Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[S:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:31]([NH:30][C:24]2[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)[S:32][CH3:14])[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1cc(N=C=S)cc(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,5-dimethoxyphenyl isothiocyanate (0.96 g, 4.9 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 2 h 15 min and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, dried (Na2SO4) and concentrated. The residue was crystallised from ethyl acetate/heptane 1:2 to give 1.27 g (65%) of the title compound. Mp 119.5-123° C.; 1H NMR (200 MHz, CDCl3): δ=2.29 (s, 3H), 3.80 (s, 6H), 3.36 (m, 3H), 7.53 (d, 2H), 7.87 (d, 2H), 9.82 (br s, 1H); EI SP/MS: 424 (M+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:24]([NH2:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)=O.C(Cl)Cl.[OH-].[Na+]>O>[NH2:1][C@H:2]([C:24]([NH2:26])=[O:25])[CH2:3][S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: ClCCl
Solvent: O
Product: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To the Boc-Cys(Trt)-NH2 (100 gm), added formic acid (600 ml) at temperature of about 10° C. to about 20° C. Heated the solution to about 20° C. to about 35° C. and stirred for 30 minutes at the same temperature. Added an additional quantity of formic acid (200 ml) and stirred for two hours. Cooled the reaction mass to about 0° C. to about −10° C. and charged methylene chloride (1000 ml), DM water (100 ml) and adjusted pH to 7.5-9.0 with 8N aqueous Sodium hydroxide solution. Heated the solution to about 25° C. to about 35° C. and separated the organic layer and extracted the aqueous layer with methylene chloride (250 ml) and separated the aqueous and organic layer. Combined the organic layer and washed with DM water and concentrated the organic layer under reduced pressure to obtain the residue. The residue was crystallized from hexane (100 ml) to obtain the H-Cys(Trt)-NH2 as white solid material.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N+:21]([O-:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>CCOCC.O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:23][CH2:24][CH2:25][CH2:26]3)[N:21]([OH:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(C2C[N+]([O-])=C3CCCCC32)cc1OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2CN(O)C3(c4ccccc4)CCCCC23)cc1OC
Temperature: 35 °C
Yield: 23.6 %

Procedure:
A volume of 75 ml of 3 M phenylmagnesium bromide in ether was added over a period of five minutes to a warm (35° C) stirred solution of 41.25 g (0.015 mole) of 3,3a,4,5,6,7-hexahydro-3-(3,4-dimethoxyphenyl)-2H-indole-1-oxide in 500 ml of tetrahydrofuran. After stirring for 2 hours at room temperature, most of the THF was distilled off at atmospheric pressure. Ice water (1 liter) was added and the paste-like solid was filtered. The damp filter cake was added to 500 ml of 1N HCl. The taffy-like material which remained out of solution was added to 10 MKOH (300 ml). The mixture was extracted into 1.5 l methylenechloride and the extract was dried (K2CO3), charcoaled, filtered and concentrated. The residue was dissolved in 200 ml of petroleum ether. There was obtained 12.5 g (23.6%) of a white solid melting at 166°-168° C. Recrystallization from 2-propanol gave pure material melting at 168°-170° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: OCCCBr
Solvent: ClCCl
Product: OCCCN1CCOCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a mixture of morpholine (33 mL, 371 mmol) and CH2Cl2 (650 mL) was added 3-bromopropanol (25.8 g, 186 mmol), and the mixture was heated at 50° C. for 18 h. The reaction was cooled, diluted with CH2Cl2, and filtered. The filtrate was chromatographed (150 g SiO2, CH2Cl2 to 5% 2 M NH3/MeOH in CH2Cl2) to give the title compound as a liquid (27.0 g, 50%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH2:15][CH2:14]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O.OC1C2N=NNC=2C=CC=1.ClCCl>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]2)=[O:23])[CH2:15][CH2:14]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)CCCN2CCOCC2)CC1

Procedure:
The procedure is carried out in a manner similar to that described in Example 63, but starting with 4.20 g of methyl cis-4-aminocyclohexane-1-carboxylate hydrochloride, 4.0 g of 4-morpholinobutyric acid, 50 mg of hydroxybenzotriazole hydrate, 11.2 cm3 of triethylamine, 200 cm3 of dichloromethane and 4.2 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. After a treatment similar to that in Example 60, the crude product is purified by flash chromatography [eluent: dichloromethane/methanol (95/5 by volume)] to give 5.0 g of methyl cis-4-(4-morpholinobutyrylamino)-1-cyclohexanecarboxylate in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[B:9](O)(O)O.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:3])[CH2:4][CH:5]([CH3:6])[O:7][BH:9][O:8]1
Reactant: OB(O)O
Reactant: CC(O)CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C)(C)OBO1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
Into a 3 liter reaction vessel equipped with stirrer, thermometer, reflux condenser and Dean Stark trap is placed 710.0 grams of 2-methyl-2,4-pentanediol; 372.0 grams of boric acid and 500 grams of toluene. With stirring the reaction mass is heated to 87° C. and, by way of the Dean Stark trap water is eliminated and the alcohol having the structure: ##STR77## is recovered. The reaction temperature gradually rises to 125° C. as water is eliminated and the total reaction time is 10 hours. The total amount of water evolved is 252.0 grams. When the water of reaction ceases to evolve, the reaction mass is cooled to 70° C. Once all of the water is removed the compound having the structure: ##STR78## as recovered weighs 1227.0 grams. This material having the structure: ##STR79## is used for Examples II, III, IV and V, infra.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](Cl)[N:12]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][CH:29]=[CH2:30])[CH:25]=[C:24]([CH3:31])[C:23]=1[OH:32]>>[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][CH:29]=[CH2:30])[CH:25]=[C:24]([CH3:31])[C:23]=1[O:32][C:13]1[N:12]=[C:11]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#Cc1ccc(N)cc1
Reactant: C=CCc1cc(C)c(O)c(C)c1
Product: C=CCc1cc(C)c(Oc2ccc([N+](=O)[O-])c(Nc3ccc(C#N)cc3)n2)c(C)c1

Procedure:
4-cyano aniline was coupled with 2,6-dichloro-3-nitropyridine by Method B in Preparation Example 1 to prepare 6-chloro-N2-(4′-cyanobenzene)-3-nitropyridine (intermediate II-1), which was coupled with 2,6-dimethyl-4-allylphenol by Method B in Preparation 2 to get Compound 15.
Reaction SMILES: NC1C=CN=CC=1.[O:8]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9]1.[C]=O.[H][H].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>C(O)C>[CH2:23]([O:22][C:19](=[O:21])[CH2:9][C@@H:10]([OH:8])[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:24]
Reactant: CCOC(C)=O
Reactant: [H][H]
Reactant: CCCC[C@H]1CO1
Agent: Nc1ccncc1
Agent: [C]=O
Solvent: CCO
Product: CCCC[C@H](O)CC(=O)OCC
Temperature: 25 °C
Yield: 85 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated ethanol (10 mL) and ethyl acetate (10 mL), and thereto were added 4-aminopyridine (47 mg, 0.5 mmol) and (S)-1,2-epoxyhexane (2.0 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (1 MPa) and hydrogen gas (1 MPa) were introduced therein and the mixture was reacted at 35° C. for 28 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (S)-3-hydroxyheptanoic acid ethyl ester (2.92 g, 85%, >99% ee) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:34])[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:33])[CH3:34])=[O:9]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 7 h
Yield: 50.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, ˜0.7 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (200 mg, 0.91 mmol) in DMSO (5.3 mL) was added PyBOP (550 mg, 1.05 mmol) and hunig base (366 ul, 2.10 mmol). The reaction mixture was stirred at 23° C. for 7 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (166 mg, 50% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.06 (d, J=2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.49-3.57 (m, 1H), 3.02 (q, J=6.8 Hz, 2H), 2.80-2.84 (m, 2H), 2.61-2.69 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.23 (s, 3H), 1.86-1.90 (m, 2H), 1.66-1.70 (m, 4H), 1.21 (d, J=6.8 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+Na] 495.2; HPLC 95.7% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:26])[CH3:25]>COCCOC>[CH2:24]([NH:26][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:25]
Reactant: CCN
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: CCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and ethylamine in DME. ES-MS m/e (%): 250 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.[S:28]1[C:32](B(O)O)=[CH:31][C:30]2[CH:36]=[CH:37][CH:38]=[CH:39][C:29]1=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:28]1[C:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:31][C:30]2[CH:36]=[CH:37][CH:38]=[CH:39][C:29]1=2.[S:28]1[C:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:15]([CH3:16])[CH3:17])[CH:18]([CH3:20])[CH3:19])[CH:6]=[C:5]3[CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:31][C:30]2[CH:36]=[CH:37][CH:38]=[CH:39][C:29]1=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(-c3cc4ccccc4s3)ccc21
Product: CN1CCC(c2c[nH]c3ccc(-c4cc5ccccc5s4)cc23)CC1
Yield: 40.8 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 5-bromo-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (0.700 g, 1.56 mmol), benzo[b]thiophene-2-boronic acid (0.336 g, 1.87 mmol), tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol), and 2M aqueous sodium carbonate solution (3 mL) in toluene (15 mL) to give 0.160 g of 5-(2-benzo[b]thienyl)-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (22%) as a solid, which was desilylated by dissolving in 1 mL of tetrahydrofuran and treating with tetrabutylammonium fluoride (1M in tetrahydrofuran, 7 mL) to give the title compound (0.048 g, 43%) as an amorphous solid. FDMS m/e=346 (M+). EA calculated for C22H22N2S.¼ H2O: C, 75.28; H, 6.46; N, 7.98. Found: C, 75.11; H, 6.84; N, 7.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22].[CH:23](=O)[CH:24]([CH3:26])[CH3:25].[OH-].[NH4+:29]>C(O)(=O)C.C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:29][C:23]([CH:24]([CH3:26])[CH3:25])=[N:22][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: [NH4+]
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1nc(-c2ccccc2)c(-c2ccc(F)cc2)[nH]1

Procedure:
To a stirred solution of 1-(4-fluorophenyl)-2-phenylethan-1,2-dione (1.0 g) in acetic acid (25 ml) and acetic anhydride (3 ml) containing ammonium acetate (5.0 g) was added isobutyraldehyde (0.5 g) and the reaction mixture was warmed to 110° for 2 h. The mixture was poured into aqueous ammonium hydroxide at 0° and the deposited solid was collected by filtration, then washed sequentially with ether and water then dried in vacuo to afford the title compound (1.09 g), λmax (EtOH) 252 (9550) and 287.8 nm (ε11,870).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[I:35][CH3:36]>ClCCl>[I-:35].[CH3:19][C:12]1[N+:13]2[C:14](=[CH:16][N:17]([CH3:36])[CH:18]=2)[S:15][C:11]=1[C:8]1[C@H:9]([CH3:10])[C@@H:5]2[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:33](=[O:34])[N:6]2[C:7]=1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:21]
Reactant: CI
Reactant: Cc1c(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Solvent: ClCCl
Product: Cc1c(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cn(C)c[n+]12
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 73.6 mg of 4-nitrobenzyl (1S,5R, 6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 0.5 ml of dry dichloromethane was added 0.95 ml of iodomethane, and the mixture was stirred under the atmosphere of argon in the darkness at room temperature for 18 hours. Unreacted reagent was removed under reduced pressure to give 89.1 mg of 4-nitrobenzyl (1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate iodide.
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.C([O-])(=O)C.[Na+:48]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:48]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate (13 g) was added and charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium (19.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1SSC1C=CC=CN=1.[S:29](Cl)(=[O:32])(=[O:31])[OH:30].[OH-].[Na+]>ClCCCl.CCOC(C)=O.CCCCCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:29]([OH:32])(=[O:31])=[O:30])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 4-(pyridin-2-yldisulfanyl)butanoic acid (725 mg, 3.16 mmol) and 1,2-di(pyridin-2-yl)disulfane (700 mg, 3.18 mmol) in 15 ml of DCE (1,2-dichloroethane) at 75° C. was added chlorosulfuric acid (300 μL, 4.51 mmol). After stirring for 20 min at 75° C., another portion of chlorosulfuric acid (300 μL, 4.51 mmol) was added. The mixture was allowed to stir at 75° C. for 20 min, then another portion of chlorosulfuric acid (200 μL, 3.0 mmol) was added. Again 25 min later, the final portion of chlorosulfuric acid (200 μL, 3.0 mmol) was added and the mixture was stirred for further 25 min. The mixture was immediately cooled on ice bath, neutralized with 1M NaOH to pH ˜7, diluted with EtOAc/Hexane (1:1), separated, and the organic layer was washed with pure water (3×25 ml) while the generated each of aqueous layer was washed with EtOAc/Hexane (1:1, 35 ml). The aqueous layers were combined, acidified with HCl/HOAc to pH 3˜4, concentrated to ˜10 ml, diluted with MeCN (100 ml), sonicated (or quickly stirred) for 1 h, filtered, and the resulting pellet washed with water/MeCN (1:10). The solution was then concentrated and purified on a Si02 cartridge (40 g) eluting with water/MeCN/HOAc (1:10:0.01). To the pooled fractions containing the product, DMF (˜5 ml) was added and evaporated to dryness to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (295 mg, 0.954 mmol, 30.2% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35]([CH:36]=O)[C:30]2=[CH:29][CH:28]=1>CO.N1CCCCC1>[Cl:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35](/[CH:36]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])[C:30]2=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2nc(Cl)ccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(Cl)ccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.057 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.009 g, 0.057 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5→90:10)) to obtain tert-butyl (Z)-4-({2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10](N)=[O:11])=[CH:9][N:4]2[N:3]=1.[OH-:14].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10]([OH:14])=[O:11])=[CH:9][N:4]2[N:3]=1
Reactant: [OH-]
Reactant: Cc1cc2ncc(C(N)=O)cn2n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2ncc(C(=O)O)cn2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide (475 mg) was dissolved in ethanol (5 ml), and 5 N sodium hydroxide solution (2 ml) was added thereto and stirred for 1 hour at 70° C. The reaction mixture was cooled to room temperature, water was added thereto, and the reaction mixture was washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (300 mg, Y.:63%) as white crystals.