Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (461 mg, 0.722 mmol) in THF (10 ml) and methanol (5 ml) was added 1N aqueous potassium hydroxide solution (2.16 ml, 2.16 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 360 mg (yield: 81.6%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C.[Cu].[I-]>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCCCCCCCC
Reactant: Fc1ccccc1Br
Agent: [Cu]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-bromofluorobenzene (17.5 g), 1-undecyne (18.3 g), tetrahydrofuran (50 ml), and triethylamine (70 ml) was added bistriphenylphosphine palladium(II)chloride (1.2 g) and copper(l) iodide (162 mg). The reaction mixture was stirred at 55° C. for 3 hr, and an additional 2-bromofluorobenzene (2.0 g) and bistriphenylphosphine palladium(II)chloride (200 mg) were added. The mixture was stirred at 55° C. overnight, allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled twice under vacuum to give 13.1 g (53%) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([O:31][CH3:32])[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:44]1[CH:43]=[C:4]([CH:3]=[C:2]([F:1])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([O:31][CH3:32])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)ccc1NS(C)(=O)=O
Yield: 53.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (95 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.42 mmol) in THF/methanol/water (2/2/1 ml) to yield 38 mg (52.1% yield) of the titled compound after purification by preparative TLC (Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 8.95 (s, 1H), 8.559-8.552 (d, 1H), 8.42 (s, 1H), 8.367-8.361 (d, 1H), 7.99 (s, 1H), 7.77-7.76 (d, 1H), 7.38 (s, 1H), 7.35-7.32 (m, 2H), 7.20-7.10 (m, 1H), 6.97-6.95 (d, 2H), 5.39 (s, 2H), 3.94 (s, 3H), 2.96 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 87.42% in method B.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]3[NH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[NH:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]3[NH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:15]1
Reactant: O=c1[nH]c2c(OC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2n1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: O=c1[nH]c2c(OC3CNC3)cccc2n1Cc1ccccc1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
4-(1-Benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzoimidazol-2-one (78 mg, 0.17 mmol) was dissolved in 0.33 mL dichloroethane and cooled to 0° C. under nitrogen. α-Chloroethyl chloroformate (0.018 mL, 0.164 mmol) was added dropwise, and the solution was refluxed for 2 hours, concentrated in vacuo, and dissolved in 20 mL methanol. The solution was refluxed for one hour, concentrated in vacuo and dissolved in 75 mL dichloromethane, and the resulting solution was washed with 75 mL 2M aqueous potassium carbonate and 75 mL water. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash (3% methanol in dichloromethane) chromatography to give 42 mg (0.14 mmol, 82%) of 4-(azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzoimidazol-2-one as a clear oil. MS: 296 (M+H)+. The corresponding hydrochloride salt, prepared by recrystallization from EtOH/HCl, gave a melting point of 181.0-184.0° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:27]([NH:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>>[CH:27]([N:30]([CH:31]([CH3:33])[CH3:32])[C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:5]3[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:14]2)=[O:17])=[N:19][CH:20]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: CC(C)NC(C)C
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cn2)CC1
Yield: 72 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using diisopropylamine. And then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>C(O)(C)C.[OH-].[Na+]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]#[C:15][CH2:14][O:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(C#CCBr)cc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a solution of 4-hydroxybenzenesulfonic acid sodium salt (2.81 g, 12.11 mmol) in 50 mL of isopropyl alcohol, 11.8 mL 2N NaOH and 5.56 g (24.2 mmol, 2 eq) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene was added. The solution was heated to 70° C. overnight. The reaction was cooled, concentrated in vacuo, filtered and air dried to afford 2.8 g (67%) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonic acid, sodium salt. Electrospray Mass Spec 321.3 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH:7][CH2:8][CH3:9])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].C(Cl)Cl.[N:18]#[C:19]Cl>O>[CH2:1]([O:3][C:4]([NH:6][N:7]([CH2:8][CH3:9])[C:19]#[N:18])=[O:5])[CH3:2]
Reactant: CCNNC(=O)OCC
Reactant: N#CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NN(C#N)CC
Reaction time: 1 h
Yield: 87.9 %

Procedure:
66.0 g of 2-ethylhydrazinecarboxylic acid ethyl ester and 42.0 g of sodium bicarbonate are stirred into 200 ml of methylene chloride and 400 ml of water. There is then introduced at room temperature in the course of 20 minutes, with continuous stirring, 30.8 g of gaseous cyanogen chloride. After one hour's subsequent stirring, the methylene chloride phase is separated and dried over sodium sulphate, and the solvent is distilled off in vacuo. There is obtained as residue 69.0 g (88% of theory) of 2-ethyl-2-cyano-hydrazinecarboxylic acid ethyl ester as colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]1([C@H:37]([NH:39][C:40]([NH2:42])=[O:41])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[NH2:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:42][C:40]([NH:39][C@@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])=[O:41])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-Chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (5C; 4.0 g, 9.73 mmol), (R)-1-(1-phenylethyl)urea (2.4 g, 14.60 mmol), cesium carbonate (7.9 g, 24.34 mmol) and BrettPhos pre-catalyst (467 mg, 0.584 mmol) were charged in a 350 mL pressure vessel with 1.4-dioxane (88 mL). The system was degassed and stirred at 100° C. for 8 h. The reaction mixture was filtered through Celite, evaporated in vacuo, dissolved in DCM, and purified by flash chromatography (0-20% EtOAc/DCM) to afford (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C34H30N6O2 [M+1]+ 539. found 539.
Reaction SMILES: C(O[CH:5]1[CH:9]([CH:10]([OH:13])[CH2:11][OH:12])[CH2:8][CH2:7][O:6]1)(C)C.CS(O)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[O:12]1[CH:5]2[O:6][CH2:7][CH2:8][CH:9]2[CH:10]([OH:13])[CH2:11]1
Reactant: CC(C)OC1OCCC1C(O)CO
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC1COC2OCCC12
Temperature: 0 °C

Procedure:
In a 50 mL round bottom flask, 1-(2-iso-propoxytetrahydro-3-furanyl)-1,2-ethanediol (2.21 g; 8.89 mmoles, 1 eq.) was dissolved in tetrahydrofuran (9 mL). After cooling at 0° C., methanesulfonic Acid (65 mg; 676.33 mmoles) was added to the mixture. The reaction mixture was thereafter heated at 45° C. for 30 min. After cooling at room temperature, triethylamine (0.3 g; 2.96 mmoles) was added to the mixture. The solvent was evaporated and ethyl acetate (9 mL; 91.98 mmoles) was added to the mixture at room temperature. Then the mixture was filtered over dicalite and the solvent was evaporated under reduced pressure to afford endo/exo bis-THF (1.562 g; GC: 71 area %) in a diastereomeric ratio of 15/85 endo/exo diastereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[C:24]([F:32])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[C:8]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[O:30])=[C:24]([F:32])[CH:23]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Ethyl-3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.691 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (161 mg, 0.691 mmol), HATU (315 mg, 0.830 mmol) and TEA (0.482 mL, 3.46 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h, and then the solution was distributed between DCM and H2O. The combined organic extract was dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM, Rf=0.5) to yield a light yellow oil of ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (320 mg, 0.571 mmol, 83.0% yield): 1H NMR (400 MHz, MeOH-d4) δ 7.94 (d, J=1.54 Hz, 1H), 7.68 (d, J=8.38 Hz, 1H), 7.27-7.36 (m, 2H), 7.22 (d, J=8.38 Hz, 1H), 6.90-6.97 (m, 1H), 4.09-4.18 (m, 2H), 3.74 (s, 2H), 3.07 (s, 2H), 1.20-1.25 (m, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M+H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[CH:55]=[CH:54][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:52][CH3:53])=[C:46]([C:49](O)=[O:50])[CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[C:36]([F:56])[CH:35]=1>CN(C=O)C.O.C(N(CC)CC)C>[Cl:33][C:34]1[CH:55]=[CH:54][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:52][CH3:53])=[C:46]([C:49]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[O:50])[CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[C:36]([F:56])[CH:35]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1cc2nccc(Oc3ccc(Cl)cc3F)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(Cl)cc3F)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Hydroxybenzotriazole (0.104 g), triethylamine (0.095 ml), N-(3-aminopropyl)morpholine (0.11 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 g) were added in turn to a stirred mixture of 4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (0.2 g) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water (20 ml) was added and the resultant suspension was transferred onto a C18 reversed-phase silica gel chromatography column and eluted with a decreasingly polar solvent gradient of water and acetonitrile. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 1.72 (m, 2H), 2.38 (m, 6H), 3.35 (m, 2H), 3.56 (m, 4H), 4.01 (s, 3H), 6.56 (d, 1H), 7.42-7.59 (m, 3H), 7.76 (m, 1H), 8.38 (m, 1H), 8.51 (s, 1H), 8.68 (d, 1H); Mass Spectrum: M+H+ 474 & 476.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:42]3[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 3,5-dichlorobenzene-1-sulfonyl chloride (25 mg, 0.10 mmol) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (9.9 mg, 12%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 7.96 (t, 1H, J=5.1 Hz), 7.84 (d, 1H, J=2.1 Hz), 7.76 (d, 2H, J=2.5 Hz), 7.57 (d, 1H, J=2.1 Hz), 7.18-6.97 (m, 12H), 4.40 (s, 2H), 4.37 (s, 2H), 4.35 (s, 2H), 4.34 (s, 2H); MS (ESI) 786.8 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:11][P:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[O:13]1.CCl>C1(C)C=CC=CC=1>[C:1]([P:12]1(=[O:11])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[O:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: CCl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 130 °C

Procedure:
56 g (0.399 mol) of benzoyl chloride were warmed to 80° to 85° C. under a nitrogen atmosphere. 92 g (0.4 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise over the course of 90 minutes while stirring. The temperature was then increased in steps to 130° C. It was kept at this temperature until evolution of methyl chloride could no longer be detected. The residue was digested with 70 ml of toluene at room temperature. 116 g (90% of theory) of the abovementioned compound, which, after rapid recrystallization from ethanol, had a melting point of 134° to 135° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C@H:13]2[C:17](=O)[NH:16][C@H:15]([CH2:19][OH:20])[CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([C@H:13]2[CH2:17][NH:16][C@H:15]([CH2:19][OH:20])[CH2:14]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1N[C@H](CO)C[C@H]1C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Temperature: 0 °C
Yield: 37.7 %

Procedure:
To a solution of lithium aluminum hydride (0.8 g) in 50 ml of tetrahydrofuran was added (2S-trans)-4-cyclohexyl-5-oxo-2-pyrrolidinemethanol (2.0 g) in 20 ml of tetrahydrofuran. After the addition, the mixture was refluxed for 24 hours, cooled to 0° C., quenched with ethyl acetate followed by saturated sodium sulphate solution, filtered, and the filtrate dried over anhydrous magnesium sulphate. Removal of the solvent followed by crystallization yielded 0.7 g of (2S-trans)-4-cyclohexyl-2-pyrrolidinemethanol as white crystals, melting point 98°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:22]Br>Br.C(O)(=O)C.C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[Br:22][CH:8]([C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(F)cc1
Reactant: BrBr
Agent: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.26 g. of 1-[3-(4-fluorobenzoyl)propionyl]-L-proline (Example 17) in 100 ml. of acetic acid is added 3 drops of 30% hydrogen bromide in acetic acid. A solution of 5.6 g. of bromine in 20 ml. of acetic acid is then added dropwise and the mixture is stirred at room temperature overnight. The mixture is evaporated to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed twice with water and then with saline, dried over magnesium sulfate and evaporated to dryness in vacuo with moderate heat, giving a white glass. This glass is scraped from the flask giving 12.2 g. of white powder. This powder is dissolved in ethyl acetate-hexane-acetic acid (75:25:2), placed on a 11/2"×20" silica gel column and eluted with the same solvent system, taking 100 ml. cuts with a 300 ml. fore-cut and a 400 ml. hold back volume. Cuts 2, 5 and 6 are combined and re-columned in the same manner. Cut 2 gives the desired product as 2.0 g. of a white glass.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:34])=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[S:35]1[C:39]2[CH2:40][CH2:41][CH2:42][CH2:43][C:38]=2[N:37]=[CH:36]1>>[NH2:1][C:2]1[S:3][C:4]([Cl:34])=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:37]4[C:38]5[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=5[S:35][CH:36]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: c1nc2c(s1)CCCC2
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(N)sc1Cl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3csc4c3CCCC4)CS[C@H]12)c1nc(N)sc1Cl

Procedure:
7β-[2-(2-Amino-5-chlorothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is reacted with 4,5,6,7-tetrahydrobenzothiazole in the same manner as described in Example 1 to give the above-identified compound.
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylphosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.