Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:19]([C:21]1[CH:48]=[CH:47][C:24]2[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:23]=2[CH:22]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].O>CO.[Pd]>[C:1]([N:5]([C:19]([C:21]1[CH:48]=[CH:47][C:24]2[N:25]=[CH:26][NH:27][C:23]=2[CH:22]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(OC)cccc1C(=O)NN(C(=O)c1ccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1)C(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CCc1c(OC)cccc1C(=O)NN(C(=O)c1ccc2nc[nH]c2c1)C(C)(C)C
Reaction time: 6 h

Procedure:
About 120 mg of 3-trityl-3H-benzoimidazole-5-carboxylic acid N-tert-butyl-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide were dissolved in 35 mL of CH3OH and added into a hydrogenation bottle, together with 2 drops of glacial acid and 0.20 g Pd/C. Hydrogenation was conducted by shaking the bottle for 6 hours and then remaining under H2 pressure for 16 hours. The Pd/C was removed by filtration and the methanol removed by an evaporator. The residue was stirred with CH2Cl2 and the CH2Cl2 was decanted. Evaporation of the CH2Cl2 yielded a solid product identified by NMR, as triphenylmethane. The residue was stirred with dilute KOH/H2O and extracted with ethyl acetate. The ethyl acetate was dried and concentrated on a rotary evaporator to yield the product 3H-benzoimidazole-5-carboxylic acid N-tert-butyl-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide. NMR analysis of the product indicated the absorbances for the methoxy and t-Butyl groups occurred at 3.69 and 1.61 vs. 3.77 and 1.59 for the starting material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([O:28][C:29]([Cl:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[ClH:31].[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]([C:29]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccc(CN2CCOC(CNc3ccccc3)C2)cc1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Oc1ccccc1)N(CC1CN(Cc2ccccc2)CCO1)c1ccccc1

Procedure:
To a solution of 4-benzyl-2-anilinomethylmorpholine (8.1 g.) in toluene (50 ml.) and hexamethylene phosphoramide (2 ml.) is added phenylchloroformate (8 ml.). A white precipitate forms which does not dissolve when the mixture is refluxed for 4 hours. The solid (10.15 g.) is crystallised from ethanol to give 4-benzyl-2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride, m.p. 248°-250°C.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1(=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NCCc2ccncc21
Yield: 72.4 %

Procedure:
2-(4-Methoxybenzyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one (I-65e: 700 mg, 2.6089 mmol) and p-toluene sulphonic acid (1.985 g, 10.436 mmol) in toluene (15 mL) were refluxed for 6 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was neutralized with sodium carbonate solution, distilled off the solvent and added 10% methanol in CHCl3. The solid precipitated was filtered and distilled off the solvent to afford the crude product. Purification by column chromatography on silica gel (7% methanol in DCM) afforded 280 mg of the product (72.53% yield).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(-c2sc(-c3ccccc3)cc2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(-c3ccccc3)cc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Hydroxy-2-(4'-methoxyphenyl)-5-phenylthiophene (200 mg, 0.71 mmol) was dissolved in 2.0 mL of pyridine and treated with acetic anhydride (0.50 mL, 5.3 mmol). The solution was stirred 4 hours at 25° C., and then most of the acetic anhydride and pyridine were removed on a rotary evaporator at reduced pressure. The residue was dissolved in 40 mL of ethyl acetate and washed with 2×15 mL of 2N aqueous hydrochloric acid, 15 mL of saturated aqueous sodium bicarbonate, and 15 mL of saturated aqueous sodium chloride. The solution was dried over sodium sulfate, decanted, and evaporated. The residual oil (224 mg) began to crystallize upon standing overnight. This was combined with other material prepared by the same method and recrystallized twice from 3-4 mL of 7% ethyl acetate in hexane to give 3-acetoxy-2-(4'-methoxyphenyl)-5-phenylthiophene as very pale pink needles, m.p. 81°-82° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[C:17]1([CH:23]([O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of freshly prepared diphenyldiazomethane22 (3.50 g, 18.0 mmol) in ethyl acetate (20 ml) was added N-Boc-trans-4-hydroxy-L-proline (3.25 g, 14.0 mmol) in ethyl acetate (30 ml). Nitrogen gas was slowly evolved from the solution and the intense purple colour of diphenyldiazomethane was gradually discharged. The solution was stirred at room temperature overnight using a CaCl2 guard tube. Evaporation of the solvent followed by precipitation of the product from ethyl acetate-petroleum ether b.p. 40-60° C. gave a white solid, N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline diphenylmethyl ester (2a), (5.10 g, 91%), m.p. 93-95° C. (lit.9 m.p. 103-104° C.), δH (200 MHz; CDCl3) 1.22 and 1.47 (9H, 2×s, Boc rotamers), 1.95-2.50 [3H, br m, CH2(3) and OH], 3.45-3.74 [2H, br m, CH2(5)], 4.40-4.65 [2H, br m, CH(2)and CH(4)], 6.95 (1H, br s, CHPh2), 7.25-7.55 (10H, br m, phenyl CH); νmax (KBr)/cm−1 3491br (O—H), 1728s (C═O ester), 1693s (C═O urethane); m/z (ES MS) 436 (M+K+, 55%), 420 (M+Na+, 100), 415 (M+NH4+, 15), 398 (M+H+, 72); [α]D25−54.3 (C=1.0, EtOH).
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:6]=[CH:7][CH:8]=[CH2:9].[CH:10]#[N:11]>>[C:10](#[N:11])[CH2:2][CH:3]=[CH:4][CH3:5].[CH3:6][CH:7]([CH:8]=[CH2:9])[C:10]#[N:11]
Reactant: C#N
Reactant: c1ccsc1
Reactant: C=CC=C
Product: C=CC(C)C#N
Product: CC=CCC#N
Reaction time: 17 h

Procedure:
In an experiment conducted similarly to that in Example 4 except that the reactants were 0.8 g. of anhydrous cuprous bromide, 1 ml. of thiophen, 6.5 g. of butadiene and 5 ml. of hydrogen cyanide, and heating was continued for 17 hours at 100°C the conversion of butadiene to mononitriles was 48%, and 3-pentenenitrile was obtained in a yield of 82.2% and 2-methyl-3-butene-nitrile in a yield of 17.8% calculated on the butadiene converted.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:2]([CH3:3])[CH3:1])=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(c2ccc(OCc3ccccc3)cc2)N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Dimethylamine (55 mL, 0.15 mol) in 100 mL of toluene was added over ten min at 0°-5° C. to a 600 mL toluene suspension of 1-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)ethan-l-one (50 g, 0.15 mol), then stirred 15 min at 0° C. A 50 mL toluene solution of TiCl4 (9.8 mL, 0.09 mol) was added dropwise over 1 h to the reaction mixture, keeping the temperature below 5° C. The brown suspension was stirred 16 h at rt then filtered through Hyflo Super Cel to give a yellow filtrate. Two Et2O washes of the filter bed were combined with the filtrate and the solution was concentrated to a thick amber oil. The oil was triturated with Et2O/ pet. ether and filtered to give 41 g (77%) of yellow solid: mp 60° C.; 1H NMR (CDCl3) d 2.64 (s, 6H, NMe2), 3.71 (s, 3H, OCH3), 5.07 (s, 2H, OCH2), 5.42 (s, 1H, =CH), 6.57-6.60 (d, 2H, J=9 Hz, ArH), 6.67-6.70 (d, 2H, J=9 Hz, ArH), 6.86-6.89 (d, 2H, J=9 Hz, ArH), 6.90-6.93 (d, 2H, J=9 Hz, ArH), 7.18-7.21 (d, 2H, J=9 Hz, ArH), 7.40-7.45 (m, 5H, ArH); MS(FD) 360[M+1]+Anal. Calcd for C24H25NO2 : C, 80.19; H, 7.01; N, 3.90. Found: C, 80.41; H, 7.12; N, 4.09.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1.[ClH:36]>CCOCC>[ClH:36].[ClH:36].[CH3:1][O:2][CH2:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]1
Reactant: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
tert-Butyl [(1R,3S)-3-(2-methoxyethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (252 mg, 0.503 mmol) was dissolved in a 2 M solution of hydrogen chloride in ether (8 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated to give the desird product as a yellow powder (0.36 g, 96%). MS calculated for C19H27F3N4O2 (M+H) 401.3; found 401.3.
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCNC(=O)C2
Temperature: 120 °C
Yield: 46.2 %

Procedure:
7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (50 mg, 0.2 mmol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (90.5 mg, 0.27 mmol), and a 4 M solution of hydrogen chloride in dioxane (0.1 mL, 2 eq), were added to 2-methoxyethanol (2 mL), and the reaction mixture was heated for 6 hours at 120° C. The reaction mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and then concentrated on SiO2. Flash chromatography on SiO2 (MeOH/dichloromethane 0-5%) gave N-{(1R,2R)-2-[5-Chloro-2-(8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (47 mg, 30%) as a beige solid. MP: 109-115° C.; 1H-NMR (CDCl3) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.18 (m, 1H), 6.00 (d, J=6.5 Hz, 1H), 5.51 (d, J=7.8 Hz, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 3.75 (m, 2H), 3.53 (m, 2H), 3.25 (m, 1H), 3.04 (t, J=6.1 Hz, 2H), 2.85 (s, 3H), 2.60 (s, 2H), 2.20 (m, 2H), 1.8 (m, 2H), 1.34 (m, 2H); LC/MS (ESI+): 509.28 (M+H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+].[SH:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:30]3[S:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 2.72 g. (0.01 mole) of 7-ACA in 50 ml. of 0.1 M, pH 6.4 phosphate buffer, was added 1.68 g. (0.02 mole) of NaHCO3 followed by 1.45 g. (0.011 mole) of 2-mercapto-5-methyl-1,3,4-thiadiazole and the mixture heated and stirred at 60° C. for five hours. The resulting slurry was then allowed to cool to about 22° C. over a one hour period. The crystalline precipitate was collected by filtration, washed with water and air dried. Yield 1.3 g., dec. pt. 206° C. Scaling up the reaction 10X gave 18.0 g.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:52][O:53][C:54]1[CH:55]=[C:56]([CH:60]=[C:61]([O:65][CH3:66])[C:62]=1[O:63][CH3:64])[C:57](Cl)=[O:58]>CC(C)=O>[CH3:66][O:65][C:61]1[CH:60]=[C:56]([CH:55]=[C:54]([O:53][CH3:52])[C:62]=1[O:63][CH3:64])[C:57]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:58]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (3.95 g, 6.48 mmol) and acetone (20 mL), water (6 mL), and potassium carbonate (2.70 g, 19.5 mmol). Cool to 0° C. in an ice bath. After 30 minutes, add dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (1.71 9, 7.4 mmol) in acetone (20 mL). Warm to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.23 (silica gel, ethyl acetate). Analysis on HPLC using a CHIRALPAK AD (10 μm×4.6 cm×250 cm) column eluting with pentane/ethanol/methanol/triethylamine (80/15/5/0.1) with a flow rate of 1.5 mL/minute indicates an enantiomeric excess of 98%, (98% ee), retention time of 22.30 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5](F)[CH:4]=1)#[N:2].Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[NH:27][CH:24]1[CH2:23][CH2:22][N:21]([CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:26][CH2:25]1)([O-:11])=[O:10]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 200 °C
Reaction time: 0.02 h

Procedure:
4-Cyano-2-fluoro-1-nitrobenzene (300 mg, 0.0018 mol, 1 eq), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D9, 330 mg, 0.0018 mol, 1 eq), diisopropylethylamine (350 mg, 0.0027 mol, 1.5 eq), and dimethylformamide (5 ml) were combined, heated to 200° C. and held for 1 min in a microwave reactor. 100 ml of water was then added and the reaction extracted with 2×75 ml dichloromethane. The dichloromethane layers were combined, dried with sodium sulfate, and evaporated to yield the title compound which was used without further purification in the next step. MS (ESI): 331 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1>CO>[ClH:4].[CH3:1][O:12][C:11]([CH:8]1[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1)=[O:13]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C1CCNCC1
Product: Cl
Reaction time: 1.25 h

Procedure:
To a cooled solution of anhydrous methanol (100 mL) was added acetyl chloride (7.1 mL, 0.1 mol) and the solution stirred for 75 min. Piperidine-4-carboxylic acid (150 mg, 1.16 mmol) was dissolved in the prepared solution (10 mL) and the reaction stirred for 16 h. The solvent was removed in vacuo to give the title compound as its hydrochloride salt. m/z (ES+)=144.12 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:18]([O:22][C:23](=[O:24])[NH:25][CH2:26][C:27](=[O:28])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(2-Pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine (1.00 g, 4.34 mmol), tert-butoxycarbonylamino-acetic acid (0.836 g, 4.77 mmol), ethyldimethylpropylcarbodiimide hydrochloride (1.00 g, 5.24 mmol), N-hydroxybenzotriazole (0.707 g, 5.24 mmol) and N-methyl morpholine (1.10 g, 10.9 mmol) were dissolved in 30 mL of DMF, and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 1.62 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.86 (d, 2H, J=6.11), 4.47 (t, 2H, J=6.78), 7.08–7.65 (m, 4H), 8.24 (s, 1H), 9.97 (s, 1H); MS (DCI/NH3) m/z 388 [M+H]+.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:25])[CH2:24][C@H:21]3[S:20][C:19](NC(=O)/C=N\OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)(C3N=C(NC(OC(C)(C)C)=O)SC=3)[C:18]=2[CH2:64][S:65][C:66]2[N:67]([CH3:71])[N:68]=[N:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[CH3:71][N:67]1[C:66]([S:65][CH2:64][C:18]2[CH2:19][S:20][C@@H:21]3[CH2:24][C:23](=[O:25])[N:22]3[C:17]=2[C:15]([OH:14])=[S:16])=[CH:70][N:69]=[N:68]1
Reactant: Cn1nncc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2SC1(NC(=O)/C=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cn1nncc1SCC1=C(C(O)=S)N2C(=O)C[C@H]2SC1
Reaction time: 1 h
Yield: 128.2 %

Procedure:
To a solution of 7μ-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)- 2-trityloxyiminoacetamido-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (900 mg: 0.869 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) is added a solution of aluminum chloride (924 mg: 6.95 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -40°-30° C. The reaction mixture is diluted with 1N-hydrochloric acid (7 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7μ-(Z)-2-(2-aminothiazol -4-yl)-2-hydroxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (366 mg). Yield: 80%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(Cl)C(F)=S.Cl.[CH3:19][N:20]([S:24]SC1C=CC(Cl)=CC=1)[C:21]([F:23])=[O:22]>CCCCC>[CH3:19][N:20]([S:24][S:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:21]([F:23])=[O:22]
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: CN(Cl)C(F)=S
Agent: Cl
Solvent: CCCCC
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F

Procedure:
Prepared by reacting 0.5 g of 4-t-butylthiophenol in pentane with 0.44 g of N-methyl-N-chlorothiocarbamoyl fluoride. The reaction proceded with a vigorous exotherm and evolution of hydrochloric acid gas. The infrared and n.m.r. spectra of the product was identical to the material prepared by Method I.
Reaction SMILES: [O:1]=[C:2]([O:8][C@H:9]1[CH2:14][C@@H:13]2[C:15]([CH3:17])([CH3:16])[C@@:10]1(C)[CH2:11][CH2:12]2)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:19]1[CH:24]=[CH:23][C:22]([CH:25](O)CNC2N=CC=CC=2)=[CH:21][CH:20]=1.Cl.[CH2:36](N(CC)CC)C>CC(OC)(C)C>[C:5]([O:7][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)(=[O:6])[CH2:4][CH2:3][C:2]([O:8][CH:9]1[CH2:14][CH:13]([CH3:36])[CH:12]2[CH2:11][CH:10]1[C:15]2([CH3:16])[CH3:17])=[O:1]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](OC(=O)CCC(=O)O)C2
Reactant: OC(CNc1ccccn1)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: COC(C)(C)C
Product: CC1CC(OC(=O)CCC(=O)OCc2ccccc2)C2CC1C2(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Benzyl-4-chloro-4-oxobutanoate (3.22 g, 1 eq, from Example 2) was dissolved in MTBE (100 mL) in a 300 mL round bottom flask. Verbanol™ (2.12 g, 1 eq) and triethylamine (1.39 g, 1 eq) were added and the reaction was heated at 40° C. and stirred overnight. The reaction mixture was extracted with a dual-layer MTBE-1N HCl system. The organic layer was washed with brine, dried over MgSO4 and concentrated. Toe crude product was purified using column chromatography to give 3.45 g of a clear oil (73%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:23][N:24]([CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:25][C:26]1[CH:31]=[CH:30]N=C[CH:27]=1.[CH:39]([NH:42]C(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:36]3[CH2:35][CH2:34][CH:33]([CH2:32][N:24]([CH3:23])[CH2:25][C:26]4[CH:27]=[N:42][CH:39]=[CH:30][CH:31]=4)[CH2:38][CH2:37]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(Cc1ccncc1)CC1CCNCC1
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Product: CN(Cc1cccnc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-piperidine-4-ylmethyl-pyridine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (36%, colourless crystals). HPLC-MS m/z=501.1 (M+1), Rt: 2.74 min.