspended to EtOH. Thus obtained solid was filtered to give 151 mg (123%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.69 (s, 3H), 6.68 (s, 1H), 7.60 (s, 1H), 12.89 (bs, 1H).
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.[Na+].ClC1C=C([N+]([O-])=O)C(F)=CC=1NCC([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[F:9]
Reactant: O=C([O-])CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])CNc1cc(F)c([N+](=O)[O-])cc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(F)c(Cl)cc2N1
Temperature: 25 °C

Procedure:
A suspension of N-(4'-chloro-5'-fluoro-2'-nitrophenyl)glycine sodium salt and N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt (0.175 g, 0.704 mmol) and tin (II) chloride dihydrate (0.475 g, 2.11 mmol) in ethanol (3.5 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and the pH was adjusted with saturated NaHCO3 (3.0 mL) to pH~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.041 g (29%) pure (1H NMR) title compound as a light yellow powder; mp 217-219° C. (dec); 1H NMR (DMSO-d6) δ 3.75 (s, 2H), 6.37 (s, 1H), 6.59 (d, 1H, J=10.5 Hz), 6.74 (d, 1H, J=7.2 Hz), 10.33 (s, 1H).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([C@@H:17]1[CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)[C:20]=2[CH2:19][CH2:18]1)[CH3:16].[NH2:41][C:42]1[C:47]([S:48]([N:51]2[CH2:56][C@@H:55]3[CH2:57][C@H:52]2[CH2:53][N:54]3C(OC(C)(C)C)=O)(=[O:50])=[O:49])=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[C@H:52]12[CH2:57][C@H:55]([NH:54][CH2:53]1)[CH2:56][N:51]2[S:48]([C:47]1[C:42]([NH2:41])=[N:43][CH:44]=[C:45]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH2:29][CH2:28][N:27]([C:21]4[C:20]5[CH2:19][CH2:18][C@H:17]([CH2:15][CH3:16])[CH2:26][C:25]=5[N:24]=[CH:23][N:22]=4)[CH2:33][C:32]=3[CH:34]=2)[CH:46]=1)(=[O:49])=[O:50]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(=O)(=O)c1cc(Br)cnc1N
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5C[C@@H]6C[C@H]5CN6)c4)cc3C2)C1

Procedure:
Prepared as dihydrochloride salt according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and (1S,4S)-tert-butyl 5-(2-amino-5-bromopyridin-3-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (reagent preparation 25) in step 1 followed by Boc deprotection. 1H NMR (400 MHz, methanol-d4): 8.65 (s, 1H), 8.52 (s, 2H), 7.74 (s, 1H), 7.53 (d, 1H), 7.08 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H), 4.56 (m, 2H), 4.46 (m, 1H), 4.36 (m, 1H), 4.21 (m, 1H), 3.69 (m, 3H), 3.53 (m, 1H), 3.38 (m, 1H), 2.99 (m, 2H), 2.74 (m, 1H), 2.42 (m, 1H), 2.05 (m, 3H), 1.83 (m, 1H), 1.47 (m, 2H), 1.24 (m, 1H), 1.01 (t, 3H); MS (EI) for C29H35N7O3S: 562 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38](Cl)[O:39][CH:40]=2)=[O:35])[CH3:32])[CH:22]=[C:23]([F:30])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:23]1[CH:22]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38]([C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[O:39][CH:40]=2)=[O:35])[CH3:32])[CH:20]=[C:19]([F:18])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 19.3 %

Procedure:
3,5-Bis(trifluoromethyl)benzeneboronic acid (67 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (14 mg, 19%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜80%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:18]2[S:19][C:20]([CH3:33])=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=3[Cl:32])[N:22]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C(O)C.C1CC=CCC=1>>[Cl:32][C:24]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([CH3:29])=[CH:28][C:23]=1[C:21]1[N:22]=[C:18]([C:15]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])[CH2:17][CH2:16]2)[S:19][C:20]=1[CH3:33]
Reactant: COc1cc(Cl)c(-c2nc(C3(c4ccccc4OCc4ccccc4)CC3)sc2C)cc1C
Solvent: C1=CCC=CC1
Solvent: CCO
Product: COc1cc(Cl)c(-c2nc(C3(c4ccccc4O)CC3)sc2C)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-[1-(2-Benzyloxy-phenyl)-cyclopropyl)-4-(2-chloro-4-methoxy-5-methyl-phenyl)-5-methyl-thiazole (0.95 g, 2 mmol) was dissolved in dry ethanol (100 mL) 30% palladium on carbon (0.39 g, 1.1 mmol) and 1,4-cyclohexadiene (20 mL, 210 mmol) was added. The reaction mixture was stirred for 2 d at room temperature. The mixture was filtered through Celite concentrated, and purified by chromatography on silica using an ethyl acetate/hexane gradient, the title compound was obtained as a white powder. Yield: 0.41 g (53%). [MH]+ =386.2, 388.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]2[NH:21][N:22]=[N:23][C:19]=2[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:21]1[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:18][C:19]=2[NH:23][N:22]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1 hr. The work up gave 213.5 mg (67.6%) of the product as a yellow solid, m.p.>250 C., mass (electrospray, m/e): M+H 316.9. HRCIMS: calcd 316.107 for C17H12N6O (M+), obsd 316.1079.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:28].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC>CN(C=O)C.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([N:27]([CH3:28])[CH3:26])=[O:10])=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (300 mg, 0.88 mmol) in DMF (1.5 mL) and DCM (1.5 mL) was added HATU (401 mg, 1.05 mmol) and triethylamine (0.37 mL, 2.64 mmol). To the mixture at room temperature was added dimethylamine (0.46 mL, 0.91 mmol). The mixture was stirred at room temperature for 2 hours, quenched with sat NaHCO3, and extracted with EtOAc. The organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 5% 2M Ammonia in MeOH and DCM to give (S)-tert-butyl 3-(biphenyl-4-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (196 mg). HPLC retention time=1.66 minutes (condition B); MS (m+1)=369.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 2.65 (s, 3H) 2.83 (s, 3H) 2.96 (d, J=7.1 Hz, 2H) 4.71-4.94 (m, 1H) 5.56 (d, J=8.6 Hz, 1H) 7.22 (d, J=8.1 Hz, 2H) 7.27 (t, J=7.5 Hz, 1H) 7.37 (t, J=7.6 Hz, 2H) 7.47 (d, J=8.1 Hz, 2H) 7.52 (d, J=7.3 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[F:41][C:42]([F:57])([S:53](F)(=[O:55])=[O:54])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[F:57][C:42]([F:41])([S:53]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:55])=[O:54])[C:43]([F:51])([F:52])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reaction time: 0.33 h

Procedure:
A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (98 wt %, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt %, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area %) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3:2 (v/v) acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22]([OH:25])CBr)[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:11](=[O:26])[CH:10]2[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:30]([CH2:29][C:28]([NH:27][CH:10]1[C:11](=[O:26])[N:12]2[CH:13]([C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[C:22](=[O:25])[CH2:6][S:8][C@H:9]12)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(O)CBr)C1SC(=O)OCC1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(=O)CS[C@H]12
Reaction time: 1 h
Yield: 124.7 %

Procedure:
To a stirred solution of 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (330 mg) in methylene chloride (6 ml) is added aluminum chloride (330 mg) at room temperature, and the mixture is stirred for 60 minutes. The reaction mixture is poured into ice cold diluted hydrochloric acid, and is extracted with ethyl acetate. The extract solution is washed with diluted hydrochloric acid and water, dried, and evaporated to give 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate (300 mg). Foam. IR: vmaxCHCl3 3420, 1780, 1685 cm-1. NMR: δCDCl3 3.37s2H, 4.53s2H, 4.85s2H, 5.07d(4)1H, 5.20-5.73m2H, 6.8-7.7m6H.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][N:10]([C@H](C3C=CC=CC=3)C)[C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O>CO.[Pd]>[N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][NH:10][C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN2CCOCC2)[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)[C@H]1NCC[C@H]1CN1CCOCC1

Procedure:
A mixture of (2S,3S)-3-morpholin-4-ylmethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage 37.2) (1.046 mmol) and 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) (0.105 mmol) in MeOH (5 mL) was hydrogenated for 6.5 h at rt. The reaction mixture was then filtered through a Fluoropore Membrane Filter (0.2 μm FG) and evaporated. The residue was dissolved in CH2Cl2 and evaporated to dryness to afford the title compound as colorless oil. ESI-MS: [M+H]+ 214; TLC: Rf=0.14 (200:20:1 CH2Cl2/MeOH/conc. NH4OH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C1COCC1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1>CCOC(C)=O.O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:20][CH:21]=1
Reactant: OC1CCOCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
Tetrahydro-2H-pyran-4-ol (200 mg) was mixed with THF (5 ml), and sodium hydride (55% suspended in oil) (120 mg) was added thereto, followed by stirring at room temperature for 5 minutes. 5-Bromo-2-chloropyrimidine (460 mg) was added to the reaction mixture, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (361 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4ccccc4n3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with quinoline-2-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=487.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1>O1CCOCC1.C(O)(=O)C>[Br:1][C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]c(C)cc1-c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
N-Bromo succinimide (1.40 g, 7.87 mmol) was added to a solution of ethyl 5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.5 g, 6.55 mmol) in a mixture of dioxane (10 mL) and acetic acid (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was warmed to room temperature and stirred for another 15 min. The mixture was quenched with 2N NaOH solution and the organic layer was separated, washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.68 g, 84%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH3:16])=[O:7])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To 3-cyano-4-isopropoxybenzoic acid (0.3 g, 1.462 mmol) in a mixture of dichloromethane (4 mL) and MeOH (1.00 mL) was added trimethylsilyldiazomethane (0.950 mL, 1.9 mmol) dropwise over a period of 3 min at 0° C. The pale yellow solution was allowed to come to room temperature over a period of 15 min. and stirred at room temperature for 1.5 h. Excess trimethylsilyldiazomethane was quenched by the slow addition of acetic acid (˜0.5 ml) at room temperature until the yellow color was discharged. The reaction mixture was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was azeotroped with THF (5 mL) and dried under high vacuum to yield methyl 3-cyano-4-isopropoxybenzoate (0.32 g, 1.460 mmol, 100% yield) as an oil. LC/MS M+1=219.9.