Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:17][N:16]=[N:15]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N=C(Cl)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Five grams (22.6 mmol) of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 3, 2.68 g (40.7 mmol) of sodium azide, 1.57 g (11.3 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 23 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 5.01 g of 1-(4-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.3%).
Reaction SMILES: C[Li].[CH3:3][Si](Cl)(C)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:31]([CH3:38])=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23].ClC(Cl)C.[Cl-].[NH4+]>C(OCC)C.[Cu]I>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:31]([CH3:3])([CH3:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][Si:21]([CH:28]([CH3:29])[CH3:30])([CH:22]([CH3:23])[CH3:24])[CH:25]([CH3:27])[CH3:26]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C=C(C)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(OCCCOC)c1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CC(C)(C)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(OCCCOC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
At 0° C., copper (I) iodide (4.11 g, 21.6 mmol) was dissolved in diethyl ether (10 mL). Methyllithium (1.6N, 27 mL) was added and the mixture was stirred for 10 minutes. The solvent was removed under reduced pressure and cold dichloromethane (10 mL) was added. The solvent was removed under reduced pressure. Cold dichloroethane (83 mL) was added and the mixture was cooled to −78° C. Trimethylsilyl chloride (2.73 mL, 21.6 mmol) was added, followed by a solution of ethyl 3-{3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]phenyl}but-2-enoate (2.43 g, 5.4 mmol) and dichloroethane (10 mL). The temperature was maintained at 0° C. for 3 hrs and the mixture was then hydrolyzed with saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 95/5) to yield 2.6 g (84%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH:9]=[O:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[CH:9]([C:5]1[N:6]=[CH:7][N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]=1[CH3:3])=[O:10]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]cnc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(C=O)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A 30% solution of sodium hydride (1.2 g, 32.6 mmol) was washed with pet ether (3×15 mL) and then slurried in THF (30 mL) under nitrogen. The slurry was cooled to 0° C. and 5-methylimidazole-4-carboxaldehyde (3 g, 27.2 mmol) was added in two portions. The mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and ethyl bromacetate (4.5 mL, 38.1 mmol) was added dropwise. The mixture was stirred at ambient temperature for 40 minutes and partitioned between ethyl acetate and water. The organic layer was isolated, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated with pet ether to provide ethyl 4-formyl-5-methylimidazol-1-ylacetate (5.3 g, 27 mmol) as a yellow solid. 1H-NMR (300 Mhz, DMSO-d6): 1.2 (t, 3H), 2.4 (s, 3H), 4.2 (q, 2H), 5.0 (s, 2H), 7.8 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(Cc2ccnc3ccccc23)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(C[C@@H]2C[C@@H](NCc3ccnc4ccccc34)CCN2Cc2ccnc3ccccc23)cc1

Procedure:
128 mg (0.225 mmol) of (2R*,4S*)-2-benzyl-1-(4-quinolylmethyl) N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 34 mg (0.872 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR39## is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =490.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH2:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])(=O)=O)=CC=1>>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[CH2:38][O:37][CH2:36][CH2:35][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2cc(F)ccc2F)cc1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCOCc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.824 g of 2-(2,5-difluorobenzyloxy)ethyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.21 (1:1 EtOAc-heptane). Rt=5.01.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34]>O>[C:22]([O:21][C:19]([N:11]([C:3]1[C:4]([CH3:10])=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=1[NH:1][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCCCCOC(=O)Cl
Reactant: Cc1cc(C#N)cc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Di-t-butyl (2-amino-4-cyano-6-methylphenyl)imidodicarbonate (104 mg, 0.3 mmol) obtained in Step 2 was added with pyridine (0.24 mL, 3 mmol, 10 eq) and heptyl chloroformate (0.11 mL, 0.6 mmol, 2 eq), and the mixture thus obtained was stirred at room temperature for 10 minutes, followed by further stirring at 80° C. for 2 hours. Upon completion of the reaction, the resulting product was added with distilled water, and extracted with ethyl acetate. The organic layer thus obtained was dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:9) to obtain the title compound in a colorless liquid (146 mg, yield: 99%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C>C1COCC1.O>[CH3:21][C:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH3:20])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Yield: 59.4 %

Procedure:
Dimethyl methylphosphonate (9.92 g, 0.08 mol) was dissolved in 60 ml anhydrous THF under argon atmosphere. To the mixture stirred at -78° C. was added drowise n-butyl lithium 1.62N, 49.5 ml, 0.08 mol) over a period of 30 minutes, and then a solution of 2,2-dimethylhexanoic acid methyl ester (5.0 g, 0.032 mol) in 10 ml anhydrous THF was added over a period of 30 minutes. The reaction mixture was warmed to room temperature. Acetic acid (5 ml) and water (10 ml) were added to the reaction mixture cooled with ice bath. After concentration, 20 ml water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxoheptylphosphonate (4.74 g, 0.019 mol, yield 59.3%, b.p.=108°-111° C./0.2 mmHg) as a colorless clear oil. The structure of this product was confirmed by the following data.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[C:6]([CH3:22])[CH:5]=1>Cl>[CH3:22][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[C:10]1[O:11][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][CH:14]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(CN3CCOCC3)o2)c(C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)ccc1-c1ccc(CN2CCOCC2)o1

Procedure:
This ester (0.51 mmol) was heated to 70° C. in 18% HCl for 2 h at which point HPLC showed all the starting material to have been hydrolysed. The reaction was cooled and the product that precipitated out of solution was collected by filtration as a white solid. With no further purification this was coupled using the standard procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#N>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)Cc1nc2ccccc2s1
Temperature: 120 °C
Yield: 72 %

Procedure:
Ethyl 2-(benzothiazol-2-yl)acetate was prepared by the method of Abbotto, Bradamante et. al. (J. Org. Chem. 2002, 16, 5753). A neat mixture of 2-aminothiophenol (6.94 g, 50 mmol) and ethyl cyanoacetate (5.65 g, 50 mmol) was heated at 120° C. for 3 hours at which time TLC analysis indicated that the reaction was complete as judged by the disappearance of starting material. The dark orange mixture was diluted with ethyl acetate/hexanes and purified by flash chromatography using 10-20% ethyl acetate/hexanes (Rf=0.35, 10% ethyl acetate/hexanes) as an eluant. After concentration by rotary evaporator, ethyl 2-(benzothiazol-2-yl)acetate could be obtained as a yellow oil in 72% yield (7.97 g). LCMS: 222.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C@@H:13]1[CH2:26][CH2:25][C:16]2([O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].O.C(C(CCCC)C([O-])=O)C.[K+:43]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N-:9][S:10]([C@@H:13]1[CH2:26][CH2:25][C:16]2([O:17][C@H:18]([CH2:23][OH:24])[C@@H:19]([CH2:21][OH:22])[O:20]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].[K+:43]
Reactant: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)Nc1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)[N-]c1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
100 mg (0.208 mmol) of ethyl (2R,3R,8R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-ene-7-carboxylate [a compound described as a low polarity compound (first peak) of Example 162 in WO 2007/032362] was dissolved in 1 mL of ethyl acetate, and 2 mL of a solution containing 38 mg (0.208 mmol) of potassium 2-ethylhexanoate hydrate in ethyl acetate was added thereto under stirring at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue, diethyl ether was added. A precipitated solid was obtained by filtration and washed with diethyl ether, whereby 92 mg of a crude product was obtained as an amorphous solid. Then, the crude product was dissolved in ethyl acetate, and the resulting solution was heated under reflux at 130° C. for 2 hours. After the resulting mixture was cooled, a precipitated solid was obtained by filtration and washed with ethyl acetate, whereby the title compound was obtained as a white crystal.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15](C)=[CH:14][C:13]([O:17]CC3C=CC(OC)=CC=3)=[CH:12][C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC(O)C.ClC(Cl)C(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([OH:17])=[C:12]([Cl:29])[C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2)cc1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)c1cc(-n2ccc(O)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C

Procedure:
To a solution of 2′-acetyl-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of part C (3.3 g, 8.7 mmol) in 2-propanol (100 mL) was added N-chlorosuccinimide (1.27 g, 9.6 mmol) and 10 drops of dichloroacetic acid. The slurry was heated at 60° C. for 3 h. The resulting slurry was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo. The residue was suspended into dichloromethane and the resulting white solid was collected by vacuum filtration to provide the chlorinated deprotected product (1.16 g): MS (ES) m/e 293 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]=[C:8]=[O:9])=[O:5])[CH3:2].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CN=C=O
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Reaction time: 168 h
Yield: 74.6 %

Procedure:
To a solution of ethoxycarbonylmethyl isocyanate (24.5 ml, 0.212 mol) in DMF (100 ml) a solution of 4-aminobenzonitrile (25 g, 0.212 mol) in DMF (100 ml) was added within 30 min at 0° C. Stirring was continued for 7 d and additional ethoxycarbonylmethyl isocyanate was added periodically (18.5 ml, 0.156 mol). The solvent was removed in vacuo and the residue was stirred in ethyl acetate/diethyl ether. The mixture was filtered to give the title compound (39.12 g, 74%; white solid of m.p. 140-144° C.) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:41][C@@H:39]([C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH3:40])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
4-(5-Bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 1 g, 3.10 mmol), EDC (0.892 g, 4.65 mmol), HOBt (0.712 g, 4.65 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.724 g, 4.65 mmol) and triethylamine (1.296 mL, 9.30 mmol) were dissolved in DMF (15 mL). The resulting brown solution was stirred at room temperature for 18 hours and was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a crude product which was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow foam (574 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (dd, J=7.07, 4.29 Hz, 3 H), 3.55 (d, J=6.32 Hz, 2 H), 3.68-3.79 (m, 1 H), 3.84-3.91 (m, 1 H), 4.22-4.39 (m, 2 H), 4.86 (m, 1 H), 4.89-5.03 (m, 1 H), 7.31-7.41 (m, 4 H), 8.45 (d, J=10.61 Hz, 2 H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[F:18][C:19]1([F:24])[CH2:21][CH:20]1[CH:22]=O>C1COCC1>[F:18][C:19]1([F:24])[CH2:21][CH:20]1[CH:22]=[CH:3][C:1]#[N:2]
Reactant: O=CC1CC1(F)F
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=CC1CC1(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (4.09 g; 23.1 mmol) in dry THF (200 mL) at 0° C. under nitrogen was added potassium t-butoxide (23.1 mmol; 1M solution in THF). The mixture was stirred for 1 hour. The solution of 2,2-difluorocyclopropanecarbaldehyde from Step A was added and the mixture was stirred while allowing to warm to ambient temperature. A portion of the solvent was removed under reduced pressure and the remaining solution was diluted with ammonium chloride solution (50 mL). The mixture was extracted into ethyl acetate (2×50 mL). The combined extracts were dried (magnesium sulfate and sodium sulfate), filtered and evaporated under reduced pressure. The material was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 3-(2,2-difluorocyclopropyl)acrylonitrile (0.50 g) as a pale yellow oil (containing some ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:46])([CH3:45])[CH2:20][C:21]2[N:22]=[N:23][N:24](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].Cl.C(O)(C)C.C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([OH:46])([CH3:45])[CH2:20][C:21]2[N:22]=[N:23][NH:24][N:25]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)(O)Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O=CO
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)(O)Cc3nn[nH]n3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethylphenyl)-4-(2-hydroxy-1-(2-trityl-2H-tetrazol-5-yl)propan-2-yl)-N-isobutylbenzenesulfonamide (22 mg, 0.032 mmol) at room temperature, was treated with a solution of HCl (6N in isopropanol, 2 mL, 12.00 mmol) and isopropanol (2 mL). The reaction mixture was stirred at 20° C. for 2 hours then the solvent evaporated in vacuo and the crude partitioned between ethyl acetate (5 mL) and water (5 mL). The organic phase was separated by hydrophilic frit then evaporated in vacuo to give a residue. LCMS analysis showed the reaction was incomplete, so the residue was redissolved in dichloromethane (DCM) (2 mL) and treated with formic acid (0.5 mL, 13.04 mmol). The solution was left to stand for 2 hours. The solvent was evaporated in vacuo then dissolved in a 1:1 mixture of MeOH and DMSO and purified by MDAP (Method F) to give the required product, 5.3 mg. LCMS (M+1) 444, RT 1.10 mins.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>CN(C)C=O>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]3SC2)o1
Reaction time: 0.25 h

Procedure:
A suspension of 3.4 g (0.01 mol) of 7-amino-3-(5-carboxymethyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness in vacuo and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([OH:26])=O)[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:36]1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([NH2:36])=[O:26])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Reactant: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(C(N)=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 826, (0.050 g, 0.108 mmol), benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium hexafluorophosphate (0.081 g, 0.216 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) were combined in 5 mL of THF. To the reaction was then added ammonia hydrochloride (0.002 g, 0.032 mmol) and the reaction was allowed to stir overnight at room temperature. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography, yielding 3.3 mg of desired product.