Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].CCOCC>C(O)C.[Pd]>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 2-hydroxy-2-phenylethanamine (17.7 g) and 1-(4-carbomethoxyphenyl) propan-2-one (24.8 g) in ethanol (300 ml) was refluxed for one hour. When cooled, 10% Pd/C (1.0 g) was added and the mixture was hydrogenated on a Parr Hydrogenator at 60° and 60 psi for six hours. The mixture was filtered and the filtrate was evaporated to an oil which was taken up in methanol (75 ml). The solution was allowed to stand at 4° to give crystals (Batch 1). Ether (75 ml) was added to the mother liquors to obtain subsequent crops (Batches 2 & 3). The mother liquors were evaporated to an oil, which was crystallised from ether (Batch 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21].Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]1[CH2:22][O:23][C:31](=[O:33])[O:21][CH2:20]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC(CO)CO)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2COC(=O)OC2)cc1OC
Temperature: 25 °C
Yield: 180.7 %

Procedure:
To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide (134 mg) in a mixture of dichloromethane (1 mL) and pyridine (1 mL) was added triphosgene (49.1 mg) at −78° C. Then, the resulting mixture was stirred for an hour at ambient temperature. The mixture was diluted with ethyl acetate and washed successively with diluted ammonium chloride, water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (7:3) to give N-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5-ylamino)benzamide (129 mg) as a solid substance.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:9].[Al+3].[Cl-:11].[Cl-:12].Cl[CH:14]([CH:20](Cl)[CH3:21])[CH2:15][Si:16]([Cl:19])([Cl:18])[Cl:17]>>[Cl:9][C:2]1[CH:7]=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[C:20]([C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[CH:6][C:7]=1[Cl:8])([CH3:21])[CH2:14][CH2:15][Si:16]([Cl:19])([Cl:18])[Cl:17]
Reactant: Clc1ccccc1Cl
Reactant: [Cl-]
Reactant: CC(Cl)C(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al+3]
Product: CC(CC[Si](Cl)(Cl)Cl)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 114.2 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 26.3 ml (230 mmol) of 2,3-dichlorobenzene and 1.23 g (9.2 mmol) of aluminum chloride were alkylated with 11.91 g (45.7 mmol) of (2,3-dichlorobutyl)trichlorosilane for 20 min at 90° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 30 min to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 5.06 g of [3,3-bis(2,4-dichlorophenyl)butyl]trichlorosilane (bp; 186-190° C./0.5 torr, yield; 23%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:8]([O:15][C:16]([NH:18][C:19](=[NH:22])OC)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:18][C:19]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]1)=[NH:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC1CCNC1
Reactant: COC(=N)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CO)C1
Temperature: 60 °C
Yield: 25.2 %

Procedure:
1.01 g (0.01 mole) (3RS)-3-hydroxymethyl pyrrolidine and 2.29 g (0.011 mole) N-benzyloxycarbonyl-O-methylisourea was dissolved (the amine not very soluble) in toluene and heated to 60° C. for three hours followed by stirring at room temperature over night. The mixture was evaporated and the 1H-NMR showed that the reaction was not completed. The mixture was therefore dissolved in 15 ml acetonitrile and heated to 60° C. for three hours followed by stirring at room temperature over night. The solvent was evaporated and the mixture was dissolved in CH2Cl2, washed once with water, dried (Na2 SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2 /MeOH 95/5 as eluent to yield 0.70 g (25%) of the product.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH3:30]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOc1ccc(CCCCC=CC(=O)O)cc1
Yield: 64 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (3.18 g, 64%) as white crystals (mp 62-63° C.), IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.40 (t, 3 H), 1.50 (m, 2 H), 1.70 (m, 2 H), 2.38 (m, 4 H), 4.00 (q, 2 H), 5.72+6.05 (m, 1 H), 6.32 (t, 1 H), 7.05 (q, 4 H), 10.10 (bs, 1 H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:9])[CH3:8]>CO.CCOC(C)=O.O>[C:25]([C:23]1[CH:22]=[N:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH:7]([CH3:9])[CH3:8])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[N:24]=1)#[CH:26]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cncc(C#C[Si](C)(C)C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cncc(-c2ccc(S(=O)(=O)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
Sodium carbonate (3 mL of 2 M, 6.000 mmol) was added to a stirred suspension of 2-[6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl-trimethyl-silane (191 mg, 0.5327 mmol) in methanol (6 mL) and the reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a beige solid (149 mg, 98% Yield). 1H NMR (400.0 MHz, DMSO) d H NMR (400.0 MHz, DMSO) d 9.38 (s, 1H); 8.86 (s, 1H), 8.40 (d, 2H), 8.01 (d, 2H), 4.78 (s, 1H), 3.50 (sept, 1H) and 1.18 (d, 6H) ppm; MS (ES+) 297.1
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:15]1[CH2:14][C:13]2[C:8]([Cl:7])=[CH:9][CH:10]=[CH:11][C:12]=2[S:18][CH2:17][CH2:16]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulphonyl chloride (1.28 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-ethylsulphonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 2.53 g (m.p. 126°-128° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[C:51]([CH3:55])=[CH:52][CH:53]=[CH:54][C:49]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NCCc1c(C)cccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc(C)c2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.44 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.25 g of N-[2-(2-hydroxy-6-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (EtOAc); Rt=5.77.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:23]([C:22]2[C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:9]=[CH:10][CH:11]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)Oc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a tetrahydrofuran solution containing 1.5 g (0.01 mole) of m-isopropoxyaniline and 1.2 g (0.011 mole) of triethylamine, while being cooled in ice water, was added slowly 2.3 g (0.011 mole) of o-trifluoromethylbenzoyl chloride. After having been stirred for 2 hours at room temperature, the reaction mixture was freed from triethylamine hydrochloride by filtration and then from the solvent by distillation under reduced pressure. The residue was recrystallized from n-hexane to obtain 2.9 g (91% yield) of the intended product melting at 95° to 97° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:13][C:12]1=[S:17]
Reactant: O=CCc1ccccc1
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Solvent: C1CCNCC1
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=C1C(=CCc2ccccc2)SC(=S)N1N=c1sc2ccccc2s1

Procedure:
A slurry of 2.98g of 3-[(1,3-benzodithiol-2-ylidene)amino] -2-thioxo-4-thiazolidinone (see example 37), phenylacetaldehyde (10 ml, excess) and acetic acid/piperidine (10 drops) in 600 ml of anhydrous glyme is heated at reflux for 4 days. The reaction mixture is filtered while hot, and the solid is collected and recrystallized from dimethylformamide to yield 1.78 g of the title compound, melting point 233°-234° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:27])[CH2:16][CH:17]([NH:20][C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH:18]=[O:19])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15](=[O:27])[CH2:16][CH:17]([NH:20][C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH:18]([OH:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C=CCOC(=O)NC(C=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(O)Cc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of benzylmagnesium chloride (20 mL, 20 mmol) in THF at −78° C. is added dropwise a 0° C. solution of 3-allyloxycarbonylamino-4-oxo-butyric acid tert-butyl ester, 102, (5.14 g, 20 mmol) in THF (100 mL). Once the addition is complete, the solution is allowed to warm to 0° C. over 30 minutes then the reaction mixture is poured into a beaker of crushed ice. The solution is extracted ×3 with CH2Cl2 (100 mL), the organic layers combined, dried over Na2SO4 and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([O:39]CC4C=CC=CC=4)[C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[CH:35][C:34]=3[CH2:54][CH3:55])=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:34]([CH2:54][CH3:55])=[CH:35][C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[C:37]([OH:39])[CH:38]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Yield: 81.8 %

Procedure:
2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate (110 mg) was dissolved in methanol/chloroform (2:1, 5 mL) with 10% Pd/C (24 mg) and hydrogen gas bubbled in for 2 hours. The mixture was filtered through Celite®, rinsed with methanol, and concentrated under vacuum to afford 80 mg of 2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(6-ethyl-4-(4-fluorophenyl)-3-hydroxyphenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate. Mass Spec (EI): 723.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#N)=[CH:4][CH:3]=1.[OH-:14].[K+].[OH2:16]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:16])=[O:14])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: [K+]
Product: Nc1ccc(C(=O)O)c2ccccc12

Procedure:
4-Amino-1-naphthalenecarbonitrile (1.5 g, 8.91 mmol) was suspended in a 50% KOH solution (18 mL). The heterogeneous solution was heated at reflux for 2-3 days. Once the solution became homogeneous and TLC showed no more starting material, the deep red solution was cooled and poured over 200 mL of water. The resulting solution was then filtered and the desired product was precipitated with concentrated HCl. The resulting red crystals were filtered and the filtrate was refiltered to give pink crystals. The first fraction of crystals was treated with activated carbon to remove some of the red color. A total of 1.51 g of the desired product was obtained: m.p. 169-171° C.; 1H NMR (CD3OD) δ 6.69 (1H, d, J=8.2 Hz), 7.38-7.43 (1H, m), 7.48-7.54 (1H, m), 8.03 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=8.2 Hz), 9.09 (1H, d, J=8.5 Hz); 13C NMR (CD3OD) δ 107.39, 114.61, 122.99, 123.92, 125.21, 127.40, 128.48, 135.04, 151.35, 171.44; HRMS Calc. for C11H7NO2, 187.0633; Found, 187.0642.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:20][CH:19]([OH:21])[C:16]([CH2:22][CH2:23][CH3:24])([CH2:17][O:18]2)[CH2:15][O:14]3)=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([O:21][CH:19]1[C:16]2([CH2:22][CH2:23][CH3:24])[CH2:15][O:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)([O:18][CH2:17]2)[CH2:20]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC12COC(c3ccc(Cl)cc3)(CC1O)OC2
Solvent: O
Solvent: c1ccncc1
Product: CCCC12COC(c3ccc(Cl)cc3)(CC1OS(C)(=O)=O)OC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanesulphonyl chloride (164 μl) was added to a stirred solution of 1-(4-chlorophenyl)-8-hydroxy-4-n-propyl-2,6-dioxabicyclo[2,2,2]octane (500 mg.) in dry pyridine (2.0 ml.). The mixture was stirred at room temperature for 6 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with 1N hydrochloric acid solution. The ethereal extracts were then washed with saturated aqueous sodium hydrogen carbonate solution. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[C:15]1([CH3:34])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[B:23]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])F>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([B:23]([C:25]2[C:26]([CH3:33])=[CH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])[C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[CH3:34])[CH:8]=[C:9]([Br:14])[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C)c(B(c2cc(Br)cc(Br)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
6.25 ml (0.01 mol) of 1.6 M butyllithium in hexane are added over 5 minutes at -78° C. to a suspension of 3.14 g (0.01 mol) of 1,3,5-tribromobenzene in 50 ml of diethyl ether. The reaction mixture is stirred at -78° C. for 2 hours, during which a yellow-orange suspension is produced. 2.68 g (0.01 mol) of solid dimesitylfluoroborane are added, and the reaction mixture is warmed to room temperature over about one hour. The mixture is then diluted with 50 ml of hexane and cooled to 0° C. The solid produced is filtered, washed several times with cold hexane and then washed with water and, finally, with methanol, until the solid is colourless. Drying gives 3.54 g (0.0073 mol; i.e. 73% of theory) of a white solid (1,3-dibromo-5-dimesitylborylbenzene). Following purification by chromatography (hexane; SiO2) a melting point of 190-191° C. is obtained. Elemental analysis for C24H25BBr2 gives: C calc.: 59.55%; found: 59.52% H calc.: 5.21%; found: 5,12%
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.BrC1C=CC(N)=CC=1Cl.ClC1C=CC(B(O)O)=CC=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The title compound was prepared as described in Example 15 substituting 4-bromoaniline and (2-chloro-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-chlorophenyl)boronic acid, respectively.
Reaction SMILES: [NH2:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9]OC(=O)CCC(O)=O)[CH2:7][S:8][C@H:3]12.[SH:23][C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][S:23][C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)CCC(=O)O)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A 4.0 ml portion of acetonitrile was added to 0.826 g of 7-amino-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid and 0.32 g of 5-mercapto-1-methyl-1H-tetrazole, and 3.71 g of DCPA was added through a dropping funnel to the mixture under cooling at -5° to 0° C., followed by rinsing the funnel with 0.5 ml of acetonitrile. The mixture was stirred at the same temperature and turned into a solution. Then, the reaction solution was stirred for 45 minutes at 14° to 15° C. to allow the reaction to proceed. The reaction solution was cooled with ice, and poured into ice-water, which was placed in a refrigerator overnight and adjusted to pH 4.0 with 25% aqueous ammonia. The precipitated powder was recovered by filtration, washed with water and acetone successively, and dried, thereby affording 0.722 g (88.0% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR values of the product were in accordance with those of the authentic sample.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:10][OH:11]
Reactant: O=Cc1sccc1Br
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1sccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
3-Bromothiophene-2-carbaldehyde (28.7 g, 0.15 mol) in ethanol (50 mL) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 g, 0.2 mol), sodium hydroxide (8 g, 0.2 mol) in water (30 mL) and ethanol (100 mL). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight when a precipitate formed. The mixture was diluted with cold water (600 ml) and the solid was collected by filtration yielding 20.5 g, (67%). The aqueous solution was further extracted with ethyl acetate. The organic solution was washed with brine, dried with magnesium sulfate, filtered and evaporated yielding 6.9 g of additional product as a light yellow solid. The total yield was 27.4 g (89%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]1.O=[C:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCCCCCC.N1CCCCC1>[CH3:23][C:17]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:10]2[N:11]=[CH:12][CH:13]=[C:14]2[N:15]=1
Reactant: Nc1ccn[nH]1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCNCC1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc2ccnn2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 4-methylbenzaldehyde (723 mg, 6.02 mmol), 1H-pyrazol-5-amine (500 mg, 6.02 mmol), and methyl 3-oxobutanoate (769 mg, 6.62 mmol) in THF (80 mL) and heptane (20 mL) was added piperidine (10 mL, 0.101 mmol). The reaction mixture was heated at reflux for 20 h. The solvent was evaporated and the crude material was dissolved in CH2Cl2. DDQ (1229 mg, 5.42 mmol) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (1120 mg, 66.2%). 1H-NMR (500 MHz, CD Cl3) δ ppm 2.44 (3H, s), 2.65 (3H, s), 3.63 (3H, s), 6.65 (1H, d, J=2.4 Hz), 7.34 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz), 8.10 (1H, d, J=2.4 Hz).