Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:37][NH:38][O:39][CH3:40]>ClCCl.O.C(N(CC)CC)C>[CH3:40][O:39][N:38]([CH3:37])[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]2[CH:8]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cn2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.8 %

Procedure:
To a solution of 0.784 g of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid in 12 mL of dichloromethane are added 1.67 mL of triethylamine, 1.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.08 g of 1-hydroxybenzotriazole. The reaction mixture is stirred for 20 minutes at room temperature. 0.39 g of N,O-dimethylhydroxylamine hydrochloride is added. The reaction mixture is stirred for 4 hours at room temperature. 60 mL of dichloromethane and 30 mL of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and then purified on a column of silica, eluting with a 95/5 mixture by volume of dichloromethane and methanol. The fractions containing the product are combined and concentrated to dryness under reduced pressure to give 0.6 g of N-methoxy-N-methyl-6-chloroimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: N.[Na].[C:3]1([P:9](C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:10]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:23]2[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1cccc(Br)n1
Agent: N
Agent: [Na]
Solvent: Cc1ccccc1
Product: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
At −78° C., 200 ml of ammonia were condensed in and 5.00 g of sodium (216.8 mmol) were dissolved therein within 5 min. The resulting dark blue solution was admixed with 11.70 g of triphenylphosphine (108.4 mmol) in portions, stirred at −78° C. for approx. 2 h and then admixed with 15.00 g (86.7 mmol) of 6-bromo-2-aminopyridine from example 14.1. After 250 ml of toluene had been added, the cold bath was removed and the ammonia evaporated off overnight. The residue was hydrolyzed with 150 ml of dist. H2O and admixed with 150 ml of saturated NaCl solution, the resulting phases were separated and the aqueous phase was extracted once with 200 ml of toluene. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The product was purified by column chromatography (first with dichloromethane to remove diphenylphosphine, then with 9:1 dichloromethane/ethyl acetate). Resulting mixed fractions were purified by sublimation at 180° C. and 10−2 mbar. 14.26 g (51.2 mmol, 59%) of 6-(diphenylphosphino)-2-aminopyridine were obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1.14 g of [4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.0 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.52 g of N,N-diisopropylethylamine in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate two times to give 1.70 g of the desired product as an amphorous compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CN([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=C(C(N)=O)[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])C.[CH3:43][CH:44]([NH2:46])[CH3:45].C[NH:48]C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:41]([S:38]([N:35]1[CH2:34][CH2:33][CH:32]([C:23]2[C:22]3[C:26](=[C:2]([C:3]([NH2:48])=[O:5])[CH:28]=[C:20]([C:14]4[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH2:11][NH:46][CH:44]([CH3:45])[CH3:43])[CH:13]=4)[CH:21]=3)[NH:25][CH:24]=2)[CH2:37][CH2:36]1)(=[O:40])=[O:39])[CH3:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Reactant: CC(C)N
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CNC(C)C)c4)cc23)CC1
Yield: 24 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (15 μL, 0.214 mmol) for the dimethylamine to afford 16 mg of the title compound (24%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])=[O:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:2]1[CH2:18][CH2:19][O:20][CH:1]1[C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17]
Reactant: O=Cc1cc2n(c1)CCc1ccccc1C2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CCn2cc(C3OCCO3)cc21
Temperature: 0 °C

Procedure:
A mixture of 5 gm. of 6,11-dihydro-2-formyl-5H-pyrrolo[2,1-b][3]benzazepin-11-one, 2.5 gm. of ethylene glycol, 0.5 gm. of p-toluenesulfonic acid and 100 ml. of toluene is refluxed for 16 hr. in an apparatus designed to remove water formed during the reaction (Dean-Stark apparatus). The reaction mixture is cooled to 0° C. and washed rapidly with ice cold 5% sodium carbonate solution (2 × 50 ml.) and dried over Na2SO4. Evaporation of the solvent leaves 6,11-dihydro-2-(2-dioxolanyl)-5H-pyrrolo[2,1-b][3]benzazepin-11-one as an oil which is of sufficient purity for use in the next step.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[F:4][C:5]([F:14])([F:13])[C:6]#[C:7][C:8]([O:10]CC)=[O:9].Cl.O1CCOC[CH2:17]1>Cl>[CH3:3][N:1]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:5]([F:14])([F:13])[F:4])[CH:17]=[N:2]1
Reactant: C=[N+]=[N-]
Reactant: C1COCCO1
Reactant: CCOC(=O)C#CC(F)(F)F
Agent: Cl
Product: Cn1ncc(C(F)(F)F)c1C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of diazomethane (0.781 g—generated from DIAZALD® (3.99 g) in diethyl ether (63 ml)), cooled by an ice/water bath, was added ethyl 4,4,4-trifluoro-2-butynoate (3.09 g) dropwise over 1 min. The cooling bath was removed and the mixture was stirred for 30 min when the solvent was removed under reduced pressure. The crude product was combined with the crude product from a similar experiment that was performed with 1,4 dioxane (5 ml) and n-pentane (15 ml) as the solvent and purified by column chromatography on silica gel to give a white solid. To a solution of a portion of this solid (100 mg) in 1,4-dioxane (2 ml) was added 2M hydrochloric acid (3 ml) and the mixture heated at reflux for 18 h, then concentrated hydrochloric acid (2 drops) was added and the mixture heated at reflux for a further 48 h. The mixture was concentrated in vacuo and the residue purified by mass directed preparative HPLC (Method A), to give the title compound, as a white solid (19 mg).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]1([C@H:7]([NH:9][CH2:10][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C@H:7]([NH:9][CH2:10][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH:13]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2cc(C(=O)N[C@H](C)c3ccccc3)ccc2C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(CN[C@H](C)c3ccccc3)ccc2C)cc1
Product: Cc1ccc(CN[C@H](C)c2ccccc2)cc1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution of N-((1R)-1-phenylethyl)[3-(4-methoxyphenyl)-4-methylphenyl]carboxamide (0.12 g, 0.34 mmol) in 10 mL of toluene was added DIBAL-H (1 mL, 1.5 mmol). The reaction was then heated to 100 C for 16 hours and cooled to RT. The reaction was quenched with 5 mL of 2N NaOH aq. soln. 100 mL of CH2Cl2 was used to extract the product. The organic phase was washed with 30 mL of brine, dried over Na2SO3 and concentrated in vacuo. The desired products were separated by silica gel column chromatography (30% to 60% EtOAc in hexane) provide ((1R)-1-phenylethyl){[3-(4-methoxyphenyl)-4-methylphenyl]methyl}amine and 4-(5-{[((1R)-1-phenylethyl)amino]methyl}-2-methylphenyl)phenol, which were treated with 1N HCl in Et2O separately to provide the HCl salts as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:28]([C:21]1[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:30])=[O:29]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(F)cc2F)c(OC)c1
Yield: 17.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (600 mg, 2.44 mmol) prepared in Example 14a, 2,4,6-trifluorobenzenesulfonyl chloride (1.50 g, 6.51 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg, 4.89 mmol) and acetonitrile (12 mL), to yield the title compound (192 mg, 18%) as a colorless amorphous solid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:32]([Pb+3])[CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.ClCCl.Cl>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:30]([CH:2]2[C:3](=[O:6])[CH2:4][CH2:5][C:1]2=[O:7])[CH:29]=1
Reactant: Brc1ccc(C2CC2)c([Pb+3])c1
Reactant: O=C1CCC(=O)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)C1c1cc(Br)ccc1C1CC1
Temperature: 80 °C

Procedure:
To a solution of cyclopentane-1,3-dione (0.57 g, 0.0058 mol) and 4-dimethylaminopyridine (3.64 g, 0.030 mol) in chloroform (33 ml) is added toluene (9 ml) then 5-bromo-2-cyclopropylphenyl lead triacetate (3.77 g, 0.0065 mol). This solution is heated at 80° C. for 20 hours then cooled to room temperature and diluted with dichloromethane and 2M aqueous hydrochloric acid. The resulting biphasic suspension is filtered through diatomaceous earth and the two phases are separated. The organic layer is further washed with 2M aqueous hydrochloric acid and the aqueous phase is extracted again with dichloromethane. All organic fractions are combined, washed with brine, dried over magnesium sulfate then concentrated in vacuo. The crude product is finally purified by flash column chromatography on silica gel (isohexane/ethyl acetate eluant) to afford 2-(5-bromo-2-cyclopropylphenyl)cyclopentane-1,3-dione as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1.C(OC(C)C)(C)C>C1CCCCC1>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34]2)[CH:21]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(Cl)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Solvent: CC(C)OC(C)C
Solvent: C1CCCCC1
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CCC4)c3)c(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(b) except for using 0.26 g (0.51 mmol) of 3-chloro-2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 32-(a) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, to the reaction mixture were added diisopropyl ether and cyclohexane, and the precipitated solid was collected by filtration and washed with cyclohexane. To the obtained solid were added methanol and 28% aqueous ammonia, and the mixture was stirred at room temperature for 3 hours. Then, the solution was concentrated under reduced pressure, and the obtained solid was washed with chloroform and dried under reduced pressure to obtain 120 mg of the title compound as a white solid. (Yield: 62%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH2:56])[CH:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1.CCN(CC)CC>CN(C=O)C>[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH:56][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C@@H:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Nitrophenyl)butyric acid (73 mg, 350 μmol), dissolved in DMF (5 ml) was treated with HOBT (60 mg, 350 μmol), EDC (76 mg, 350 μmol) and N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (160 mg, 300 μmol). The pH was adjusted to ~7.5 with Et3N (170 μl, 385 μmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 ml) and H2O (100 ml). The organic layer was washed with H2O (2×50 ml), dried (MgSO4), filtered and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 1:1 to 1:2 hexane: EtOAc) to give the title compound.
Reaction SMILES: [N:1](=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11])[NH2:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.CCOCC>[OH2:11].[C:25]([NH:2][N:1]=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Product: O
Reaction time: 45 h
Yield: 96 %

Procedure:
A solution of 3-hydrazonomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (93 mg) in a mixture of acetic anhydride (0.5 ml) and pyridine (0.2 ml) is kept at room temperature for 45 hours. The mixture is diluted with ether. The obtained precipitate is collected by filtration and dried to leave 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid monohydrate (101 mg). m.p. 184°-190° C (decomposition). Yield: 96%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:38])([F:37])[C:12]1[CH:13]=[N:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)[CH:16]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C>O1CCCC1>[F:37][C:11]([F:10])([F:38])[C:12]1[CH:13]=[N:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:33])=[CH:35][CH:36]=3)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)[CH:16]=1
Reactant: CCOC(=O)CCN
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
To a mixture of ethyl 3-aminopropanoate hydrochloride (418 mg, 2.72 mmol), 4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzoic acid (732 mg, 1.82 mmol), 1-hydroxybenzotriazole hydrate (292 mg, 1.91 mmol), and N,N-diisopropylethylamine (1.20 mL, 7.26 mmol) in tetrahydrofuran (18.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (557 mg, 2.90 mmol). The mixture was stirred for 48 hours at ambient temperature. The reaction mixture was concentrated and the crude material was purified by column chromatography (0-100% ethyl acetate in heptane) to afford racemic ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (684 mg, 85%) as a solid. The racemate was further purified via chiral SFC to afford 300 mg of Isomer 1 and 300 mg of Isomer 2, which were used in conversion to the final enatiopure products. 1H NMR (400 MHz, CDCl3, δ): 7.94 (q, J=0.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 6.84 (t, J=5.8 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 4.42-4.34 (m, 1H), 4.31 (d, J=4.7 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.71 (q, J=6.1 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.88-1.71 (m, 2H), 1.53-1.31 (m, 2H), 1.27 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). Chiral SFC: Chiralpak AD-H, 10×250 mm; Mobile Phase 65:35 CO2/methanol, 65 mL/min, Retention time: 3.95 min (Isomer 1), 6.81 min (Isomer 2).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:19])[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[F:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][NH:10][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cccc(F)c3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Fc1cccc2c1CNC2
Yield: 55.8 %

Procedure:
The procedure described in Reference Example 6-(3) was followed using 2.30 g of 2-(p-toluenesulfonyl)-4-fluoroisoindoline, 2.30 g of phenol, 20 ml of 48% hydrobromic acid, and 3.5 ml of propionic acid. Purification of the crude product by vacuum distillation (bath temperature: 110°-150° C., pressure: 7 mmHg) gave 604 mg of 4-fluoroisoindoline.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.[NH2:16][C:17]1[C:18]([CH3:35])=[N:19][S:20][C:21]=1[NH:22][C:23]([C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](OC)=[O:28])=[O:24]>CN(C=O)C>[CH3:35][C:18]1[C:17]([N:16]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:21]([N:22]2[C:23](=[O:24])[C:25]3[C:26](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:27]2=[O:28])[S:20][N:19]=1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(N2C(=O)c3ccccc3C2=O)c1N1CCCC1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
DIEA (332.7 mg, 448.4 μL, 2.574 mmol), 1,4-dibromobutane (555.8 mg, 307.4 μL, 2.574 mmol) was added to a solution of methyl 2-[(4-amino-3-methyl-isothiazol-5-yl)carbamoyl]benzoate (150 mg, 0.5149 mmol) in DMF (4 mL) and the mixture was stirred at 130° C. for 40 min in a microwave. The reaction mixture was concentrated in vacuo to yield 2-(3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-yl)isoindoline-1,3-dione that was used in next step without further purification. MS (ES+) 314.1.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[N:12]=[C:13]([C:16]2(O)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:14][CH:15]=1>ClCCl>[Br:10][C:11]1[N:12]=[C:13]([C:16]2([F:7])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Br)cs2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
Diethylaminosulfur trifluoride (DAST) (0.083 mL, 0.627 mmol) was added to a 0° C. of tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.207 g, 0.570 mmol) in dichloromethane (2.8 mL). After 5 minutes, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 5-50% ethyl acetate-hexane) to afford tert-butyl 4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate (0.163 g, 78%) as a colorless, waxy solid. MS (ESI, pos. ion) m/z 387, 389 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1C=C(C2N=C(C=O)C3C(C=2)=C[C:17]([O:21]C)=[C:16](OC)C=3)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[BH4-].[Na+].C[C:30]([CH3:32])=[O:31]>C(O)C>[CH3:16][CH2:17][O:21][C:30]([CH3:32])=[O:31].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: CC(C)=O
Reactant: COc1cc2cc(-c3cccc(C(C)(C)C)c3)nc(C=O)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 1 h
Yield: 63 %

Procedure:
3-(3-(tert-Butyl)phenyl)-6,7-dimethoxyisoquinoline-1-carboxaldehyde (97 mg) in 5 mL ethanol was treated slowly with NaBH4 (26 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H2O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a pale yellow solid (50 mg, 63% yield). 1H NMR (400 MHz) (CDCl3) δ 8.07 (m, 1H), 7.86-7.83 (m, 1H), 7.82 (s, 1H), 7.39-7.37 (m, 2H), 7.13 (s, 1H), 6.98 (s, 1H), 5.12 (s, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.35 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 154.47, 153.14, 151.62, 150.31, 148.21, 138.90, 133.85, 128.51, 125.55, 123.97, 123.65, 119.64, 115.25, 105.84, 101.22, 61.32, 56.13, 56.10, 34.90, 31.45. IR (thin film NaCl) 3345, 2957, 1621, 1577, 1506, 1467, 1416, 1362, 1276, 1247, 1163, 1090, 1023, 991, 874, 834, 800, 701.