Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)[CH:70]=[CH2:71]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:17])[N:72]([CH2:69][CH:70]=[CH2:71])[CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:13]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: C=CCNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-allylcyclohexylamine (0.029 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.032 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C(OC([N:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:23])C(C)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CO.O>[C:16]1([CH2:15][C:14]([NH:13][CH:11]2[CH2:12][NH:9][C:10]2=[O:23])=[O:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C(C)C)N1CC(NC(=O)Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Cc1ccccc1)NC1CNC1=O
Yield: 58.2 %

Procedure:
1-(1-Acetoxy-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (13.8 g.) was dissolved in a solution of methanol (100 ml.) and water (100 ml.). Potassium carbonate (6 g.) and sodium borohydride (1.65 g.) were added to said solution under ice-cooling, and the mixture was subjected to reaction at 20° C. for an hour. The precipitated crystals were collected by filtration, washed with water and dried to give 3-(2-phenylacetamido)-2-azetidinone (5.15 g.). Furthermore, the same compound (1.35 g.) was recovered from the filtrate. Total yield was 6.5 g. Mp 191° to 193° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].Br[CH:22]([CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:29]([O:28][CH2:27][CH:22]([N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:23]([O:25][CH3:26])=[O:24])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Reactant: COC(=O)C(Br)COC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(COC(C)(C)C)C(=O)OC)cc1
Temperature: 60 °C
Yield: 26.3 %

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (388 mg, 1.33 mmol, preparation described in example 1, step a)), was dissolved in DMF (5 mL). Intermediate XI with R3═CH2OtBu, e.g. methyl 2-bromo-3-tert-butoxypropanoate (478 mg, 2 mmol) and potassium carbonate (368 mg, 2.66 mmol) were added. The mixture was heated overnight at 60° C. Solvents were evaporated. The crude residue was suspended in ethyl acetate (10 mL) and was washed with 1N HCl solution (7 mL) and with brine (7 mL). Organic phase was dried over MgSO4, fitrated and evaporated. The crude mixture was purified by flash chromatography, using a 8:2 mixture cyclohexane/ethyl acetate as eluent. The desired product, e.g. methyl 3-tert-butoxy-2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (157 mg, 26.3%) was isolated as a light yellow oil, in 96.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:11][N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: CNC(C)(C)C
Reactant: O=C(Cl)c1cccc(F)c1
Product: CN(C(=O)c1cccc(F)c1)C(C)(C)C

Procedure:
3-Fluorobenzoyl chloride was reacted with N-methyl-N-tert-butylamine using General Method E1 or E2 to produce N-methyl-N-(tert-butyl)-3-fluorobenzamide. This compound was used in General Method A to prepare the title compound. Kugelrohr distillation afforded 12.07 g of analytically pure desired material. m.p. 32°-35° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.Cl.C([O-])([O-])=O.[K+].[K+].[CH3:33][C:34]([O:37][C:38]([O:40]N=C(C1C=CC=CC=1)C#N)=O)([CH3:36])[CH3:35]>[Pd].CO>[C:38]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:10]1)([O:37][C:34]([CH3:33])([CH3:35])[CH3:36])=[O:40]
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
The 13.7 g (40 mmol) of methyl 1,4-dibenzylpiperazine-2-acetate, 150 mL of MeOH, 50 mL of 1 N HCl (aqueous) and 3 g of 10% Pd/C were combined and hydrogenated with H2 (50 psi) for 24 hours. The reaction was filtered, the filtrate was concentrated in vacuo to remove most of the MeOH, and the residue was made basic with K2CO3 to pH=9-10, and 9.8 g (40 mmol) of BOC-ON was added slowly at 0° C. The reaction was stirred at 0° for 1 hour, allowed to warm up to room temperature, stirred for 2 hours, and extracted with ethyl acetate (2×200 mL). The combined extracts were treated with 50 mL of 10% HCl (aqueous). The aqueous layer was washed with ethyl acetate, basified with K2CO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 7.89 g of methyl 4-Boc-piperazine-2-acetate; 1H NMR (CDCl3) δ 1.4 (s,9), 2.31 (dd,1), 2.37 (dd, 1), 2.55 (b, 1), 2.69-3.02 (m,4), 3.75 (s,3), 3.88 (b, 2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([OH:11])[C:3]=1[CH3:12].[OH-].[Na+].C([O:19][C:20](=[O:23])[CH2:21]Br)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([CH3:12])=[C:4]([O:11][CH2:21][C:20]([OH:23])=[O:19])[C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(C)c(O)c(C)c(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(C)c(OCC(=O)O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A mixture of 20 mL of CH2Cl2, 20 mL H2O, 415 mg (1 eq) of tetramethylhydroquinone (D), 200 mg of NaOH, 540 mg (1.1 eq) of t-butylbromoacetate, 760 mg of C were stirred at room temperature, under argon, for 12 hr. Initially, D was not completely soluble, but with time, in 1 hr, it completely dissolved. After 12 hr, acid was added to bring the pH to 7.0, 200 mL of CH2Cl2 was added, and the reaction mixture was extracted with brine (4×200 mL), dried over Na2SO4, and evaporated under reduced pressure to yield crude product. 5 mL of TFA was added to the crude product, and the mixture was stirred for 1 hr. TFA was evaporated and the crude product charged on silica gel (230-400 mesh, CH2Cl2 -EtOAc, 2:1) to yield 270 mg (49%) of product 27.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O-:23])=[O:22])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CC(CN3CCC(C(=O)[O-])CC3)OC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N2CC(CN3CCC(C(=O)O)CC3)OC2=O)cc1
Reaction time: 0.08 h

Procedure:
1 g of tert-butyl (1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylate is dissolved in 12 ml of dichloromethane, and 12 ml of trifluoroacetic acid are then added; the mixture is left to stand for 5 min., concentrated by evaporation and worked up in the customary manner; 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylic acid, FAB 330, is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]#[CH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]#[CH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C#CCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCNc1nc(NCC=C)nc2c(C)csc12
Yield: 54.2 %

Procedure:
285 mg (1.2 mmol) of 2-chloro-7-methyl-4-(2-propynylamino)thieno[3,2-d]pyrimidine and 1.14 mg (19.2 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 168 mg (yield: 54.2%) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][C:14](O)=[O:15])[CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][C:14]([Cl:24])=[O:15])[CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CC(=O)O)O2
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CC(=O)Cl)O2

Procedure:
To a suspension of (RS)-2-(2,3-dihydro-5-acetyloxy-4,6,7-trimethylbenzofuranyl) acetic acid (see example 2) (4.4 g) in benzene (36 ml) is added dropwise oxalyl chloride (7 ml) over 30'.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:7]([N:10]([CH2:20][C:21](=O)[CH3:22])[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:9])[CH3:8]>C(O)C>[Cl:29][C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([Cl:3])[C:26]=1[O:27][CH3:28])[C:7]([N:10]1[CH2:20][C:21]([CH3:22])=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]1=[O:19])([CH3:8])[CH3:9]
Reactant: COc1c(Cl)cc(C(C)(C)N(CC(C)=O)C(=O)Cc2ccccc2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Yield: 66.6 %

Procedure:
0.5 g (0.008 mol) of potassium hydroxide powder was added to an ethyl alcohol solution of 8.2 g (0.02 mol) of N-(3,5-dichloro-4-methoxy-α,α-dimethylbenzyl)-N-(2-oxopropyl)phenylacetamide prepared by the method of Reference Example 8, and the mixture was refluxed under heating for 20 minutes. The reaction solution was cooled, and then ethanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography to obtain 5.2 g (yield: 66%) of the desired compound as colorless crystals.
Reaction SMILES: O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[N:40]1([S:46]([C:49]2[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.[CH2:56]([O:61][C:62](=[O:82])[C:63]1[C:68](I)=[CH:67][N:66]=[C:65]([NH:70][S:71]([C:74]2[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=2[Cl:81])(=[O:73])=[O:72])[CH:64]=1)[CH2:57][CH2:58][CH2:59][CH3:60].CC(C)([O-])C.[K+]>CN1CCCC1=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:56]([O:61][C:62](=[O:82])[C:63]1[C:68]([S:55][C:52]2[CH:51]=[CH:50][C:49]([S:46]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)(=[O:48])=[O:47])=[CH:54][CH:53]=2)=[CH:67][N:66]=[C:65]([NH:70][S:71]([C:74]2[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=2[Cl:81])(=[O:72])=[O:73])[CH:64]=1)[CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1I
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
A solution of (oxydi-2,1-phenylene)bis-(diphenylphosphine) (DPEphos) (43 mg, 0.08 mmol) and tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.02 mmol) in N-methylpyrrolidinone (10 ml) was stirred at room temperature for 5 minutes under nitrogen. 4-(Piperidine-1-sulfonyl)-benzenethiol (121 mg, 0.4 mmol), 2-(2,4-dichloro-benzenesulfonylamino)-5-iodo-isonicotinic acid pentyl ester (218 mg, 0.4 mmol) and potassium t-butoxide (90 mg, 0.8 mmol) were added and the reaction stirred overnight at 100° C. The solvent was removed under reduced pressure and the residue taken up in chloroform. The chloroform solution was washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2-(2,4-dichloro -benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as a yellow foam (15 mg, 6%). 1H NMR (CDCl3): 10.82 (1 H, s, NH); 8.17 (1 H, s, Ar); 8.09 (1 H, d, Ar); 7.61 (2 H, m, Ar); 7.57 (1 H, s, Ar); 7.38 (4 H, m, py and Ar); 4.22 (2 H, t, OCH2); 2.90 (4 H, m, 2×CH2N pip); 1.66 (2 H, m, OCH2CH2); 1.54 (4 H, m, 2×CH2 pip); 1.33 (4 H, m, OCH2CH2CHCH2CH3); 1.19 (2 H, m, CH2 pip); 0.88 (3 H, t, CH2CH1). HPLC (Luna 2, Gradient 5): rt=7.82 minutes. LCMS rt=8.34 minutes, 673 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:44]([O:46]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43])=O)(C)(C)C.C(OC(N[C@H](C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)CSCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(C2NC3C(C=2)=CC=CC=3)=O)C1=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:44]([OH:46])=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A mixture of a mixture (0.66 g) of (3R)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one and (3S)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one, anisole (0.6 ml), trifluoroacetic acid (1.5 ml) and dichloromethane (15 ml) was stirred for 3.0 hours at room temperature. After removal of the solvent, the residue was mixed with ethyl acetate (50 ml) and water (50 ml). The mixture was adjusted to pH 6-7 with 5% aqueous solution of sodium bicarbonate under stirring. The organic layer was separated and concentrated. The resultant precipitate was collected by filtration, washed with water and dried to give a mixture (0.20 g) of (3R)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one and (3 S)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14]1([C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:23]=[C:22](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]12([NH:11][C:12](=[O:13])[NH:11][CH2:1][CH2:2][CH2:3][C:22]3[CH:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=4)[N:23]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)NC34CC5CC(CC(C5)C3)C4)cc2-c2ccccc2)cc1
Yield: 84 %

Procedure:
The titled compound was prepared in 84% yield from 1-adamantyl isocyanate using the procedure detailed for compound 7. mp 139.4-143.5° C. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J=9 Hz, 2H), 7.37-7.28 (m, 5H), 7.21-7.15 (m, 2H), 6.36 (s, 1H), 5.70-5.64 (m, 2H), 4.68-4.60 (m, 1H), 4.29 (s, 1H), 3.23 (q, J=7 Hz, 2H), 2.78 (t, J=7, 2H), 2.08-1.87 (m, 9H), 1.67-1.59 (m, 6H), 1.29-1.22 (m, 2H). MS (ESI) m/z: 534.25 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([CH:32]=[CH:33][CH:34]=O)=[CH:30][CH:29]=1.O>O1CCCC1>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:17][C:16]=1[CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31](/[CH:32]=[CH:33]/[CH:34]=[CH:5]/[C:3]#[N:4])=[CH:30][CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C=C/C#N)cc1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Sodium hydride (60% in oil, 0.32 g) was added, in small portions at 0° C., to a solution of diethyl cyanomethylphosphonate (1.3 g) in tetrahydrofuran (50 ml). The mixture was stirred for 15 minutes at the same temperature, to which was then added 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamoaldehyde (2.0 g), followed by stirring for 30 minutes under ice-cooling. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), which was then concentrated to give (E,E)-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile (1.5 g, 68%). Recrystallization of the product from ethyl acetate--hexane afforded colorless needles, m.p.120°-121° C.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].C(N(CC)CC)C.[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].O>ClCCl>[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](=[O:23])[O:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11])[CH3:20]
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1

Procedure:
To a solution of 1-(hydroxymethyl)-4-propyl-pyrrolidin-2-one a24 (4 g, 25.44 mmol) and triethylamine (1.2 eq, 30.53 mmol, 3.089 g; 4.26 ml) in 25 ml of dichloromethane was added dropwise a solution of diethylcarbamyl chloride (1.1 eq, 27.99 mmol, 3.795 g, 3.55 ml) in dichloromethane (5 ml) at room temperature. The crude mixture was allowed to react under agitation and inert atmosphere overnight. Hydrolysis (15 ml of water), extraction (CH2Cl2), drying of the combinated organic layers (MgSO4), filtration and solvent evaporation under reduced pressure gave (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate a26 (100%) which was used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:4]([OH:37])[CH:3]=1.CN(C)C=O.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])(=O)=O>ClCCl.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:4]([O:37][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(Br)cc1O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 98.3 %

Procedure:
(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 1.79 mmol) was dissolved in anhydrous dichloromethane (5 mL), anhydrous N,N-dimethylformamide (5 mL) and stirred under nitrogen at room temperature. 2,6-Lutidine (1.0 mL, 920 mg, 8.6 mmol) was added followed by drop-wise addition of tert-butyldimethylsilyl trifluromethane sulfonate (1.2 mL, 1.38 g, 5.22 mmol). The reaction was stirred under nitrogen at room temperature for 2.25 h. 2,6-Lutidine (0.25 mL, 230 mg, 2.15 mmol) was added followed by addition of tert-butyldimethylsilyl trifluromethane sulfonate (0.4 mL, 460 mg, 1.74 mmol) and after a total of 4.5 h at room temperature the reaction was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution, water (4 times) and brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.23 g, 99% yield); Rf 0.57 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.33-7.14 (m, 6H), 7.09-6.91 (m, 6H), 4.99 (d, J=2.3 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 3.06 (ddd, J=4.9, 2.5, 2.3 Hz, 1H), 1.97-1.69 (m, 4H), 1.03 (s, 9H), 0.84 (s, 9H), 0.33 (s, 3H), 0.29 (s, 3H), −0.01 (s, 3H), −0.20 (s, 3H) ppm.