Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H]>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
1.4 Grams of a palladium on carbon catalyst was added to a mixture of 154 grams of 5-nitrotetrahydroanthraquinone and 3000 grams of methyl cellosolve, into which was fed hydrogen at room temperature under normal pressure for hydrogenation. After hydrogen was absorbed in an amount of 2 mols per mol of the 5-nitro compound, the catalyst was separated by filtration. To the resultant filtrate was added 60 grams of triethylamine, followed by agitating at 100° C. for 3 hours and feeding air at 100° C. for 1 hour. Then, methyl cellosolve was removed by distillation until crystals began to precipitate. The solution was allowed to cool and the crystals were separated by filtration, washed with water and dried to obtain 118 grams of 1-aminoanthraquinone having a purity of 98.0%.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:21]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[Cl:21][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to the boiling point and left stirring at reflux for 1 hour. 4-chlorobenzyl chloride (14.4 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was stopped by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/1 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 4.4 g of [1-(4-chlorobenzyl)-1H-indazol-3-yl]methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[OH-:12].[Na+]>O>[Cl:1][C:2]1[NH:7][C:6](=[O:12])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(Cl)nc(Cl)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(Cl)[nH]c(=O)c1F
Temperature: 80 °C

Procedure:
To the solution obtained as the product of part (iii) was added water (6 ml). The mixture was stirred at 80° C. and 4N sodium hydroxide (45 ml) was added slowly over 2 hours. At the end of this period the reaction was cooled and washed with dichloromethane (15 ml). The aqueous layer was then added to dichloromethane (60 ml) and the pH adjusted to 1 with concentrated hydrochloric acid. The organic layer was separated and the pH adjusted to 3 using concentrated aqueous ammonia solution. The precipitate of ammonium chloride was removed by filtration and the filtrate was then concentrated to a volume of 15 ml and diluted with ethyl acetate (150 ml). This solution was concentrated to a volume of 30 ml and the crystals of the title compound that formed were collected by filtration and dried (8 g), then characterised by 1H-NMR and mass spectrometry.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[N+:5]([CH:8]=[CH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:7])=[O:6].Cl>C(#N)C.O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:7])=[O:6]
Reactant: O=[N+]([O-])C=Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])CCc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A solution of sodium borohydride (2.0 g) and 40% w/v aqu. NaOH was added dropwise to a solution of the the product from step (b) (1.9 g) in acetonitrile (55 ml) at 0° C. The pH was maintained at 3-6 by periodic additions of 2N aqu. HCl. The resulting solution was stirred at 0° C. for 2 hours, then diluted with water and extracted with DCM. The combined extracts were washed with brine, dried and evaporated in vacuo to give a yellow oil which was eluted through a silica column using chloroform as eluant to give the desired product as a pale yellow oil (0.78 g).
Reaction SMILES: Br[CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:18]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH:2]([C:23]1[NH:24][CH:25]=[C:21]([N+:18]([O-:20])=[O:19])[N:22]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccc2ccccc2c1)c1nc([N+](=O)[O-])c[nH]1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A yellow slurry consisting of ethyl 2-bromo-2-(2-naphthyl)acetate (384.04 grams, 1.31 mol), 4-nitroimidazole (148.13 grams, 1.31 mol), potassium carbonate (362.11 grams, 2.62 mol), and dimethyl formamide (2500 mL) was stirred at ambient temperature until complete as determined by hplc (16 hours). The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (4×500 mL). The organic extracts were combined and washed with saturated sodium bicarbonate solution (2×500 mL), 10% citric acid solution (2×500 mL), saturated sodium chloride solution (2×500 mL), dried using sodium sulfate, and evaporated. A portion (50 grams) of the crude product was purified by column chromatography on silica gel eluting with dichloromethane:heptane (16:3) gradient to dichloromethane:heptane:methanol (16:3:0.2) giving 30.99 grams of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate which was 90% pure by hplc. A 1 gram sample of the product was purified a second time using a Biotage Flash 40S system eluting with dichloromethane:heptane:methanol (16.9:3:0.1) to give 0.90 grams (46%) of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate as a tan oil. MS (FIA) m/z 326.4 [(M+H)+]. 1H nmr (CDCl3): δ 1.25-1.31 (t, 3H), 4.28-4.39 (m, 2H), 6.16 (s, 1H), 7.36-7.44 (dd, 1H), 7.54-7.62 (m, 3H), 7.84-7.90 (m, 3H), 7.90-7.95 (m, 2H).
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[Cl:42][C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1
Reactant: NNc1nc2ccc(Cl)cc2s1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(Cl)cc3s2)s1

Procedure:
The compound 3n was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-chloro-benzothiazole (199 mg, 1 mmol) at 70° C. for 2 h (yield 287 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#Cc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-n2cnc(C#N)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 8.8 %

Procedure:
A solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (3.2 g, 11.98 mmol), 1H-imidazole-4-carbonitrile (2.017 g, 14.37 mmol) and ethyl-diisopropyl-amine (8.4 ml, 47.9 mmol) in 10 ml of dioxane is heated to reflux for 24 hours. The solution is allowed to cool to room temperature and evaporated. The residue is chromatographed on silica gel using gradients of dichloromethane and methanol to give 0.36 g (1.05 mmol, 8.8%) of amorphous 5-(4-cyano-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester, ES-MS: m/z 341 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7](=[O:14])[CH2:8][N:9](C=O)[CH:10]=[O:11])=[CH:5][CH:6]=1.[OH-].[K+].C(O)C>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:14])[CH2:8][NH:9][CH:10]=[O:11])=[CH:5][CH:6]=1
Reactant: O=CN(C=O)CC(=O)c1ccc(Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=CNCC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the crude crystal of 2-chloro-5-(diformylaminoacetyl)-thiophene were added potassium hydroxide (0.60 g), ethanol (70 ml) and tetrahydrofuran (40 ml), and the mixture was stirred at room temperature for one hour. After removing the solvent under reduced pressure, tetrahydrofuran (150 ml) and anhydrous magnesium sulfate were added to the residue, and insoluble material was removed by filtration and washed with tetra-hydrofuran. The filtrate and the washed solution were combined and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether-ethyl acetate to obtain 2-chloro-5-(formylaminoacetyl)thiophene (14.81 g) as pale brownish crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>O1CCOCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: COc1ccccc1B(O)O
Reactant: Brc1cccc2[nH]ccc12
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
0.73 g of 2-methoxyphenylboronic acid and then 1.66 g of potassium carbonate are successively added to a solution of 0.78 g of 4-bromoindole in 15 ml of dioxane and 5 ml of water under argon. The reaction mixture is stirred at ambient temperature for 15 minutes, and then 0.16 g of dichlorobis(tri-o-tolylphosphine)palladium(II) is added. The reaction mixture is stirred at ambient temperature for 16 hours, and then at 60° C. for 18 hours, and, finally, at 110° C. for 3 hours. After returning to ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 15 ml of a 2N sodium hydroxide solution and 30 ml of ethyl acetate. The mixture is filtered through Clarcel®, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×30 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 30 g cartridge of 15-40 μm silica, elution being carried out with a 60/40 v/v cyclohexane/dichloromethane mixture, at a flow rate of 30 ml/min. 0.44 g of 4-(2-methoxyphenyl)indole is thus obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O>C(Cl)Cl>[Br:2][CH2:13][C:7]1[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: OCc1cc(I)ccc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1ccc(I)cc1CBr

Procedure:
Phosphorus tribromide 1.0 M soln. in DCM (18.9 mL, 18.9 mmol) was added dropwise to a 0° C. solution of (2-fluoro-5-iodo-phenyl)-methanol G-6 (9.52 g, 37.8 mmol) in DCM (215 mL) and the resulting mixture was stirred for 1 h before being quenched with water. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with 5% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.92 min; No ionisation; 1H NMR (DMSO) δH: 7.93 (dd, J1=7.1 Hz, J2=2.3 Hz, 1H), 7.74 (ddd, J1=8.6 Hz, J2=4.9 Hz, J3=2.3 Hz, 1H), 7.10 (dd, J1=10.0 Hz, J2=8.7 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][NH2:16]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][NH2:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCN
Product: NCCNc1ccnc2cc(Cl)ccc12
Temperature: 85 °C

Procedure:
A mixture of 4,7-dichloroquinoline (2.0 g, 10 mmol) and 1,2-diaminoethane (2.7 g, 45 mmol) is heated at 85° C. for 5 hours with magnetic stirring. After adding 1N soda (15 ml), the solid obtained is extracted with ethyl acetate (100 ml) at 50° C. The organic phase is washed with distilled water and then using a saturated NaCl solution and then again with distilled water and finally is dried on sodium sulphate. The solvent is evaporated and the product obtained is vacuum-dried (1.3 g, 58%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][S:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[S:26][N:25]=4)[CH2:32][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CCN2CCC(c3nsc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2
Temperature: 70 °C
Reaction time: 7 h
Yield: 57.8 %

Procedure:
A mixture of 0.5 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 0.5 g of 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine hydrochloride, 1.5 g of potassium carbonate and 0.5 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70° C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 0.5 g of 6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:40])([O:38]C)[O:36]C)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.C[Si](Br)(C)C.C(O)(C)C.N>ClCCl.O>[CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:36])([OH:40])[OH:38])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COP(=O)(OC)C(Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)C1CCC1
Agent: C[Si](C)(C)Br
Agent: N
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
The dimethyl ester product from part (e) (1.04 g., 1.81 mmole) is dissolved in dichloromethane (10 ml.) and treated with trimethysilylbromide (0.52 ml., 605 mg., 3.96 mmole). The mixture is stirred under argon overnight then concentrated in vacuo. Dioxane (15 ml.) and water (5 ml.) are added and the resulting mixture is stirred for 15 minutes and then concentrated. Residual water is chased three times with acetonitrile (20 ml.) giving 1.06 g. of [1-[[N2 -(cyclobutylcarbonyl)-N6 -[(phenylmethoxy)carbonyl]-L-lysyl]-2-phenylethyl]phosphonic acid as an organe-yellow foam. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.42.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:51]1[C:53]2([CH2:58][CH2:57][N:56]([C:59]([NH:61][C@@H:62]([CH2:66][C:67]([F:76])([F:75])[CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63](O)=[O:64])=[O:60])[CH2:55][CH2:54]2)[CH2:52]1>CN(C=O)C>[C:6]([C:3]1([NH:2][C:63]([C@@H:62]([NH:61][C:59]([N:56]2[CH2:55][CH2:54][C:53]3([CH2:51][CH2:52]3)[CH2:58][CH2:57]2)=[O:60])[CH2:66][C:67]([F:75])([F:76])[CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[O:64])[CH2:5][CH2:4]1)#[N:7]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CC(F)(F)Cc2ccccc2)NC(=O)N2CCC3(CC2)CC3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
13.3 mg of 1-aminocyclopropanecarbonitrile hydrochloride (1.0 eq.), 15.2 mg of HOAt (1.0 eq.), 57 μl of DIPEA (3 eq.) and 42.5 mg of HATU (1.0 eq.) were added successively to a solution of 41.0 mg of (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpentanoic acid (0.11 mmol) in 5 ml of DMF. The reaction mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freeze-dried. In this way, N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-azaspiro[2.5]octane-6-carboxamide was obtained as a colorless amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:13])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:12]=[C:8]3[O:9][CH2:10][O:11][C:7]3=[CH:6][C:5]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A mixture of nitroaniline 220 (5.55 g, 30.5 mmol) and cyanamide (5.37 g, 122 mmol) were melted together at 100° C., cooled to 50° C., cHCl (15 mL) added dropwise and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×30 mL), washed with ether (3×5 mL) and dried to give 1-oxide 221 (3.24 g, 51%) as a yellow powder: mp (MeOH/DCM) 290-295° C.; 1H NMR [(CD3)2SO] δ 7.45 (s, 1H, H-9), 7.00 (br s, 2H, NH2), 6.94 (s, 1H, H-5), 6.23 (s, 2H, H-7); 13C NMR [(CD3)2SO] δ 160.0, 155.1, 149.0, 147.0, 125.3, 103.1, 101.3, 95.8. Anal. calcd for CBH6N4O3: C, 46.6; H, 2.9; N, 27.2. Found: C, 46.7; H, 2.9; N, 27.3%.
Reaction SMILES: [Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 37.7 %

Procedure:
Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (9.3 g, 0.0215 mol) was dissolved in methylene chloride (35 ml), dimethylamine hydrochloride (4.9 g, 0.0645 mol), formaldehyde solution (2.25 g, 0.075 mol) and t-butyl alcohol (300 ml) were added and the mixture was heated to reflux at 95° C. for 4 hours. After removing the solvent under reduced pressure the residue was redissolved in methylene chloride, washed successively with water, dried over sodium sulfate and concentrated. The product was purified over a silica column using hexane-ethyl acetate mixture as the eluant to yield benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (3.6 g, 40%) as a white foam. IR (Nujol) ν max 1723, 1800 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To lithium aluminum hydride (427 mg, 11.2 mmol) suspended in dry ether (5 ml) at 0° C. is added 1 g of 4-(4-methylphenyl)butanoic acid (5.614 mmol) dissolved in dry ether (10 ml) over a period of 30 minutes. The reaction mixture is then warmed to room temperature and stirred for 4 hours. Water (0.43 ml), NaOH (15% solution, 0.43 g) and water (1.29 ml) are then added successively and the resulting solution is stirred for 30 minutes. The precipitate is filtered and washed with ether and dried. This is then concentrated and purified by flash chromatography (silica gel; ethyl acetate/hexanes) as the eluting medium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccccc1-c1ccc(F)cc1
Product: Fc1ccc(-c2ccccc2CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-2-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(Br)nc1
Solvent: CCOCC
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 2,5-dibromo-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.