Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](=S)(OC2C=CC(C)=CC=2)=O)=[CH:12][CH:11]=1.Cl>C1COCC1>[OH:7][C:2]1[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[S:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: Cc1ccc(OS(=O)(=S)c2ccc(C)cc2)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(SC2=C(O)C(=O)CCC2)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A 1.0M solution of lithium bis(trimethyl)silylamide in THF (28.7 mL, 28.77 mmol) was added to 30 mL of dry THF stirring under N2, and the solution was cooled to -10° C. A solution of 1.54 g (13.7 mmol) 1,2-cyclohexanedione in 7 mL of THF was added in a slow stream via syringe. The reaction mixture turned darkreddish brown. The reaction mixture was stirred for 15 min at -10° C. and then cooled to -50° C. A solution of 4-methylphenyl 4-methyl-benzenethiosulfonate (3.5 g, 14.2 mmol) in 10 mL of THF at -50° C. was added in one portion via syringe. The reaction mixture was stirred for 2 h at -50° C. and allowed to warm at ambient temperature until approximately 0° C., and then 100 mL of 0.1 N HCl was added. The mixture was extracted with 300 mL and then 100 mL of diethyl ether, and the combined organic extracts were dried over anhydrous sodium sulfate. Concentration in vacuo provided a yellow solid which was purified by flash chromatography over silica gel using CH2Cl2, 10% EtOAc/Hexane, and then 3% MeOH/CH2Cl2 as eluent. The desired product, 2-hydroxy-3-[(4-methylphenyl)thio]-2-cyclohexenone [Compound Iy], was isolated as a white solid (1.939 g, 60%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]>C(O)C>[CH3:29][O:28][CH2:27][CH2:26][O:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COCCOCOCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCOCOCCOC)C(=O)OCC

Procedure:
A solution of 37.80 of diethyl malonate dissolved in 20 ml of absolute ethanol was added dropwise to a solution of sodium ethoxide prepared by gradually adding 3.00 g of metallic sodium to 30 ml of absolute ethanol. To the mixture was added a solution of 30.01 g of 1-bromo-5-(2-methoxyethoxy)methoxypentane (prepared as described in Preparation 40) dissolved in 10 ml of absolute ethanol. The mixture was heated under reflux for 21 hours, after which it was allowed to cool, and then the solvent was distilled off. The residue was mixed with water, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel, and 32.78 g of the title compound was obtained from the fractions eluted with a 4:1 by volume mixture of hexane and ethyl acetate, as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1)=[O:4].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.CC(C)=O>[Br-:1].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][N+:27]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=2)=[O:4])=[CH:28][CH:29]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc(C(=O)CBr)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Solvent: CC#N
Solvent: CC(C)=O
Product: COc1cc(C(=O)C[n+]2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Product: [Br-]
Temperature: 25 °C
Yield: 92.7 %

Procedure:
2.90 g (10.6 mmol) of 2-bromo-1-(3-methoxy-4-nitrophenyl)-1-ethanone [described in Bull. Soc. Chim. Fr., (1962), pp 2255-2261] are added in portions to 2.07 g (10.6 mmol) of 4-[N-(tert-butoxycarbonyl)amino]pyridine [described in Tetrahedron; (2001), vol 57(43), pp 9033-9044] in suspension in 10 mL of acetonitrile and 20 mL of acetone. The reaction medium becomes homogeneous by stirring at room temperature and then precipitation occurs. The medium is stirred for 1 hour at room temperature. The precipitate formed is filtered, washed with acetone and dried. 4.6 g of a white powder are obtained.
Reaction SMILES: [CH3:1]S(O)(=O)=O.C(OC([N:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1)=O)(C)(C)C>CO>[NH:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([O:18][CH3:1])=[O:17])[CH2:14]1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Solvent: CO
Product: COC(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)nipecotic acid (1145 mg, 5 mmol) and methanol (5 mL). When the mixture was stirred at 25° C. for 16 hours, (S)-methyl nipecotate was produced, and the object (S)-nipecotic acid was not produced.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:47]([O:55][CH3:56])(=[O:54])[CH2:48][CH2:49][CH2:50][C:51]([O-])=[O:52].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][C:47]([O:55][CH3:56])=[O:54])[S:3][C:4]=1[C:8]1[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Reactant: COC(=O)CCCC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCN3CCOCC3)s2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.3 %

Procedure:
To a degassed solution of 5-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-(2-morpholin-4-ylethyl)thiophene-2-sulfonamide (6) (100 mg; 0.22 mmol; 1 eq) in anhydrous THF (10 ml). N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (104.4 mg; 0.33 mmol; 1.50 eq), mono-methyl glutarate (68 μl; 0.54 mmol; 2.50 eq) and N,N-diisopropylethylamine (148 μl; 0.87 mmol; 4 eq) are added successively. The reaction mixture is stirred at room temperature for three days. Solvents are evaporated under vacuum. The resulting crude product is dissolved in EtOAc and washed with NH4Cl sat. solution, water, brine and dried over MgSO4. After evaporation of the solvents, the crude product is purified by flash chromatography (CH3Cl/MeOH gradient from 1/0 to 1/1 over 40 min), affording Compound (7) as a yellow solid (68.5 mg; 61.18%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2.[OH:27]O>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)=[O:27]
Reactant: O=C1CCc2cc(OCCCCSc3nc4ccccc4[nH]3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3nc4ccccc4[nH]3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-benzimidazolyl-mercapto)-butoxy]-3,4-dihydrocarbostyril and hydrogen peroxide.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 45 g (0.2 mol) of 4-(benzothiazol-2-yl) toluene in 1000 ml of dry carbon tetrachloride were added 35.6 g (0.2 mol) of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 12 hours, and then allowed to cool down to room temperature. The precipitated succinimide was filtered off and the filtrate evaporated to dryness in vacuo, whereupon 55 g of crude crystals were obtained. Recrystallization from 1500 ml of cyclohexane gave 41 g of purified 4-(benzothiazol-2-yl) bromomethylbenzene as colorless flakes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(CC)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[B:16]([OH:19])[OH:17]
Reactant: Cn1ccc2ccccc21
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(B(O)O)cc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1-Methylindole (0.38 mL, 3 mmol) was dissolved in THF (10 mL), and the solution was cooled to -78° C. To this solution was added sec-butyllithium (1.9 mL, 2.5 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.34 mnL, 3 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue was taken directly to the next step.
Reaction SMILES: [C:1]1([CH2:11][C:12](Cl)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:16][N:17](C)[OH:18].[CH3:20]CN(CC)CC.N#N>C(Cl)Cl>[CH3:20][O:18][N:17]([CH3:16])[C:12](=[O:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CN(C)O
Reactant: O=C(Cl)Cc1cccc2ccccc12
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 235.3 %

Procedure:
To a solution of the 1-naphthylacetylchloride (21.90 g, 107.0 mmol) in CH2Cl2 (100 mL) was added dimethylhydroxyl amine hydrochloride (13.57 g, 139.1 mmol) and the solution cooled to 0° C. Et3N (43.20 mL, 31.32 mmol) was added to the solution dropwise under an atmosphere of N2. The mixture was then allowed to warm to room temperature where it was stirred for 12 hours and then filtered to remove a white solid. The filtrate was concentrated under vacuum and the residue was diluted with EtOAc (100 mL) and then was washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and then stripped of solvent under vacuum. The crude product was subjected to silica gel chromatography (EtOAc/Hexanes, 1:9) to give N-methoxy-N-methyl-2-naphthalen-1-yl-acetamide 16.90 g (69%) as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.06 (dd, 1 H), 7.87 (dd, 2H), 7.77 (dd, 1 H), 7.56-7.39 (m, 4 H), 4.22 (s, 2H), 3.60 (s, 3H), 3.22 (s, 2H).
Reaction SMILES: [Na].[CH2:2]([N:9]=[N+:10]=[N-:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:12].[Na+].[OH2:14]>C(O)C>[CH2:2]([N:9]1[C:3]([CH2:8][CH3:7])=[C:4]([C:5]([OH:14])=[O:12])[N:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCc1c(C(=O)O)nnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4.3 grams (g) (187 mmoles) of sodium pellets in 80 milliliters (ml) of absolute ethanol under nitrogen was added 18.0 g (125 mmoles) of ethyl propionyl acetate followed by 16.6 g (125 mmoles) of benzyl azide. The resulting reaction mixture was stirred under reflux for two days. Upon cooling to room temperature, 45 ml of 4N aqueous sodium hydroxide was added dropwise and the mixture was refluxed for 3 hours. The reaction was again cooled to room temperature and concentration in vacu gave a gummy solid. This residue was dissolved in 125 ml of water and extracted with ether. Acidification (pH 1) with 12 molar hydrochloric acid caused precipitation of 25.1 g (87%) of 1(2 or 3)-benzyl-5-ethyl-1H-1,2,3-triazole-4-carboxylic acid as a tan solid. The structure was confirmed by nuclear magnetic resonance (n.m.r.) and infrared spectroscopy (I.R.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)c(Cl)c1
Yield: 30.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (0.6 g) was obtained, melting point: 242° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25]OC(=O)C)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(OC(=O)[NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])(C)(C)C.CCN(C(C)C)C(C)C>C(#N)C>[NH2:39][C:40]([CH3:43])([CH3:44])[CH2:41][O:42][CH2:25][C:22]1[CH:23]=[CH:24][N:20]2[C:21]=1[C:16]([NH:15][C:11]1[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:30]=[CH:31][CH:32]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]3)=[N:17][CH:18]=[N:19]2
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(N)COCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Temperature: 0 °C
Yield: 11.8 %

Procedure:
A mixture of acetic acid 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethylester (100 mg, 0.24 mmol), (2-hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester 156 mg, 3 equiv) and DIPEA (62 μL, 1.5 equiv) in dry acetonitrile (0.2 mL) in a vial was placed in a microwave reactor (Personal Chemistry's Smith Creator) and irradiated for 10 min at 109° C. The solvent was removed and the residue was taken up in dry DCM (3 mL) and cooled to 0° C. TFA (3 mL) was added and after 1.5 hr, the solvents were removed. The residue was partitioned between DCM and saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and the solvent was removed. Purification by radial chromatography (1 mm silica gel plate, gradient elution with 0 to 5% MeOH in DCM) gave the title compound (13 mg, 12% yield): MS: 460 (M+H)+; HPLC Ret Time: 1.34 min, YMC Xterra ODS S7 3.0×50 mm, 2 min gradient, 5 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]3)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:31])([F:30])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[S:16]=[C:10]1[CH2:11][O:12][CH2:13][CH:14]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:27]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18]([F:31])([F:30])[F:17])=[CH:26][N:25]=4)=[O:28])[CH:7]=[CH:6][CH:5]=3)([CH2:15]2)[NH:9]1
Reactant: Nc1cccc(C23CC2COCC(=S)N3)c1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: O=C(Nc1cccc(C23CC2COCC(=S)N3)c1)c1ccc(OCC(F)(F)F)cn1

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (1SR,7RS)-1-(3-amino-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13B) (166 mg, 0.712 mmol) and 5-(2,2,2-trifluoro-ethoxy) -pyridine-2-carboxylic acid [CAS No. 881409-53-6; described in example 49] (150 mg, 0.68 mmol). The title compound was obtained as a light yellow gum (266 mg, 90%). MS (ISP): m/z=438.1 [(M+H)+].
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:13])=[O:12])[C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1.C(=O)(O)[O-].[Na+].CC(O[CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>P([O-])([O-])([O-])=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][S:1][C:2]3[CH:3]=[C:4]([C:11]([NH2:13])=[O:12])[C:5]4[N:6]([N:8]=[N:9][N:10]=4)[N:7]=3)[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)c1cc(S)nn2nnnc12
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC(=O)c1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)nn2nnnc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a hot solution (50°-55° C.) of 6-mercapto-8-aminocarbonyl-tetrazolo[1,5-b]pyridazine (2 g; 0.010 mole) and 2.8 g of sodium bicarbonate in 90 ml of buffer phosphate (pH 6.4), 7-ACA (4.6 g; 0.017 mole) was added portionwise and the mixture was heated at 60° C. for 4 hours. After cooling at 10° C. the precipitated 7-amino-3-[(8-aminocarbonyl-6-tetrazolo[1,5-b]pyridazinyl-thiomethyl]-3-cephem-4-carboxylic acid was collected by filtration. The solid was suspended in 150 ml of Me2CO:H2O (1:2), stirred for 30 minutes and filtered again. The collected precipitate was washed with Me2CO and dried under vacuum at 60° C. to give the title compound (80%), m.p. 228°-230° C. (dec.).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([O:11][C:12]([NH:14][OH:15])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[CH3:3][CH:2]([CH3:4])[C:1]([O:15][NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[O:5]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2-methylpropanoate is prepared from isobutyryl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 using the method described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (6.36 g, 83%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.51 (1H, br. s.), 2.65 (1H, sept, 7.0 Hz), 1.40 (9H, s), 1.13 (6H, d, 7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[C:17]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)Nc2n[nH]cc2C1c1cccc(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichlorobenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=12.Br[CH2:23][C:24]#[N:25]>>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[C:5](=[O:8])[N:6]([CH2:23][C:24]#[N:25])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cnc(O)c32)cc1
Reactant: N#CCBr
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(CC#N)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 83, Step 1, using 4-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyri din-7-ol and bromoacetonitrile as the starting materials. LCMS calculated for C16H13BrN3O3S (M+H)+: m/z=406.0, 408.0. found: 405.9, 407.9.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH3:12][O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=C3)[CH:16]=1>ClCCl>[CH3:12][O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[C:2]3[CH:1]=[O:5])[CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccnc(-c2ccc3[nH]ccc3c2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc3[nH]cc(C=O)c3c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To anhydrous dichloromethane (35 mL) was added oxalyl chloride (0.23 mL, 2.71 mmol). N,N-dimethylformamide (0.27 mL, 3.48 mmol) was added at 0° C., and the mixture was stirred for 30 min at 0° C. To this reaction solution was added 2-(1H-indol-5-yl)isonicotinic acid methyl ester (0.44 g, 1.74 mmol) obtained in Preparation 36, which was then stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (40 mL) and 20% aqueous ammonium acetate solution (30 mL) were added, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and washed with aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give 2-(3-formyl-1H-indol-5-yl)isonicotinic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 199 %

Procedure:
To the product from step 1 (1.64 g, 4.1 mmol) was added 4M HCl in dioxane (45 mL) and the resulting mixture was stirred at rt for 5 h. The solvent was removed in vacuo to obtain the title product (1.38 g, 99%) 1H NMR (400 MHz, DMSO-d6) δ 1.67-2.15 (m, 5H), 3.17-3.21 (m, 2H), 3.88 (s, 2H), 4.07-4.12 (dd, 1H J1=8.4 Hz, J2=10.8 Hz), 4.18-4.22 (dd, 1H J1=3.6 Hz, J2=10.8 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8 Hz); 7.33 (d, 2H, J=8.8 Hz)
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH:39]1[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41]([OH:43])=[O:42]>C1COCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([N:39]2[CH2:46][CH2:45][CH2:44][C@H:40]2[C:41]([OH:43])=[O:42])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 66.2 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the solution of 1.0 g of L-proline and 1.0 g of triethylamine dissolved in aqueous THF is added, and treated in the same manner as Example 1 to give 1.5 g (68%) of the titled compound.