Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][CH:20]1[CH2:21][N:18]([C:1]([Cl:4])=[O:2])[CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 35.6 g (0.36 mole) of phosgene in 200 ml of methylene chloride at 5° C. was stirred with 50 g (0.36 mole) of potassium carbonate for 1 hr. To the mixture was added dropwise 115 g (0.3 mole) of 1-diphenylmethyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 400 ml of methylene chloride. After stirring for 18 hr, the reaction mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator to a viscous oil residue, 133.2 g. Trituration of the residue with hexane gave a solid which was recrystalized from cold hexane to yield 52 g (62%) of white crystals, m.p. 72.5°-74° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20](OC)(OC)[CH:21]([CH3:23])[CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:20]([CH:21]([CH3:23])[CH3:22])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)(OC)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Product: CC(C)c1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1

Procedure:
25 g 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester was refluxed with 125 mL 1,1,1-trimethoxy-2-methyl-propane overnight. The excess of reagent was removed under vacuum and the residue was purified by chromatography on silica gel to give 16 g of the desired product. 1H NMR (400 MHz, MeOD): δ 4.08-4.04 (m, 2H, CH2), 3.20-3.13 (m, 2H, 2CH), 3.01 (br, 2H, CH2), 2.07-2.03 (m, 2H, CH2), 1.75-1.68 (m, 2H, CH2), 1.46 (s, 9H, 3CH3), 1.36 (d, J=6.8 Hz, 6H, 2CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)[CH3:2].Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([S:16][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) were serially added bromodiphenylmethane (3.38 g, 13.7 mmol) and potassium carbonate (1.90 g, 13.7 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer pas washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (2.70 g). This compound (1.40 g, 2.87 mmol) was dissolved in dichloromethane (30 mL) followed by addition of m-chloroperbenzoic acid (55%, 2.00 g, 6.32 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. This reaction mixture was washed with saturated sodium hydrogen carbonate solution and water, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl[(2-diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.10 g). To a solution of this compound (1.10 g, 2.12 mmol) in tetrahydrofuran (10 mL)-methanol (5 mL) was added 1N-aqueous sodium hydroxide (3.0 mL) dropwise and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture was added 1N-hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 550 mg of the title compound. Yield 39%.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[F:50][C:51]1[CH:52]=[C:53]([CH:63]=[CH:64][C:65]=1[NH:66][C:67]1[N:72]=[C:71]([NH:73][C:74]2[C:75]([C:89](=[O:92])[NH:90][CH3:91])=[N:76][C:77]([C:80]3[CH:81]=[N:82][N:83]([CH2:85][CH2:86][CH2:87][OH:88])[CH:84]=3)=[CH:78][CH:79]=2)[C:70]([C:93]([F:96])([F:95])[F:94])=[CH:69][N:68]=1)[CH2:54][P:55](=[O:62])([O:59]CC)[O:56][CH2:57][CH3:58]>>[F:50][C:51]1[CH:52]=[C:53]([CH:63]=[CH:64][C:65]=1[NH:66][C:67]1[N:72]=[C:71]([NH:73][C:74]2[C:75]([C:89](=[O:92])[NH:90][CH3:91])=[N:76][C:77]([C:80]3[CH:81]=[N:82][N:83]([CH2:85][CH2:86][CH2:87][OH:88])[CH:84]=3)=[CH:78][CH:79]=2)[C:70]([C:93]([F:96])([F:94])[F:95])=[CH:69][N:68]=1)[CH2:54][P:55](=[O:59])([OH:62])[O:56][CH2:57][CH3:58]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(F)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(F)c1
Yield: 93.9 %

Procedure:
Prepared analogously to Compound 3A using diethyl (3-fluoro-4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 22B, 156 mg, 230 μmol) to afford 141 mg of the title compound (94%). 1H NMR (400 MHz, CD3OD) δ=9.05 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.26 (d, J=11.9 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.88 (quin, J=7.0 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 3.05 (d, J=21.0 Hz, 2H), 2.96-3.00 (m, 3H), 2.11 (quin, J=6.5 Hz, 2H), 1.13 (t, J=7.1 Hz, 3H). MS (ESI): m/z=653.66 [M+H]+. UPLC: tR=1.09 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:3])=[O:24]
Reactant: CC(C)=O
Reactant: OCCCCCCCCCBr
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 9-bromononanol (2.2 g,10 mmols) with cooling with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with hexane (40 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of potassium carbonate (40 ml). The aqueous layers were combined, then made acidic (pH=1) with 10% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.8 g (yield: 77%) of 9-bromononanoic acid was obtained as colorless needle-like crystals.
Reaction SMILES: N[C:2]1[C:3]([CH2:9][C:10]#[N:11])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])(O)=[O:13].[Na+]>Cl>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][N:6]=1)[NH:11][C:10](=[O:13])[CH2:9]2
Reactant: O=C([O-])O
Reactant: N#CCc1cc(Cl)ncc1N
Agent: Cl
Agent: [Na+]
Product: O=C1Cc2cc(Cl)ncc2N1
Yield: 46 %

Procedure:
(5-Amino-2-chloro-4-pyridyl)acetonitrile (1.40 g, 8.4 mmol) was taken up in 6N HCl solution (100 mL) and heated between 50° and 100° C. for 2 hours. After cooling, the solution was adjusted to pH 7 by addition of solid NaHCO3 and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using ethyl acetate as eluant. (Some methanol was used to help dissolve the solid). Fractions containing the desired product were combined and concentrated to leave the title compound as a solid (650 mg, 46%), m.p. 230° C. (dec.) The NMR spectrum indicated that this material contained a small amount of the by-product, 2-amino-5-chloro-6-azaindole in addition to the title compound. Nonetheless, this material was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[C:1]([N:11]([C@@H:12]([CH3:22])[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH3:23])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CI
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc([N+](=O)[O-])cc1)N(C)C(=O)OCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of (S)-(-)-N-carbobenzyloxy-α-methyl-4-nitrobenzylamine (8.2 gm, 28 mmol) and methyl iodide (2.6 mL, 42 mmol) in DMF (50 mL) was cooled under nitrogen in an ice bath to 5-10° C. and sodium hydride (60% suspension in mineral oil) (1.2 gm, 31 mmol) was added in portions over 15 min while maintaining the temperature at 5-10° C. The reaction was stirred for 1 hr and then slowly quenched into a mixture of ice water, 2N hydrochloric acid (20 mL) and ether and the layers were separated. The ether layer was washed with water and brine and the aqueous layers were consecutively extracted with a second portion of ether. The pooled ether layers were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography using 10-30% ethyl acetate/hexanes to give 6.6 gm (77%) of the title compound. [α]D (EtOH)=-97°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Yield: 81.9 %

Procedure:
3,5-Dibromophenol (10.0 g), 4-methoxybenzyl bromide (8.8 g) and potassium carbonate (27.3 g) were combined in acetone (300 mL) and refluxed for 3 h. Then the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure and the resulting crude oil was purified on a silica gel column using ethyl acetate and hexanes to give light yellow oil which was then crystallized from hexanes to give the title compound (12.1 g, 82% yield). HRMS calcd for C14H12O2Br2 M+ 369.9203, observed 369.9198.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>S(=O)(=O)(O)O>[OH:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1ccc(O)cc1C(=O)O
Reaction time: 48 h

Procedure:
A solution of 2,5-dimethoxybenzoic acid (10.0 g, 54.9 mmol) in 55 mL concentrated sulfuric acid was heated to 55 deg. C. for 48 h. The reaction was then poured into ice. A precipitate formed, and the mixture was allowed to stand overnight. The resulting crystals were collected by filtration and dried in vacuo. The material was further purified by silica gel chromatography to give 5-hydroxy-2-methoxybenzoic acid as a white solid. MS m/z=169.0 [M+1]+. Calc'd for C8H8O4: 168.15.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH3:13].[K+].[Br-].Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>C(#N)C>[Br-:10].[CH2:11]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:19]2([CH2:18][CH3:17])[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH:4]=1)[CH2:12][CH3:13]
Reactant: BrCCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Reactant: CCCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromopropane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[CH2:13])=[C:4]([NH2:23])[N:3]=1.CN1CCOCC1.COC1N=C(OC)N=C(Cl)N=1.Cl.[CH3:43][O:44][C:45](=[O:54])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[NH2:47]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:47][C@H:46]([C:45]([O:44][CH3:43])=[O:54])[CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])=[O:20])=[CH:21][CH:22]=2)=[CH2:13])=[C:4]([NH2:23])[N:3]=1
Reactant: C=C(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 270 mg (1 eq) of 4-[5-(2,6-diamino-4-hydroxypyrimidin-5-yl)-pent-1-en-2-yl]benzoic acid and 104 mg (1.2 eq) of N-methylmorpholine in 4.0 ml of anhydrous tetrahydrofuran, was vigorously stirred for 5 minutes at room temperature. To this mixture, 165 mg (1.1 eq) of 2,4-dimethoxy-6-chloro-1,3,5-triazine were added and the sol was stirred for 40 minutes at room temperature. An additional 104 mg (1.2 eq) of N-methylmorpholine were introduced followed by 236 mg (1.3 eq) of dry dimethyl-L-glutamate hydrochloride. The solution then was continuously stirred for 4 hours at room temperature. The solvent was removed under reduced pressure and the residue dissolved in chloroform. Extraction with saturated aqueous sodium bicarbonate removed unreacted acid, triazine and triazinone. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:10 methanol:chloroform. M.S.:m/z=471.2081 (M+, calc. for C23H29N5O6 : 471.2118). 1H-N.M.R. (CDCl3, 300 MHz): 1.41(quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 2.00-2.55(m, 8H, 4×--CH2 --); 3.56(s, 3H, CH3O); 3.68(s, 3H, CH3O); 4.68 (dt, 1H, CH, J=6, 7.5 Hz); 4.84 (s (broad), 2H, NH2); 4.97 (s, 1Holef.); 5.18 (s, 1Holef.); 5.86 (s (broad), 2H, NH2); 7.29 (d, 2Harom., J=9 Hz); 7.62 (m, (broad), 1H, NHglu); 7.64 (d, 2Harom., J=9 Hz); 11.20 (s (broad), 1H, NHpyr).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11]>C1(C)C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[C:15](/[CH:16]=[N:1]/[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1

Procedure:
A mixture of 4-amino-benzonitrile (23.6 g, 0.2 mmol) in toluene (200 mL) was treated with a solution of 3-nitro-benzaldehyde (30.2 g, 0.2 mmol) in toluene (50 mL). The resultant mixture was allowed to reflux for 6 h. Toluene was removed under vacuum. The residue was purified by recrystallization from ethanol to afford 4-{[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amino}-benzonitrile as yellow solid (50 g, yield %: 95.0%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:40]([F:43])([F:42])[F:41])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][CH:14]=3)[C:6]=2[CH:39]=1.[H-].[Na+].[CH3:46]I.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:40]([F:43])([F:41])[F:42])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([O:12][CH3:46])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:18]=3)[C:6]=2[CH:39]=1
Reactant: CI
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 4, 590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg, 1.13 mmol). Then the mixture was added MeI (0.08 ml, 1.23 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was added water (30 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3:1) to afford 550 mg (91%) of the title compound as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCC(=O)O
Reactant: CCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC(=O)NCC(=O)O
Yield: 27.6 %

Procedure:
Glycine (20 mmol) was reacted with octanoyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 1 Part A. The crude crystalline product (3.06 g, 76%) was recrystallized from EtOAc (15 ml) to give the title compound (1.11 g, 28%), m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].Cl>CCO.CCOCC>[ClH:1].[CH3:31][CH:30]([NH:33][CH:26]1[CH2:27][CH2:28][N:23]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[CH:12][N:11]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:24][CH2:25]1)[CH3:32]
Reactant: CC(C)N
Reactant: O=C1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
1-[(4-{[4-(4-chlorophenyl)pyrimidin-2yl]amino}phenyl)carbonyl]piperidin-4-one (400 mg, 0.980 mmol) was dissolved in 10 mL EtOH along with isopropylamine (58 mg, 0.980 mmol). Sodium cyanoborohydride (62 mg, 0.986 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water, extracted with ethyl acetate followed by flash chromatography (EtOAc/MeOH; 90:10) to give a residue. This was taken up in ETOH saturated with HCl(g), diluted with ether, filtered to give 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl 4-[(methylethyl)amino]piperidyl ketone hydrochloride (0.150 g, 30% yield): HPLC Retention time; 6.02 min. (Method B) M+1; 450.4.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:46]([SH:49])[CH:47]=[CH2:48].[Cl-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:49][CH2:46][CH:47]=[CH2:48])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Reactant: C=CCS
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (25 g) in N,N-dimethylformamide (150 ml) were added triethylamine (6.42 ml) and 2-propene-1-thiol (8.0 ml), and the mixture was stirred at 25° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride (1.5 l), followed by collecting the precipitated solid by filtration, which was washed with water and diisopropyl ether, and then dried to give benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate-1-oxide (24.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]#[N:11])=[N:3]1.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:14][N:13]=[C:10]([C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[N:2]([CH3:1])[N:3]=1)[NH2:11]
Reactant: Cn1nc(C#N)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1nc(C(N)=NO)cc1[N+](=O)[O-]
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazole-3-carbonitrile (2.4 g, 15.8 mmol, Princeton) and hydroxylamine hydrochloride (3.29 g, 47.3 mmol) in EtOH (0.50 mL) was added potassium carbonate (10.9 g, 79 mmol) and the mixture was refluxed for about 2 h. The reaction mixture was filtered hot and the collected solid was rinsed with EtOH (50 mL) and then MeOH (100 mL). The filtrate was concentrated under reduced pressure. The crude material was partitioned between DCM (40 mL) and water (20 mL). The aqueous layer was acidified to about pH 2 using 1 N HCl and back extracted with DCM (20 mL). The aqueous layer was basified using saturated NaHCO3 and the precipitate was collected by vacuum filtration and dried to afford N′-hydroxy-1-methyl-5-nitro-1H-pyrazole-3-carboximidamide (1.24 g, 4.49 mmol, 67%). LC-MS (Table 1, Method g) Rt=1.07 min, m/z 186 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.78 (s, 1H), 7.22 (s, 1H), 5.71 (s, 2H), 4.16 (s, 3H).