Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:13])/[CH:10]=[CH:11]/[CH3:12].[H-].[Na+].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH:11]([P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:12])#[N:13]
Reactant: CC(C)COP(C)[O-]
Reactant: C/C=C/C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COP(C)(=O)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 50.0 g of isobutyl P-methylphosphonite and 22.8 g of crotononitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.8 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. , under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(3-cyanoprop-2-yl)-P-(methyl)phosphinate, b.p. 110°/0.125 mbar, 31P-NMR spectrum: δ=+55.9 and +55.5 ppm (CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])[CH3:2].Cl[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>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:7]1=[O:15])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: ClCc1ccc2ccccc2c1
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc3ccccc3c2)c2ccccc21
Yield: 81 %

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 440 mg. (0.002 mole) of 2-oxo-1-benzimidazolineacetic acid ethyl ester and 353 mg. (0.002 mole) of 2-chloromethylnaphthalene were reacted to afford 583 mg. (81%) of 3-(β-naphthyl)methyl-2-oxo-1-benzimidazolineacetic acid ethyl ester, isolated as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]=[CH:3]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])(C)C.[K+].O>[CH2:16]([O:23][CH:4]1[CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C:2](=[O:1])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC(=O)C1
Temperature: 20 °C
Reaction time: 12 h
Yield: 183.5 %

Procedure:
To a mixture of tert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate (540.00 mg, 2.56 mmol, 1.00 Eq) in BnOH (2.76 g, 25.56 mmol, 10.00 Eq), was added t-BuOK (28.68 mg, 255.61 umol, 0.10 Eq) in one portion under N2. The mixture was stirred at 20° C. for 12 hours. LCMS showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 20 min. The aqueous phase was extracted with EA (40 mL*2). The combined organic phase was washed with saturated brine (20 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 5-benzyloxy-3-oxo-azepane-1-carboxylate (1.50 g, crude) as yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=1>CN(C=O)C>[CH3:29][C:22]1[CH:21]=[C:20]([CH:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[C:3]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.6 %

Procedure:
Sodium Hydride (19.09 g, 477 mmol) was added portionwise over 30 minutes to an ice cooled solution of ethyl phenylmethyl propanedioate (115 ml, 477 mmol) in DMF (500 ml). Upon complete addition, the reaction was allowed to warm to room temperature. After stirring for 30 minutes, a solution of 4-fluoro-2-methyl-1-nitrobenzene (30 ml, 239 mmol) in DMF (250 ml) was added, the reaction heated to 100° C. and stirred at this temperature for 16 hours under an atmosphere of argon. The reaction was then left to stand at room temperature for 72 hours. The reaction was quenched with concentrated HCl (˜100 ml) with stirring and cooling (ice bath), diluted with ethyl acetate (2 L), washed with water (3×2 L), brine (1 L), dried over sodium sulfate, filtered and concentrated to give a dark yellow oil (˜150 g). Purification was by silica chromatography, 1500 g cartridge, sample loaded as a toluene solution to the pre-conditioned column). A gradient of 0 to 5% acetone in pentane eluted the higher running component, this was followed by a gradient of 5 to 15% acetone in isohexane to elute the excess benzyl ethyl malonate and required product. Product-containing fractions were concentrated to give the title compound as a pale yellow oil (71.21 g). MS (ES−) [C19H19NO6—H]− 356. 1H-NMR (400 MHz, d6-DMSO) δ 1.14 (3H, t, J 7), 2.50 (3H, s), 4.01-4.21 (2H, m), 5.14-5.25 (2H, m), 5.27 (1H, s), 7.28-7.49 (7H, m), 8.00 (1H, d, J 8)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([O:20][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 19.4 g amount of p-nitrobenzenesulfonyl chloride is added to 16.5 g of phenol in 80 ml of pyridine. The mixture is heated on a steam bath for one hour then is filtered and cooled to room temperature. The resulting yellow solution is poured into 300 ml of 10% aqueous sodium carbonate solution and stirred vigorously until the product is crystallized out. The solid is filtered, washed with water and dried, then is recrystallized from 300 ml of hot ethanol to give 20.0 g of 4-nitro-benzenesulfonic acid phenyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butanol and DBU in DME. EI-MS m/e (%): 258 (M+, 20), 202 ([M—C4H8]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([C:29]4[CH2:33][CH2:32][CH2:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:35])([CH3:34])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:35])([CH3:34])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3=CCCC3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3CCCC3)cc21
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of (2R,5R)-4-[2-(6-cyclopent-1-enyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (see Table 1) (60 mg, 0.12 mmol) in THF (5 mL) and MeOH (5 mL) was added palladium on carbon (10%, 10 mg) and the mixture was hydrogenated for 2 h. The catalyst was filtered and the filtrate evaporated to afford the title compound (52 mg, 87%) as a white solid. MS [M+H]+=501.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][OH:12])[CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=1
Reactant: OCc1cc(-c2ccco2)on1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(-c2ccco2)on1
Reaction time: 1 h

Procedure:
To a solution of 1.41 g of (5-furan-2-yl-isoxazol-3-yl)-methanol and 1.77 mL of TEA in 45 mL of methylene chloride was slowly added 0.73 mL of methanesulfonyl chloride at 0° C. After stirring for 1 hr, the reaction solution was washed with water and 1N HCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 10.0 g of methanesulfonic acid 5-furan-2-yl-isoxazol-3-ylmethyl ester. This concentrate was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc2ncc(C#N)c(O)c2n1
Product: CCOc1ccc2ncc(C#N)c(Cl)c2n1
Yield: 100 %

Procedure:
A solution of 6-ethoxy-4-hydroxyl-[1.5]naphthyridine-3-carbonitrile (500 mg, mmol) in POCl3 was heated at reflux for 2 hrs under nitrogen. The temperature was reduced to 45-50° C. (bath) and heated at this temperature for an additional 2 hrs. After cooling, the solvent was removed by rotary evaporation. The residue was treated with a mixture of ice and water, made basic by using NH4OH, and extracted with CH2Cl2. The combined extracts were washed (brine), dried (Na2SO4), and concentrated to give the title compound as a white solid (522 mg, 100%). H-NMR δ(DMSO-d6): 1.437 (3H, t, CH3), 4.572 (2H, q, CH2), 7.495 (1H, d, C8-H), 8.407 (1H, d, C7-H), 9.108 (1H, s, C2-H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][CH:7]=1.O=C1CCC(=O)N1[O:23][C:24](=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:3]2[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Cc1cncnc1NCC1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cncnc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine (0.20 g, 0.97 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.24 g, 0.97 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–10 (10% NH4OH in MeOH)/99–90 CH2Cl2) to give 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[N:6][CH:5]=1.[H-].[Na+].BrCC1C=CC=CC=1[CH:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:6][CH:5]=1
Reactant: SC(c1ccccc1)c1ccccc1CBr
Reactant: CCNc1ccc(C(=O)OC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCCc2ccccc2SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of methyl-6-ethylaminonicotinate in (59 mg, 0.332 mmol) DMF (0.8 mL) was added to sodium hydride (12 mg, 0.293 mL) in DMF (0.8 mL) at 0° C. The reaction was stirred for 1 hour and a solution of 2-(2-bromomethylphenyl sulfanylmethyl)benzene 5 (81 mg, 0.276 mmol) in 80 μL of DMF was added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The solution was quenched with water and extracted with EtOAc (7×). The organic layers were combined, washed with water and brine twice, dried over MgSO4 and evaporated to give a white solid that was recrystallized from EtOAc/hexane. The solid was purified with 5% EtOAc/hexane by chromatography to yield 350 mg (70%) of the named compound.
Reaction SMILES: C1(O)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[O:14].[OH-].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[CH3:23])[CH3:32]
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCOC(=O)COc1c(C)cc(C(=O)c2cccs2)cc1C
Reaction time: 3 h

Procedure:
There was kept for 3 hours at 60° C. a solution in 150 ml of dimethylformamide of 10 g of the phenol obtained according to (B), 3 g of potassium hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl ether, and the impurities extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of the ester were obtained which melted at 89° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:28](B(CC)CC)[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:28][CH3:29])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:13])([F:14])[F:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCB(CC)CC
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2I)OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(Cl)ccc2c1C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 110 °C

Procedure:
To the mixture of ethyl 6-chloro-5-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.3g, 0.7 mmol), potassium carbonate(109 mg, 2.87 mmol) and tetrakistriphenyl-palladium (0) (81 mg, 0.07 mmol) in 3 mL of anhydrous DMF was added triethylboron (1.0M/THF, 1.05 mL, 1.05 mmol) under nitrogen. The resulting mixture was heated to 110° C. for five hrs. The reaction was cooled to room temperature, and diluted with 100 mL of ethyl acetate. The resulting organic phase was washed with brine. After removing the solvent, the residue was dissolved in 3 mL of THF, followed by addition of a solution of lithium hydroxide hydrate in 3 mL of water. To the resulting mixture was further added 3 mL of ethanol. The resulting solution was then heated to 80° C. for three hrs. The volatiles were then removed. The residue was diluted with water, and acidified in an ice/water bath with dilute hydrochloric acid. The product was extracted with ethyl acetate. The organic extracts were washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on short silica gel with 3:7 EtOAc/hexane+1% HOAc to remove the polar impurities. After concentrating the collected fraction, the residue was further purified on reverse phase HPLC. It gave 75 mg slightly yellow solid. M.P.=171.5-172.5° C. 1H NMR (CDCl3/400 Mz), 8.07(s, 1H), 7.32(d, J=8.8 Hz, 1H), 6.82(d, J=8.8 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 2.91(m, 2H), 1.18(t, J=7.6 Hz, 3H). 13C NMR(CDCl3/400 MHz) 169.5, 152.8, 141.5, 136.5, 134.1, 127.7, 123.4(q, J=287.7 Hz), 118.6, 116.3, 115.5, 69.8(q, J=33.4 Hz), 23.1, 14.7. 19F NMR(CDCl3/400 Mz) −78.72(d, J=6.8 Hz). MS(ES−)=305.0 (M−H, 100). High resolution MS(ES−), m/e calc. For C13H10ClF3O3: 305.0198 (M−H), found: 305.0157.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=[C:2]([CH3:1])[CH:7]=1)[CH3:9])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)nc(OCC(F)(F)F)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(OCC(F)(F)F)n1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (50 mg, colorless oil) from 1-(2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethanone (44 mg, 0.19 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39](Cl)=[O:40])[N:37]=1)=[O:31].Cl>O.O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:40])[N:37]=1)=[O:31]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1

Procedure:
7β-Amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, 157 g, is suspended in a mixture consisting of 500 ml of tetrahydrofuran and 500 ml of water, and to this, 141 g of sodium hydrogen carbonate is added in small portions with stirring. With stirring at 5° C., 150 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetylchloride hydrochloride is added over 20 minutes, and the reaction mixture is stirred for further 1 hour at the same temperature. After completion of the reaction, the pH is adjusted to 3.0 with 10% hydrochloric acid, and the reaction mixture is extracted twice with 1 liter each of a mixture of ethyl acetate-tetrahydrofuran (1:1). The extract is dried over anhydrous magnesium sulfate, the solvent is evaporated off under reduced pressure to leave colorless powder, which is washed with 200 ml of ethyl acetate and filtered, to give 253 g of the desired compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C([Li])CCC.C=O.N1C=CC=CC=1.[C:24]([O:27][C:28](=O)C)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:27][CH2:28][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:26])[CH3:25]
Reactant: C#CCOc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A 0.5-L reactor (#1) was equipped with a thermometer, an addition funnel, an overhead stirrer, and a nitrogen inlet. 150 mL of THF was charged followed by 27.5 g (0.21 mole) of phenyl propargyl ether. The solution was cooled to −20° C. 100 mL (0.25 mole) of n-butyllithium in hexanes was charged into an addition funnel. This solution was added to the reactor at a temperature between −25 and −35° C. The temperature was controlled by the rate of addition and the mixture was stirred for 1 h at −25 to −35° C. A second 1-L reactor (#2) was equipped with a thermometer, an overhead stirrer and a cannulation device. 120 mL of THF was charged followed by 9.4 g (0.42 mol) of paraformaldehyde as a solid in one portion. The resulting suspension was stirred for 5 min. and cooled to 5–10° C. The contents of reactor #1 were cannulated into reactor #2 maintaining temperature in reactor #2 between 5 and 15° C. The temperature in reactor #1 was maintained below −15° C. The cooling bath from reactor #2 was removed and the reaction mixture was allowed to warm up slowly to 20–25° C. Stirring was continued for 16 h at ambient temperature. 200 mL of water was added to the reaction mixture and the mixture was stirred for 15–30 min at ambient temperature. The reaction mixture was extracted twice with 200 mL and then 100 mL of ethyl acetate. The combined organic solution was washed with 200 mL of water. The organic solution was dried with 50 g of anhydrous sodium sulfate. The drying agent was filtered off and rinsed with 50 mL of ethyl acetate. The filtrate was transferred into a 1-L reactor fitted with an overhead stirrer. Pyridine (67 mL, 0.83 mol) was charged followed by acetic anhydride (39 mL, 0.42 mol). The solution was stirred overnight at ambient temperature. The solution was washed sequentially with water (200 mL), sodium bicarbonate solution (2×150 mL) until pH=7–8, hydrochloric acid solution (2×150 mL) until pH=1–3, and brine (1×150 mL). The solution was dried with anhydrous sodium sulfate (50 g). The drying agent was filtered off, and the filtrate was concentrated in vacuo at a temperature that did not exceed 60° C. to yield 37 g (87% yield, HPLC strength 65%) of product as a dark-red slightly viscous fluid.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
To a solution of the product of Step A, cyanoacetamide (1.33 g, 15.8 mmol), and MeOH (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to a suspension of NaH (60% in mineral oil) (1.45 g, 36 mmol) in DMF (16 mL) at rt. After the slow addition was complete, the reaction was heated to 95° C. for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aq 18% citric acid solution. The mixture was extracted twice with CH2Cl2 and the organic layers were washed with brine. The combined organic layers were dried (Na2SO4) and concentrated. The solid residue was triturated with ether, filtered, and air dried to afford the product. (LC-2) HPLC/MS: 375 (M+1), 377 (M+3); Rt=3.47 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH2:22][Cl:23])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Yield: 97.7 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-benzoic acid methyl ester (10 g, 54.8 mmol) and potassium carbonate (22.75 g, 164.4 mmol) in DMF (100 mL) was added 1-bromo-2-chloro-ethane (22.7 mL, 274 mmol). The mixture was heated at 70° C. for 3h and monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine. The organic layer was dried (Na2SO4) and concentrated to afford 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (13.1 gm, 97%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 6.90 (d, 1H), 4.35 (t, 2H), 3.90 (m, 8H).