Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(OC1C=C(C)C=CC=1C)C1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])(=O)C.O1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:12]([C:11]1[C:16]([CH3:17])=[CH:28][C:29]([O:30][CH2:31][C:32]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:8])[CH:6]=1)([OH:14])=[O:13]
Reactant: C1COCCO1
Reactant: C/C=C(/C(=O)OC)c1ccccc1C(Oc1cc(C)ccc1C)C(C)=O
Product: C/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)O)cc1C

Procedure:
In a similar manner to the process for precursor δ), 9.6 g of methyl 2-[2-(acetyl-2,5-dimethylphenoxymethyl)phenyl]-E-but-2-enoate in 60 ml of dioxane were reacted to give the carboxylic acid. After concentrating on a rotary evaporator a yellow oil remained which in addition to 70% of the title compound contained a further 30% of the diacid formed by hydrolysis of the methyl butanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][O:17][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of Intermediate 92a (667 mg, 2.83 mmol) and Et3N (630 μL, 4.53 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (950 μL, 3.54 mmol) and the mixture was stirred at RT for 1 h. The mixture was washed with sat. sodium hydrogen carbonate solution then brine, dried and concentrated in vacuo. The residue was purified by FCC, 2-6% MeOH in DCM, to give the title compound as a pale green viscous oil (1.11 g, quant.). LCMS (Method 3): Rt 4.76 min, m/z 393 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:7]1[C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([F:15])[CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
Compound A (80.0 g, 311 mmol) and 3-fluoro-4-methylphenylboronic acid (52.7 g, 342 mmol) were suspended in isopropyl alcohol (260 mL, 3.5 mol). A solution of sodium carbonate (56.1 g, 529 mmol) in water (260 mL, 15 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.1 mmol) was then added and the mixture was stirred at 90° C. for 17 hours. The mixture was concentrated under reduced pressure and suspended in water (200 mL). The aqueous phase was extracted with EtOAc (600 mL) and separated. The organic phase was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (4-6% 5×120 g column) to yield compound B as a clear oil (68.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[CH3:20])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(C)c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-methoxy-2-methylaniline and was obtained as a white solid as described in Example 1. 1H NMR (CDCl3): 8.88 (bs, 1H), 8.19 (d, J=7.2, 1H), 7.61-7.47 (m, 3H), 6.81-6.79 (m, 2H), 3.81 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:28][CH:27]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Product: CN(C)CCOc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 11 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone with 4-(2-dimethylaminoethyloxy)-aniline.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a 250 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (6.32 g, 45.7 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a brown filterable solid was isolated by filtration providing crude 4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (5.97 g, 13.14 mmol, 86% yield). MS (ES+) m/e: 453.0, 454.0 [M+H]+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[C:29](=[O:31])[CH3:30].Cl>C1COCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]3=2)[CH:10]=[CH:11][C:2]=1[C:29](=[O:31])[CH3:30]
Reactant: Brc1ccc2ccc3ccccc3c2n1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc2ccc3ccccc3c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 2-bromobenzo[h]quinoline (1.52 g, 5.89 mmol) in THF (36 ml) was cooled to −78° C. After 10 minutes a solution of 2.5 M n-butyllithium in n-hexane (2.47 ml, 6.18 mmol) was added. The resulting dark red solution was again stirred at −78° C. for 1 hour after which N,N-dimethylacetamide (0.60 ml, 6.45 mmol) was added drop-wise. The solution was stirred for 1 h at −78° C. and allowed to warm slowly to ambient temperature. A solution of 1 M HCl (7.4 ml, 7.4 mmol) was then added to the organic phase was separated and the aqueous phase was extracted with Et2O (2×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/acetate=95/5) to give 1.00 g (77% yield) of 1-(benzo[h]quinolin-2-yl)ethanone in the form of a yellow solid: mp 113-115° C.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:16]
Reactant: CC[O-]
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)c2nnc(N)n2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 2.5 g) were dissolved in ethanol (50 ml), admixed under argon with sodium ethoxide (3.86 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 1.76 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Yield: 79.3 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.7749 g, 1.35 mmol), benzyl bromide (0.4618 g, 0.321 ml, 2.7 mmol), 18-crown-6 (0.714 g, 2.7 mmol) and sodium hydride (0.1037 g, 4.32 mmol) in THF (6 ml) were heated at 60° C. for 1 hour. The mixture was diluted with water and extracted into ethyl acetate. The organics were collected and dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 15% ethyl acetate/iso-hexane, to afford the title compound as a clear oil (712 mg, 79%).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[I:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2](=[O:1])[CH3:14])=[O:13]
Reactant: CC(O)CNC(=O)c1cccc(I)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
N-(2-Hydroxypropyl)-3-iodobenzamide (1.09 g, 3.57 mmol) obtained in Step 1 was dissolved in dichloromethane (40 mL), cooled to 0° C., and stirred at room temperature for 1 hour after adding Dess-Martin periodinane (1.82 g, 4.28 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration was purified by silica gel column chromatography to give 3-iodo-N-(2-oxopropyl)benzamide (1.01 g, 93%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=O)=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[NH3:42]>[Ni].O.CO>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([NH2:42])=[O:38])=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C#N)c1
Reactant: N
Agent: [Ni]
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(N)=O)ccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 16 h
Yield: 36 %

Procedure:
To 0.5 mL of Raney Nickel in water was added a solution of 2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.55 g, 1 mmol) in methanol (25 mL). The solution was then saturated with ammonia gas for 10 minutes. The reaction vessel was then shaken vigorously under an atmosphere of hydrogen (40 psi) for 16 hours. The mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (88:12 CH2Cl2:MeOH) to afford to give the amide (0.20 g, 36%). 1H NMR (CDCl3) δ 1.73 (m, 1H), 2.01 (m, 2H), 2.35 (m, 1H), 2.85 (m, 2H), 3.88 (t, 2H, J=15.9 Hz), 4.16 (m, 1H), 4.21 (d, 1H, J=9.6 Hz), 4.26 (d, 1H, J=7.8 Hz), 5.71 (br, 1H, NH), 6.12 (br, 1H, NH), 7.19 (m, 3H), 7.46 (d, 1H, J=7.8 Hz), 7.55 (br, 2H), 7.80 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 8.64 (dd, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 21.71, 24.65, 29.44, 49.92, 53.09, 61.84, 112.81, 117.49, 122.30 (4C), 122.97, 130.44 (2C), 131.98, 132.32, 133.56, 135.37, 138.05 (2C), 147.13, 147.29, 155.27, 156.87, 167.82. ES-MS m/z 437 (M+H). Anal. Calcd. for C26H24N6O.0.6CH2Cl2: C, 65.54; H, 5.21; N, 17.24. Found: C, 65.93; H, 5.51; N, 17.44.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), (S)-tert-butyl 2-aminopropanoate hydrochloride (25.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=465.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.7 Hz, 0.4H), 1.28 (d, J=7.2 Hz, 3H), 1.44 (s, 9H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.51 (t, J=7.8 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 3.05-3.21 (m, 4H), 3.37-3.48 (m, 1H), 3.49-3.62 (m, 1H), 3.73-3.83 (m, 1H), 4.20-4.29 (m, 1H), 6.64 (d, 7.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: C([Li])CCC.[OH:6][C:7]([C@H:10]1[C@@H:13]([CH2:14][CH:15]=[CH2:16])[N:12]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:25])([CH3:9])[CH3:8].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(O)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:24])=[C:17]([N:12]1[C@H:13]([CH2:14][CH:15]=[CH2:16])[C@H:10]([C:7]([CH3:9])([O:6][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[CH3:8])[C:11]1=[O:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C=CC[C@@H]1[C@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@H](C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A solution of n-butyl lithium (0.46 ml of 1.38 M solution in hexane) was added to a solution of methyl 2-[(3R, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) at -70° C. and the mixture was stirred for 15 minutes at -70° C. A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (3.2 ml) was added to the reaction mixture at -70° C. and the mixture was stirred for 10 minutes at -70° C. The mixture was allowed to warm to 0° C. during 30 minutes and stirred at 0° C. for 1.5 hours. Acetic acid (0.043 ml) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with brine, aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give methyl 3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (123 mg) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[Br:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CC(CC)=O.CCOCC>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][Br:23])=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: BrCc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O

Procedure:
To a solution of 1-(2,4-dihydroxy-3-propyl phenyl) ethanone (10.0 g; 0.051 m) in dry methylethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol. eq) and sodium iodide (0.5 g). To the stirred suspension was then added α,α'-dibromo-p-xylene (13.5 g; 0.051 m) and the suspension gently heated at reflux for five hours. The cooled suspension was evaporated under reduced pressure, the residue dissolved in water and extracted with dichloromethane (×2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered, and evaporated to dryness under reduced pressure to give a yellow solid. The solid was stirred with ether (200 ml) for 1 hour and filtered to remove any disubstituted impurity. The filtrate was evaporated under reduced pressure to leave a yellow solid. The solid was chromatographed on a U30 Sorbsil solumn using dichloromethane to give a white solid; recrystallised from ethanol, m.p. 98°-99° C.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.[C:23](=O)(O)[O-].[Na+].C(O)C>[Pd].CN1C(=O)CCC1>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@@H:13]([CH:15]([OH:14])[CH3:23])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CC(O)[C@@H]1COc2ccc([N+](=O)[O-])cc2O1
Temperature: 51 °C

Procedure:
A 500 mL three necked Morton flask equipped with magnetic stir bar, thermocouple, gas inlet adapter and gas outlet adapter is charged with (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (20.00 g, 66.4 mmol), sodium bicarbonate (5.58 g, 66.4 mmol), palladium (5% on carbon, 50% water, 3 g), ethanol (136 mL) and NMP (24 mL). The flask is immersed in an oil bath and heated to 50-52° C. (internal) to effect solution. The stirring is stopped and the flask is flushed with hydrogen gas (300 mL). Stirring is resumed and hydrogen gas is titrated into the solution [1550 mL (69.2 mmol) over 5.5 h]. Heating is discontinued, and a flow of nitrogen is used to sweep the head space for 20 min. Once the solution is cooled to 25° C., the mixture is filtered through a pad of celite and the filter cake is washed with ethanol (50 mL). The resulting solution is concentrated by rotary evaporation removing ˜200 mL of ethanol. The solution is transferred to a separatory funnel and i-PrOAc (220 mL) is added followed by water (200 mL). The mixture is thoroughly shaken and the bottom aqueous layer is drained and discarded. The product containing organic layer is washed with water (3×50 mL), and transferred to a 500 mL three necked flask equipped with a magnetic stir bar, thermocouple, heating mantel, and a distillation head. The i-PrOAc is removed by distillation at atmospheric pressure. Once ˜180 mL has been collected, pyridine (80 mL) is added and the distillation is continued until the head temperature is 108° C. The solution is allowed to cool to room temperature and used directly as illustrated in Schemes I and II, and as described in the Examples below.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]=[O:14])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Mg+].[Br-].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:14])[CH3:16])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-oxoethyl)-2-azetidinone (2.27 g, 0.01 mole) is dissolved in 50 ml ether and cooled to -20° C. under N2. A solution of CH3MgBr in ether (0.011 mole CH3MgBr) is added dropwise over 1/2 hours at -20° C. and the reaction mixture is stirred for another 1/2 hr at -20°, allowing to rise to 25° C. The reaction mixture is treated with a saturated solution of MgSO4 (2 ml) and allowed to stir for 15 min. The Mg salts are filtered off and washed with ether. The combined filtrate and washings are dried and evaporated. Chromatography of the residue on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11]OS(C)(=O)=O)=[N:7][C:6]=2[CH:17]=1.[CH3:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.CCN(CC)CC>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1nc2cc(Br)ccc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2s1
Temperature: 60 °C

Procedure:
The methanesulfonic acid 2-(5-bromo-benzothiazol-2-yl)-ethyl ester from Example 1B, and 2 equivalents (7.3 mmol) of 2-(R)-methylpyrrolidine (at a concentration of 10 mg/mL solution in acetonitrile), was combined with excess Et3N (0.99 g, 9.8 mmol), and the resulting mixture was heated to 60° C. for 2 hr. The solvent was removed under vacuum, and the residue dissolved in CH2Cl2. and washed with saturated NaHCO3 (twice). The organic layer as dried over MgSO4 and concentrated in vacuo to give crude product, 1.15 g (97.1%). 1H NMR (400 MHz, CDCl3) δ ppm 1.06 (d, J=6.04 Hz, 3 H) 1.78-1.6 (m, 3 H) 1.88 (m, 1H) 2.20 (m, 1 H) 2.38 (m, 1H) 2.55 (m, 1H) 3.23 (m, 4 H) 7.37 (dd, J=8.44, 1.85 Hz, 1 H) 7.61 (d, J=8.51 Hz, 1 H) 8.02 (d, J=1.92 Hz, 1 H). MS m/z 125, 127 (M+H)+, (M+3H)+.