Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:26]O>>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:26])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (1.0 g, 3.44 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride (818.1 mg, 6.89 mmol) over 1 h. The reaction was warmed to room temperature and stirred for 1 h. The solvent was removed under reduced pressure. The reaction mixture was washed with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (3×10 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 789 mg (97%) of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate as the HCl salt. LCMS-ESI (M/z) calculated for C11H12N2O2; 204.1. found 205.0 [M+H]+, tR=3.25 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 3H), 7.83 (d, J=8.3 Hz, 2H), 7.51 (t, J=8.8 Hz, 2H), 4.37 (t, J=6.7 Hz, 1H), 3.68 (s, 3H), 3.23 (qd, J=14.4, 7.7 Hz, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[CH2:2][CH3:3].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[Cl-].[Zn+2].[Cl-]>[C:14]([C:9]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1ccc(OC)c(OC)c1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1cc(OC)c(OC)cc1C(C)=O
Yield: 74 %

Procedure:
Following the same procedure as in Example 3 a), a mixture of 18.02 g (0.1 mole) of 4-propyl-1.2-dimethoxybenzene, 5.13 g (0.05 moles) of acetic anhydride and 0.7 g (5 mmoles) of anhydrous zinc chloride was reacted at 80-90° C. for 6 hrs. After washing, separation of the organic phase and evaporation u.v (20° C./21 mbar) a residue was obtained that after purification on silica gel column (eluant n-hexane: ethyl acetate 90/10 v/v) gives 8.0 g (0.037 moles) of 1-acetyl-6-propyl-3,4-dimethoxybenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O1CCOCC1>[Ni].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 55.5 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidin-4-one (2.8 g, 12.7 mmol) in a mixture of 1:4 dioxane: methanol (100 mL) was hydrogenated over Raney nickel (1 g) under balloon pressure at ambient temperature overnight. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The resulting solid was washed with petroleum ether (2×10 mL) and dried to afford 1-(4-amino-phenyl)-piperidin-4-one (1.34 g, 55%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:27])[CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)Cl.O1CCOCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:27])[CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)N2CCN(C3CCC3)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(CC(=O)N2CCN(C3CCC3)CC2)CC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl {1-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperidin-4-yl}carbamate (9.2 mmol) in DCM, is added 4N HCl in dioxane (10 mL) slowly. The mixture is heated at 50° C. for 30 min. The solvent is removed in vacuo to give the title compound as a white solid (trihydrochloric acid salt).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:23][C:24]1[C:28](C(Cl)=O)=[C:27]([CH3:32])[O:26][N:25]=1>C(Cl)Cl>[CH3:23][C:24]1[C:28]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[C:27]([CH3:32])[O:26][N:25]=1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(C)c1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-tert-butyloxycarbonyl-piperazine (4.581 mmol, 0.9 eq) and diisopropylethylamine (5.09 mmol, 1.0 eq) in methylene chloride (5 mL) was added to a 40 mL vial. 3,5-Dimethyl-isoxazole-4-carbonyl chloride (5.09 mmol, 1.0 eq) was added to the vial and the reaction was shaken overnight at room temperature. When the reaction was complete, it was diluted with methylene chloride (5 mL) and washed with 4 mL of 1N HCl followed by 4 mL of 10% potassium carbonate. The organic layer was concentrated in vacuo. The crude residue was dissolved in 5 mL of dioxane and 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was shaken overnight at room temperature then centrifuged. The supernatant was removed and the remaining solid was shaken with hexane then centrifuged. The supernatant was removed, and the solids were collected and dried in vacuo to give (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone. LR-MS: 210.2 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1.[C:19](Cl)(Cl)=[O:20].CCO>C1(C)C=CC=CC=1>[F:14][C:8]1[CH:7]=[C:6]([N:5]2[CH2:4][C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:19]2=[O:20])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(NCc2ccccc2N)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(N2Cc3ccccc3NC2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a stirred suspension of crude N-(2-aminobenzyl)-3-fluoro-4-methoxyaniline (246 mg, 1 mmol) in 10 mL toluene at 0° C. under a drying tube was added phosgene solution (20% in toluene, 683 μL, 1.30 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 30 minutes. The solution was then warmed to reflux. After 1 hour, the reaction was concentrated to dryness and the residue dissolved in a minimum of hot 95% EtOH. A precipitate formed which was isolated by filtration with 95% EtOH and dried to give a tan solid (65 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 7.01 (m, 2H), 6.81 (d, 1H), 4.80 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([NH2:28])[CH:27]=3)=[O:21])=[CH:18][N:17]([CH:29]([CH3:31])[CH3:30])[C:15]=2[N:16]=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40](O)=[O:41])=[N:37][CH:38]=1>>[NH2:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]([C:22]3[CH:27]=[C:26]([NH:28][C:40](=[O:41])[CH2:39][C:36]4[CH:35]=[CH:34][C:33]([Br:32])=[CH:38][N:37]=4)[CH:25]=[N:24][CH:23]=3)=[O:21])=[CH:18][N:17]([CH:29]([CH3:31])[CH3:30])[C:15]=2[N:16]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Reactant: O=C(O)Cc1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 with DIPEA using (2-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone (Preparation 122) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a colourless oil in 57% yield, 75 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](=S)=[S:15].O.Cl>N1C=CC=CC=1>[SH:15][C:14]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: S=C=S
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nnc(S)o1

Procedure:
The reactions of Equation 36 above can be run according to similar procedures described in E. Hoggarth, J. Chem. Soc., 4811 (1952). Thus, in reaction 36a, 2-nitrobenzhydrazide XLVIII is reacted with carbon disulfide in pyridine solvent at 25° to 80° C. for about 4 to 16 hours, followed by addition of water and acidification with hydrochloric acid to form a 2-mercapto-5-(2-nitrophenyl)-1,3,4-oxadiazole of Formula (L). In reaction 36b, L is reacted with sodium hydroxide and methyl iodide in water at 0° to 30° C. for 0.2 to 1 hour to form Xk".
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:28](=O)([O-])[O-:29].[K+].[K+].C(Cl)(=O)OCC>CN(C)C=O>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:28](=[O:29])[O:27][C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:10]2[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(O)(c2ccccc2)c2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of (1,1-dimethylethyl)3-(hydroxydiphenylmethyl)-1-piperazine carboxylate (9.6 g, 26 mmol) in N,N-dimethylformamide (180 mL) were added potassium carbonate (20 g, 0.14 mol) and ethyl chlorocarbonate (14 g, 0.26 mol), and the mixture was stirred at 50° C. for 16 hours. To the reaction solution were further added potassium carbonate (20 g, 0.14 mol) and ethyl chlorocarbonate (14 g, 0.26 mol), and the mixture was further stirred at 50° C. for 18 hours. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (6.9 g, yield 64%) as a solid.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2([CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.[C:21](=[O:23])=[O:22]>C1COCC1>[O:9]1[C:10]2([CH2:15][CH2:14][CH:13]([C:16]3[S:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=3)[CH2:12][CH2:11]2)[O:6][CH2:7][CH2:8]1
Reactant: O=C=O
Reactant: c1csc(C2CCC3(CC2)OCCO3)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C2CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 5 mL, 12 mmol) was added dropwise into 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-thiazole (2.50 g, 11 mmol) in THF (10 mL) at −78° C. The reaction was kept at −78° C. for 30 min. The solution was added to solid dry ice (˜5 g) dropwise. After addition, the reaction was warmed to room temperature slowly over 1 hour and quenched with 1 N NaOH (˜10 mL) solution. The solvent was removed and the residue was partitioned between ether and water. The aqueous layer was adjusted to pH=6 with 5% HCl and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1

Procedure:
A solution of 7.0 g (18.7 mmol) tert-butyl (1′-benzyl-[1,4′]bipiperidinyl-4-yl)-carbamate and 14.3 mL (185 mmol) TFA in 80 mL DCM was refluxed overnight. The mixture was evaporated down i. vac., the residue was combined with 200 mL 30% K2CO3 solution and extracted three times with 100 mL EtOAc, discarding the first 100 mL of extract. The combined organic phases were dried over Na2SO4, filtered and evaporated down. The product was reacted further without purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6].[CH2:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)=[O:38])=[CH:12][CH:13]=1)=[O:6]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCC(C)COC(=O)Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(OC(=O)OCC(C)CC)cc3)cc2)cc1
Temperature: 60 °C

Procedure:
p-(2-Methylbutyloxycarbonyloxy)phenol (0.25 g) prepared in the above (i) was dissolved in pyridine (5 ml) and cooled with ice, followed by dropwise adding a solution of 4'-octyl-4-biphenylcarboxylic acid chloride (0.37 g) dissolved in toluene (5 ml), heating on a water bath at 60° C., reacting the mixture, adding toluene (50 ml), separating the toluene layer, washing with 6N-hydrochloric acid, further with 2N-NaOH aqueous solution, then with a saturated NaCl aqueous solution to make the layer neutral, drying over sodium sulfate, concentrating, and twice recrystallizing from a mixed solution of ethyl acetate (20 ml) and ethanol (10 ml) to obtain the objective 4'-octyl-4-biphenylcarboxylic acid p-(2-methylbutyloxycarbonyloxy)phenyl ester. This product exhibited SA phase and Ch phase and its phase transition points, C-SA point, SA-Ch point, and Ch-I point were 78.3° C., 150.2° C. and 165.2° C., respectively. Further its values of elemental analysis accorded well with its calculated values as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH:17]1([O:15][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reaction time: 16 h

Procedure:
A mixture of N-tert-butoxycarbonyl L-methionine (30 g.), cyclopentanol (31 g.), DMAP (44 g.), EDC (30 g.) and dichloromethane (200 ml.) was stirred under an inert atmosphere for 16 hours. It was then washed with 1M. aqueous citric acid (200 ml.), saturated sodium carbonate solution (100 ml.) and brine, dried and evaporated to dryness to give N-tert-butoxycarbonyl L-methionine cyclopentyl ester as a gum(36 g.).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C@H:3]1[OH:17].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:17][C@H:3]1[C@H:4]([NH:8][C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][CH2:6][CH2:7][C:2]1([F:18])[F:1])(=[O:29])=[O:28]
Reactant: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1OS(C)(=O)=O)c1ccccc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of (23) (1.02 g, 4.01 mmol) in THF (20 mL) was added triethyl amine (0.56 mL, 4.01 mmol), followed by methanesulfonyl chloride (0.34 mL, 4.41 mmol). The reaction was allowed to stir at 35° C. overnight. After cooling to room temperature, the reaction mixture was filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20-60% ethyl acetate in hexanes) to yield (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexyl methanesulfonate (1.01 g, 3.03 mmol, 76% yield). In a microwave vial, the sulfonate intermediate (1.02 g, 3.07 mmol) was dissolved in THF (15.4 mL) and triethylamine (0.58 mL, 4.15 mmol). The vial was sealed and was heated to 100° C. and was stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under pressure. The resultant residue was directly purified by column chromatography (silica gel, 0-70% ether in hexanes, linear gradient) to yield aziridine 73.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]#[N:13])=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[Mg].O1CCCC1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]#[N:13])[CH:7]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: N#CC1=C(c2ccc(F)cc2)CCc2cc(Br)ccc21
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1c2ccc(Br)cc2CCC1c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 6-bromo-2-(4-fluorophenyl)-3,4-dihydronaphthalene-1-carbonitrile (8 g), magnesium (3 g), tetrahydrofuran (300 ml) and methanol (300 ml) was stirred at 0° under an atmosphere of argon for 1.5 h. The reaction mixture was then poured into 2N hydrochloric acid (300 ml), and the organic solvents were evaporated under reduced pressure. The residue was extracted with ethyl acetate (300 ml), the extract was dried and evaporated to dryness and the residue was triturated with diethyl ether to give 6-bromo-2-(4-fluorophenyl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile as a white solid, m.p. 146°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C.C1COCC1.C(OCC)C>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccc1CCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([C:21]3[CH:33]=[CH:32][O:31][C:22]=3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:39]=[CH:40]\[CH2:41][OH:42])CCC>O1CCOCC1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([N:12]([C:17]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]3[C:20]([C:21]4[CH:33]=[CH:32][O:31][C:22]=4[CH2:23][O:24]3)=[CH:19][CH:18]=2)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10])=[C:2](/[CH:39]=[CH:40]\[CH2:41][OH:42])[CH:7]=1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Temperature: 70 °C
Yield: 78.3 %

Procedure:
A mixture of methyl 7-{N-[2-bromo-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 93, 0.200 g) and (Z)-3-tributylstannanyl-prop-2-en-1-ol (Intermediate 1, 0.230 g) in dioxane (9 mL) and water (1 mL) was de-gassed and flushed with nitrogen. tris-(Dibenzylideneacetone)dipalladium (0.034 g) and tri-tert-butylphosphonium tetrafluoroborate (0.022 g) were added and the reaction mixture was heated to 70° C. for 30 minutes. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, pre-equilibrated with ammonia solution in DCM, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-100%. The resultant product was triturated with ether to give methyl 7-{N-[4-fluoro-2((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.150 g) as a cream powder.
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: C=C(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 0 °C

Procedure:
A mixture of 7β-amino-3-methylceph-3-em-4-carboxylic acid (16.09 g., 75.2 m.moles), dioxan (100 ml.), sulphuric acid (10 ml.) and isobutylene (90 ml.) was shaken in a pressure bottle until a clear solution resulted (21/2 hours). The solution was cooled and poured into a mixture of aqueous sodium bicarbonate (600 ml.), ice (100 g.), and ethyl acetate (150 ml.). The aqueous layer was twice more extracted with ethyl acetate and the extracts were washed with brine and dried. Evaporation left a gum which was triturated with petrol (b.p. 40° - 60°) to give off-white crystals (11.17 g., 55%). A sample was recrystallised from ether to give the pure ester, m.p. 126°, [α]D + 107° (EtOH), λmax. 271 nm. (E1cm.1% 239) (Found: C, 53.1; H, 6.5; N, 10.1; S, 11.5 C12H18N2O3S requires: C, 53.3; H, 6.7; N, 10.35; S, 11.85%).