Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(N)c(C=O)cc1Br
Yield: 54.7 %

Procedure:
To a stirred solution of 2-amino-4-methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (7 g, 39.7 mmol). LCMS monitored the reaction until the starting material consumed completely. The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) C8H8BrNO2 requires: 229, 231. found: 230, 232 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (4.7 g, 13.38 mmol) and potassium carbonate (4.62 g, 33.4 mmol) in dry DMF (50 ml) were stirred and heated at 50° C., under nitrogen, for 75 mins. The mixture was allowed to cool to room temperature and then cooled to 0° C. and 1-bromo-3-chloropropane (2.106 g, 13.38 mmol) was added. The mixture was stirred at 0 to 10° C. for approximately 5 hours then allowed to warm to room temperature and stirred for approximately a further 40 hours when LCMS indicated approximately 70% of the desired product. The mixture was allowed to settle and the supernatant was pipetted off and the solvent evaporated on a rotary evaporator using a high vacuum pump at about 23° C. Chloroform and water was added to the combined residues which were stirred and the phases separated using a hydrophobic frit. The aqueous layer was re-extracted with further portions of chloroform and the combined chloroform extracts were evaporated under high vacuum at 23° C. to give a yellow solid (2.798 g). This crude material was combined with similar material obtained from two similar preparations (0.56 g and 0.995 g) and purified by flash column chromatography on silica using 2:1 ethyl acetate/chloroform as eluant to give the title compound as an off-white solid. (3.011 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Li].FC([I:19])(F)F.O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([I:19])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: FC(F)(F)I
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(Cl)nc(Cl)c(F)c1I
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,6-dichloro-5-fluoronicotinic acid (10 g) in THF (100 mL) at −78° C. was treated with 1.6M methyllithium in diethyl ether (62.5 mL), stirred at −25° C. for 1.5 hours, cooled to −78° C., treated with trifluoromethyl iodide (22.6 g) over 30 minutes, stirred at −78° C. for 1.5 hours, −25° C. for 1.5 hours, and 0° C. for two hours, treated with water, concentrated to remove the organic solvents, washed with diethyl ether, acidified with 1M HCl, and extracted with diethyl ether; and the extract was dried (Na2SO4), filtered, and concentrated.
Reaction SMILES: [Si](OC[C@H]1OC(=O)C[C@@H]1C1OCCO1)(C(C)(C)C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCO[CH:28]1[C@@H:32]([CH2:37][CH2:38][OH:39])[C@H:33]([OH:36])[CH2:34][OH:35].C1COCC1.O>C1COCC1.C(Cl)Cl.CO.C(CO)C>[OH:36][C@H:33]1[C@H:32]2[C@H:28]([O:39][CH2:38][CH2:37]2)[O:35][CH2:34]1
Reactant: OCC[C@H](C1OCCO1)[C@H](O)CO
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Agent: [Al+3]
Agent: [H-]
Solvent: CCCO
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2OCC[C@H]21
Yield: 42.1 %

Procedure:
According to the above general procedure, a solution containing 216 mg (0.714 mmol) (4S,5S)-5-(tert-butyldimethylsilanyloxymethyl)-4-[1,3]-dioxolan-2-yldihydrofuran-2-one (3a) in THF (25 mL) was reduced with 98 mg (2.58 mmol) LiAlH4 in THF (7 mL) to give the crude protected triol (4) (132 mg, 96%). The crude triol (4) (76 mg (0.40 mmol)) was cyclized in 6 mL acidified THF:water (5:1). Column chromatography (silica gel 20 g, ethyl methanol in CH2Cl2 10%) gave compound (5) (37.6 mg, 84%) as a colorless solid, Rf=0.35, [α]25D −25°, c 1.0, MeOH. 1H-NMR (400 MHz, CDCl3) δ: 1.67 (mc, 1H), 2.14 (mc, 1H), 2.63 (bs, 1H), 2.79 (mc, 1H), 3.75-3.88 (m, 3H), 3.94 (dd, 1H, J=3.0 Hz, J=10.2 Hz), 4.20 (d, 1H, J=2.7 Hz), 5.86 (d, 1H, J=4.9 Hz). 13C-NMR (125.8 MHz, CDCl3, Dept) δ: 29.19 (−), 52.38 (+), 69.52 (−), 75.60 (−), 78.14 (=), 109.23 (+). C6H10O3; Exact Mass: 130.06; Mol. Wt.: 130.14; C, 55.37; H, 7.74; O, 36.88.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[H-].[Na+].[CH3:22]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:22])[C:10]2[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[CH3:19]
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of (6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (276 mg, 1 mmol) in dry THF (2 ml) was treated with sodium hydride (60% in oil, 60 mg, 1.5 mmol) at room temperature. After stirring for 2 minutes, an excess of methyl iodide (0.5 ml) was added and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a pale yellow solid (255 mg). 1H NMR (CDCl3) δ6.85 (s, 2H), 3.26 (s, 3H), 2.50 (s, 3H), 2.27 (s, 3H), 2.03 (s, 6H), 1.39 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A mixture of 2-chloro-1H-indole-3-carboxaldehyde (2.2 g, 12. 25 mmol), 4-t-butylphenylboronic acid (4.36 g, 24.49 mmol), copper acetate (4.45 g, 24.50 mmol), 4A molecular sieve (2.5 g), pyridine (3.0 mL) and dichloromethane (40 mL) is stirred overnight at room temperature. The reaction mixture is diluted with dichloromethane (100 mL), washed with water (50 mL), with 3N aqueous hydrochloric acid (10 mL), the precipitate removed by filtration and the dichloromethane layer is washed again with water (50 mL), aq sodium bicarbonate, with brine, dried and filtered. The filtrate is concentrated to give a solid. The crude is crystallized from dichloromethane-methanol to afford 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (3.09 g, 81% yield) as a yellow solid. TLC (silica gel, 20% ethyl acetate/heptane) Rf=0.50; ESI/MS 312 (M+H), RT 4.32 min; NMR: 10.12 (1H, s); 8.20 (1H, d, J=6 Hz); 7.71 (2H, d); 7.53 (2H, d); 7.38 (2H, m); 7.11 (1H, d); 1.38 (9H, s).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH3:29][C:22]1[N:21]=[C:20]([N:16]2[CH2:17][CH2:18][C:12]3([O:11][N:10]=[C:9]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:13]3)[CH2:14][CH2:15]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#Cc2ccccc2)=NO3)n1
Yield: 60.3 %

Procedure:
A solution of Compound 1c (50 mg, 0.21 mmol), 2-chloro-6-methyl-3-nitropyridine (39.5 mg, 0.23 mmol) and triethylamine (31.9 μL, 0.23 mmol) in N,N-dimethylacetamide (1.14 mL) was stirred at r.t. for 24 h and poured into water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SP1®TM-Biotage) eluting with a Petroleum Ether-Me2CO 95:5 mixture. A further purification with CH2Cl2 as eluent afforded 47.7 mg of the title compound (67.7%) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:39])[C:10]=1[C:11]([NH:13][CH2:14][CH2:15][C@H:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[CH3:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[CH3:17])=[O:12])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C[C:54]2N(O)N=[N:57][C:55]=2[CH:56]=1.C(N)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:55]([NH:57][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:39])[C:10]([C:11]([NH:13][CH2:14][CH2:15][C@H:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][C:37]=3[CH3:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH3:17])=[O:12])=[C:2]([CH3:1])[CH:3]=1)([CH3:56])[CH3:54]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C(=O)O)cc2C)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C(=O)NC(C)C)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
3,5-Dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-terephthalamic acid (50.0 mg, 0.09 mmol), EDCI (19.9 mg, 0.10 mmol) and HOBT (14.1 mg, 0.10 mmol) were combined in DMF (4 mL) to give a pale yellow solution. To this solution was added isopropylamine (8.9 μL, 0.10 mmol) followed by DIPEA (19.7 μL, 0.11 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded N′-isopropyl-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-terephthalamide as a white foam (10.1 mg, 19%). 1H NMR (CDCl3) δ 1.02 (br s, 3H), 1.22 (d, 6H, J=7 Hz), 1.83 (m, 3H), 2.22 (m, 1H), 2.29 (s, 3H), 2.34 (s, 6H), 2.55 (m, 1H), 2.80 (m, 4H), 3.38 (m, 1H), 3.62 (m, 1H), 3.76 (m, 1H), 4.10 (s, 2H), 4.23 (sext, 1H, J=6 Hz), 6.04 (d, 1H, J=7 Hz), 6.59 (d, 2H, J=8 Hz), 6.72 (t, 1H, J=7 Hz), 7.05 (d, 1H, J=5 Hz), 7.16 (t, 2H, J=8 Hz), 7.34 (br s, 1H), 7.39 (s, 2H), 8.27 (s, 1H), 8.33 (d, 1H, J=5 Hz). ES-MS m/z 570 (M+H), 593 (M+Na). Anal. Calcd. For C35H47N5O2: C, 73.78; H, 8.31; N, 12.29.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:56]1[CH:57]=[C:58]([O:68][CH3:69])[C:59]([O:64][CH2:65][O:66][CH3:67])=[C:60]([CH:63]=1)[CH:61]=[O:62]>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.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[CH3:69][O:68][C:58]1[C:59]([O:64][CH2:65][O:66][CH3:67])=[C:60]([CH:63]=[C:56]([N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:6])[CH:57]=1)[CH:61]=[O:62]
Reactant: O=C1NCCO1
Reactant: COCOc1c(C=O)cc(Br)cc1OC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCOc1c(C=O)cc(N2CCOC2=O)cc1OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
2-oxazolidinone (0.38 g, 4.36 mmol), dipalladium tris(dibenzylideneacetone) (0.17 g, 0.18 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (0.32 g, 0.55 mmol) and cesium carbonate (1.66 g, 5.1 mmol) were added to a dioxane solution (20 ml) of 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (1.0 g, 3.6 mmol) and the mixture was stirred at 100° C. for 24 hours under an argon atmosphere. The reaction solution was cooled to room temperature and ethyl acetate was added thereto. The mixture was filtrated by cerite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue. The insoluble matter thus purified was obtained by filtration and dried to obtain 3-methoxy-2-methoxymethoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde (0.5 g) as white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[I-].[K+].CN(C)C(=O)C>O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A mixture of 13.6 parts of 1H-imidazole, 16.8 parts of ethyl 4-fluorobenzoate, 0.1 parts of potassium iodide and 54 parts of N,N-dimethylacetamide was stirred and refluxed for 20 hours. The reaction mixture was cooled to room temperature and poured onto a lot of water. The product was extracted a few times with benzene. The combined extracts were washed thoroughly with water, dried, filtered and evaporated. The residue was stirred in hexane. The product was filtered off and dried, yielding 7.2 parts (33.3%) of ethyl 4-(1H-imidazol-1-yl)benzoate; mp. 100.3° C. (intermediate 18).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].O.[O:14]=[C:15]1[CH:22]2[CH:17]([CH2:18][CH:19]=[CH:20][CH2:21]2)[NH:16]1>C1C=CC=CC=1>[OH:3][CH:2]([N:16]1[C:15](=[O:14])[CH:22]2[CH:17]1[CH2:18][CH:19]=[CH:20][CH2:21]2)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C1NC2CC=CCC12
Reactant: O=CC(=O)OCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3 h

Procedure:
Benzyl glyoxylate (2.73 g) was refluxed in benzene (25 ml) with provision for the removal of water. After 45 minutes 8-oxo-7-azabicyclo[4,2,0]oct-3-ene (1) (ref: I. A. Paquette and T. Kakihana, J. Amer. Chem. Soc., 1968, 90, 2897) (1.23 g) was added and refluxing continued for 3 hours. Removal of solvent under reduced pressure followed by chromatography gave two separate isomers of the alcohol (2)(90%) Isomer I, m.p. 92°-93°, λmax (CHCl3) 3450, 1750 (b) cm-1. δppm (CDCl3) 1.76-2.73 (4H, m, 2-CH2), 3.12-3.33 (1H, m, β-lactam proton), 3.76-3.93 (1H, m, β-lactam proton), 4.40 (1H, d, J 6 Hz, exch., D2O), 5.16 (2H, s, CH2), 5.47 (1H, d, J 6 Hz collapsing to s on D2O exch., CH-OH), 5.67-5.83 (2H, m, CH=CH), 7.34 (5H, Ar). M+ at m/e 287 (Found: C, 66.2; H, 5.9; N, 4.9. C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%). Isomer II, m.p. 100°-101°, νmax (CHCl3) 3450, 1750 (b), δppm (CDCl3) 1.80-2.63 (4H, m,2-CH2), 3.13-3.36 (1H, m, β-lactam proton), 3.93-4.13 (1H, m, β-lactam proton), 4.20 (1H, bs, exch., D2O), 5.16 (2H, s, CH2), 5.50 (1H, b, sharpening to s on D2O exchange), 5.50-6.00 (2H, m, CH=CH), 7.34 (5H, Ar). H+ at m/e (Found: C, 67.2; H, 6.0; N, 4.8. C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCC([O-])(C)C.[Na+].ClCCl.C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:14]([O:13][C:11]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 0.001000 mol), tert-butyl piperazine-1-carboxylate (186.2 mg, 0.001000 mol), sodium tert-pentoxide (110.1 mg, 0.001000 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (24.5 mg, 0.0000300 mol) and 1,1′ bis(diphenylphosphino)ferrocene (16.6 mg, 0.0000300 mol) was deaerated and then charged with nitrogen. To the mixture was added toluene (3.0 mL, 0.028 mol), and the resulting mixture was heated at 100° C. overnight. The mixture was poured into ice-water and was extracted with ethyl acetate (4×10 mL). The combined organic layer was washed with water and brine successively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/hexane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[F:17])[S:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10]2=[O:20])(=O)=O.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CCN(CC)CC.CN(C=O)C.O.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>[CH3:18][C:12]1([CH3:19])[CH2:11][C:10](=[O:20])[C:9]2[C:14](=[CH:15][C:16]([F:17])=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:8]=2)[S:13]1
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)c(F)cc2S1
Temperature: 95 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-7-fluoro-thiochroman-6-yl trifluoromethanesulfonate (Compound 205, 1.28 g, 3.57 mmol) in 6.0 mL Et3N and 15.0 mL DMF was sparged with argon for 15 minutes. To this solution was added trimethylsilylacetylene (2.0 g, 20.4 mmol) and bis(triphenylphosphine)-palladium(II) chloride (100.0 mg, 0.14 mmol). The solution was heated to 95° C. for 6 hours, cooled to room temperature and stirred overnight. The solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl and dried over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3 to 5% EtOAc/hexanes) afforded 850.0 mg (78%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCl3)δ: 8.22 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=9.3 Hz), 2.85 (2H, s), 1.46 (6H, s), 0.25 (9H, S).
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:19]([O:11][C:8]([CH:2]1[CH2:3][CH:4]2[O:7][CH:1]1[CH2:6][CH2:5]2)([CH3:9])[CH3:10])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(O)C1CC2CCC1O2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(C)(C)C1CC2CCC1O2
Reaction time: 1 h
Yield: 82 %

Procedure:
In 80 ml of toluene were dissolved 12.5 g of 2-(7-oxanorbornan-2-yl)-2-propanol, 12.1 g of triethylamine, and 0.4 g of 4-(N,N-dimethylamino)pyridine. Then 9.1 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 13.8 g of 2-(7-oxanorbornan-2-yl)-2-propyl acrylate. The two-step yield was 82%.
Reaction SMILES: C(C1N=C([N:9]([C:38]2[S:39][CH:40]=[C:41]([C:43](=[O:46])[CH2:44][CH3:45])[N:42]=2)[C:10](=[O:37])[C@@H:11]([N:20]2[C:24](=[O:25])[C@@H:23]([C:26]3[CH:35]=[CH:34][C:29]4[O:30][CH2:31][CH2:32][O:33][C:28]=4[CH:27]=3)[NH:22][C:21]2=[O:36])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])SC=1)(=O)C.CO.[BH4-].[Na+].P([O-])([O-])(O)=O.[K+].[K+]>[Cl-].[Na+].O>[O:30]1[C:29]2[CH:34]=[CH:35][C:26]([C@@H:23]3[C:24](=[O:25])[N:20]([C@@H:11]([C@H:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH3:13])[C:10]([NH:9][C:38]4[S:39][CH:40]=[C:41]([CH:43]([OH:46])[CH2:44][CH3:45])[N:42]=4)=[O:37])[C:21](=[O:36])[NH:22]3)=[CH:27][C:28]=2[O:33][CH2:32][CH2:31]1
Reactant: CCC(=O)c1csc(N(C(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc4c(c3)OCCO4)C2=O)c2nc(C(C)=O)cs2)n1
Agent: O=P([O-])([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCC(O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc4c(c3)OCCO4)C2=O)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
(2S,3S)-N-(4-Acetyl-thiazol-2-yl)-2-[(R)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (from example 5a) (20 mg, 0.037 mmol) was dissolved in warm dry methanol (5 mL). The reaction mixture was then cooled in an ice bath and sodium borohydride (1.56 mg, 0.041 mmol) was added. The reaction was stirred at 5° C. for 30 minutes, additional sodium borohydride (1.56 mg, 0.041 mmol) was added and stirring continued for 1 hour. The clear solution was treated with 1.5 N aqueous potassium hydrogen phosphate (1 mL) and the cloudy mixture was stirred for a few minutes, then diluted with saturated brine and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The pale yellow residue was taken into a small amount of dichloromethane (0.5 ml) then treated with diethyl ether (2 mL) and this turbid solution was further precipitated with of hexanes (3 mL). The mixture was stirred for 5 minutes then filtered over a 1.7 cm funnel, washed with hexanes and air dried to give (2S,3S)-2-[(R)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-N-[4-(1-hydroxy-propyl)-thiazol-2-yl]-3-phenyl-butyramide as a white solid (14.5 mg, 73%).