Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH3:19])[C@@:6]([OH:8])([CH3:7])[CH:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].O>ClCCl>[C:20]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:19])[CH:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Cl
Reactant: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)OC[C@H]1OC(n2ccc(=O)[nH]c2=O)[C@](C)(F)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 1-((2R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (about 0.30 g, 1.09 mmol) in dichloromethane (about 5 ml) was added a solution of valeroylchloride (about 0.33 ml, 2.70 mmol) in dichloromethane (about 5 ml) at about 0° C. and stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane to elude title compound (0.10 g) as a colorless solid. Yield: 27%; 1H NMR (300 MHz, CDCl3): δ 8.31 (bs, 1H), 7.39-7.35 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 6.36 (d, 1H, J=22.5 Hz), 5.76-5.72 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 4.58-4.52 (m, 1H), 4.40-4.36 (m, 1H), 4.26-4.20 (m, 1H), 2.64 (s, 1H), 2.40-2.35 (t, 2H), 1.65-1.59 (m, 2H), 1.44 (d, 3H, J=23.1 Hz), 1.37-1.25 (m, 5H), 0.95-0.90 (t, 3H); ES Mass: [M+Na]+: 381 (100%), [M+1]+ 359 (40%); IR cm−: 3504, 3145, 1710, 1676, 1560, 1265, 1180, 1039, 938, 824; HPLC: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:26][CH3:27])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCCC1
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.2 g, 4.3 mmol) in dry DMF (15 mL), cesium carbonate (2.78 g, 8.5 mmol) and ethyl iodide (3.35 g, 21.47 mmol) were added. The resulting reaction mixture was heated at 80° C. for 18 h. On completion, the reaction mixture was cooled to room temperature and filtered, and the residue washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to afford methyl 5-chloro-3-(cyclohexyl(ethyl)amino)-2-methylbenzoate (0.25 g, 22.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+]([O-])=O)=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.C([Br:17])(=O)C>C(O)(=O)C>[Br:17][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N+:7]([O-:9])=[C:6]([CH3:10])[CH:5]=1
Reactant: CC(=O)Br
Reactant: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1c[n+]([O-])c(C)cc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5-Methoxy-2-methyl-4-nitro-pyridine-1-oxide (Step AL5) (1.9 g, 10.3 mmol) and acetyl bromide (22.9 mL, 310 mmol) was added to acetic acid (40 mL) and the reaction was stirred at 80° C. for 1 h. The mixture was concentrated (1/3) and a solution of NaOH was added. The resulting mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The product was crystallised (EtOAc/TBME). ESI-MS: tR=0.54 min, [M+H]+ 218.1/220.1 (LC-MS 1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:51][CH:52]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.5 %

Procedure:
A solution of triphenylphosphine (344 mg, 1.31 mmol) in methylene chloride (10 mL) cooled to 0° C. was treated with N-bromosuccinimide (263 mg, 1.48 mmol). The reaction solution was stirred at 0° C. for 5 min. At this time, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl) propionic acid (250 mg, 0.87 mmol) was added. The reaction was allowed to slowly warm to 25° C. over 45 min. At this time, 5-chloro-2-aminopyridine (145 mg, 1.13 mmol) and pyridine (0.11 mL, 1.31 mmol) were added to the reaction mixture. The reaction was stirred at 25° C. for 20 h. At this time, the reaction was diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded N-(5-chloro-pyridin-2-yl)3-cyclopentyl-2-(R)-(3,4-dichloro-phenyl)-propionamide (289 mg, 84%) as a white solid: mp 125-128° C.; [α]23589=−65.6° (c=0.16, chloroform); EI-HRMS m/e calcd for C19H19Cl3N2O (M+) 396.0563, found 396.0565.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=1.S(=O)(=O)(O)[O-].[K+]>CC(C)=O.O>[CH:3]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=1)=[O:2]
Reactant: COC(OC)c1cc(C(=O)OC(C)(C)C)n[nH]1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(C=O)[nH]n1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 1,1-dimethylethyl 5-[bis(methyloxy)methyl]-1H-pyrazole-3-carboxylate (18.6 g) in acetone (100 ml) was added 1M potassium bisulphate solution (200 ml) and the resultant suspension stirred at RT overnight. The mixture was diluted with water (200 ml), stirred for 10 min, filtered and the resultant solid washed sequentially with water, isopropanol and hexane and dried under high vacuum to give the title compound (11.2 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].Cl.[NH2:14]O>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[O:12][N:14]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: O=c1ccoc2ccc(F)cc12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Oc1ccc(F)cc1-c1ccno1
Reaction time: 18 h
Yield: 12 %

Procedure:
The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol (180 ml) and the resulting mixture is heated to reflux. The reaction is allowed to stir for 18 hours before cooling and concentrating. The residue is taken up in toluene and filtered to give 690 mg of 4-fluoro-2-isoxazol-5-yl-phenol and from the filtrate 594 mg of 4-fluoro-2-isoxazol-3-yl-phenol.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl.C(Cl)Cl.[N:31]1C=CC=[CH:33][CH:32]=1>>[CH2:32]([NH:31][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]=1[OH:15])[CH3:33]
Reactant: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCCCC(CC)COc1ccc(C(=O)NCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
In 30 ml of pyridine was dissolved 3.00 g (11.3 mmol) of 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid (compound 14), and 2.89 g (28.4 mmol) of acetic anhydride was added to the solution dropwise on an ice-water bath. After the dropwise addition, the mixture was stirred for 20 minutes, poured into 120 ml of a 12% aqueous solution of hydrochloric acid, and extracted with 150 ml of ethyl acetate. The organic layer was washed successively with three 150 ml portions of dilute hydrochloric acid, three 150 ml portions of water, and three 100 ml portions of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration. The resulting crude product was dissolved in 10 ml of methylene chloride, and a few drops of DMF were added thereto. To the mixture was further added dropwise 1.57 g (13.2 mmol) of methylene chloride at room temperature, followed by stirring for 15 minutes. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in methylene chloride. The solution was added to 10 ml of a 70% aqueous solution of ethylamine on an ice bath. After the inner temperature was raised to room temperature, 300 ml of dilute hydrochloric acid was added thereto, and the mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed successively with three 300 ml portions of water and two 300 ml portions of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was recrystallized from hexane to obtain 2.06 g (62%) of N-ethyl-4-(2-ethylhexyloxy)-2-hydroxybenzamide represented by the following chemical formula (hereinafter referred to as compound 28) as white crystals. The analytical results are shown below. ##STR49##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([F:33])[C:27]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:5][NH:6][C:7](=[O:24])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[NH:20][CH2:21][CH2:22][CH3:23]>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([F:33])[C:27]=1[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[NH:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)NCc1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [Pd]
Product: CCCNc1cc(C(F)(F)F)ccc1CCC(=O)NCc1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 59.3 %

Procedure:
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide (20 mg, 0.041 mmol) was reduced with Pd/C under hydrogen atmosphere to yield title compound (12 mg, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][Si:8]([CH2:20][CH2:21][C:22](OCC)=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].[H-].[Na+].C1(C)C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][Si:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:22]1=[O:23])=[O:5])[CH3:2]
Reactant: CCCCC[Si](CCC(=O)OCC)(CCC(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCC[Si]1(c2ccccc2)CCC(=O)C(C(=O)OCC)C1
Yield: 88 %

Procedure:
194 g of di(2-ethoxycarbonylethyl)phenyl-n-pentylsilane was added to a suspension of 18.5 g sodium hydride and 800 ml of toluene, and the mixture was stirred for 3 hours at 100 ° C. while ethanol was distilled away. After cooling, 500 ml of 20% hydrochloric acid was added to the reaction mixture to make it neutral, and then the toluene layer was concentrated to obtain 150 g of 2-ethoxycarbonyl-4-n-pentyl-4-phenyl-4-silacyclohexanone.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=O)N)[CH2:7]1)=[O:5])[CH3:2].[Br:17][C:18]1[N:23]=[C:22](C=O)[CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:17])[N:23]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCCN(C(N)=O)C1
Reactant: O=Cc1cccc(Br)n1
Product: CCN(CC)C(=O)C1CCCN(Cc2cccc(Br)n2)C1

Procedure:
14] N,N-Diethylcarbamoyl-piperidine-3-carboxamide (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give N,N-diethyl 1-(6-bromopyridin-2-ylmethyl)piperidine-3-carboxamide as a colorless oil. MS m/z: 354.1 (M+H). Calc'd for C16H24BrN3O—354.29.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51](O)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B3) (420 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (300 mg, 1 equiv), HATU (396 mg, 1.2 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (3.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (171 mg).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]1[S:3]2.Cl.[Cl-].[Na+].C(OCC)(=O)C>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cn3cnnn3)[C@H]1S2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cn3cnnn3)[C@H]1S2
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylate (0.91 g.) in a mixture of dimethylformamide (5 ml.) and acetic acid (1.5 ml.) was added zinc powder (1.2 g.) under ice-cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was poured into a mixture of 2% hydrochloric acid saturated with sodium chloride (30 ml.) and ethyl acetate (50 ml.), extracted and the aqueous layer was further extracted with ethyl acetate (10 ml.). The combined ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After drying, residue obtained by distilling off the solvent under reduced pressure was crystallized by adding a small amount of ethyl acetate and the crystals were collected by filtration to give 2-methyl-2,3-methylene-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylic acid (0.45 g.), mp 167° to 170°C (dec.).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:30][O:29][CH2:28][CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:31][N:26]1[CH2:27][CH2:28][O:29][CH2:30][C@@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CCOC[C@@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCOC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 51.0 mg, 1.27 mmol) in DMF (1.50 mL) was added Intermediate A (51.0 mg, 0.32 mmol) and the reaction stirred for 20 min. Intermediate 83c (75.0 mg, 0.32 mmol) was added in DMF (1.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (31 mg, 26%). LCMS (Method 4): Rt 0.32, m/z 380.0 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>O>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][CH:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]1
Reactant: CN(C)CCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: O
Product: CN(C)CCCNC1CC(C)(C)NC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
1808.9 g (11.65 mol) of 2,2,6,6-tetramethyl-4-piperidinone and 1191.1 g (11.66 mol) of N1,N1-dimethyl-1,3-propanediamine are combined in a 4 l reactor and stirred for 2 hours at 60° C. Then, the reaction water is distilled off in vacuum. Thereafter the reaction solution is transferred to an autoclave and admixed with 76 g of Raney nickel. The autoclave is flushed 3 times with 5 bar nitrogen each time. Then, the hydrogenation is carried out by repeated pressurization with 50 bar hydrogen, wherein the reaction mixture is stirred vigorously during the entire reaction time. Then, the reaction mixture is separated by fractional distillation. The product has a boiling point of 130° C. at 4.5 mbar. 2062 g of product could be isolated having a purity of 98.6% and a yield of 72% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (3.5 mL) was added 4-formylbenzonitrile (53.7 mg, 410 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (52.6 mg, 492 μmol) was added and the stirring was continued overnight. The reaction mixture was poured into 0.1N HCl solution (25 ml). The volume was reduced and the resulting suspension was filtered to give an off white solid as desired product (109 mg, 67% yield). MS +m/z: 358 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:8](=[O:10])[CH2:7][CH2:6][CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)CCC1CC(=O)C1
Product: CC(C)(C)c1ccc(NC(=O)CCC2CC(=O)C2)c([N+](=O)[O-])c1

Procedure:
reacting 3-(3-oxocyclobutyl)propanoic acid with 4-tert-butyl-2-nitroaniline to yield N-(4-tert-butyl-2-nitrophenyl)-3-(3-oxo-cyclobutyl)propanamide; and
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C=O)C.O>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 60 °C

Procedure:
4-Hydroxypiperidine (658 mg, 6 5 mmol) and 1,2-difluoro-4-(methanesufonyl)benzene (1.98 g, 5.1 mmol) were combined in DMF (5 mL). Sodium carbonate (705 mg, 6.7 mmol) was added and the mixture was heated at 60 ° C. for 18 h. The mixture was cooled to room temperature and then poured into a mixture of water (10 mL) and a saturated sodium chloride solution (10 mL). The mixture was extracted three times with ethyl acetate (15 mL) and the extracts were combined, washed with brine, dried (MgSO4), and concentrated under vacuum to afford 1.46 g of crude 1a, which was used in the subsequent step without purification: LC-MS 274.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].[Cl-].[Na+]>C1COCC1>[OH:49][CH2:48][C:47]([NH:46][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH2:24][OH:25])[CH:16]=1)=[O:22])([CH3:51])[CH3:50]
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) in THF (2.7 mL) was added 1-hydroxybenzotriazole hydrate (43.0 mg, 0.28 mmol), N-ethyldiisopropylamine (120 μL, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (43.0 mg, 0.28 mmol) and 2-amino-2-methyl-1-propanol (25.3 mg, 0.28 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (32 mg, 26%) as a white solid. MS: m/e=435.3 [M+H]+.