Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].[CH2:8](N(CC)CC)[CH3:9].C(OC(Cl)=O)C>ClCCl>[CH2:8]([O:7][PH:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])[CH3:9]
Reactant: CCCC[PH](=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCC[PH](=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butyphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butylphosphinic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:18])[N:8]2[C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[C:4]([Cl:19])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[CH:75][C:74]=1[N+:80]([O-:82])=[O:81]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[Cl:19][C:4]1[N:3]=[C:2]([NH:1][C:73]2[CH:78]=[C:77]([F:79])[CH:76]=[CH:75][C:74]=2[N+:80]([O-:82])=[O:81])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[C@H:11]1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](O)CC3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
All glassware was dried in vacuum oven at 60° C. for 1 day prior to reaction. Finely ground cesium carbonate and finely ground 2-amino-6-chloro-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one were dried at 60° C. under high vacuum for one day prior to experiment. To an oven-dried 2-neck flask under Ar was added 2-amino-6-chloro-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (6.78 g, 23.9 mmol), cesium carbonate (11.71 g, 35.9 mmol, 1.5 equiv.) and anhydrous toluene (100 mL) and the mixture was stirred at room temperature for 15 min. Then, Pd(OAc)2 (2.41 g, 3.59 mmol, 0.15 equiv.), racemic BINAP (5.21 g, 8.36 mmol, 0.35 equiv.) and 1-bromo-5-fluoro-2-nitrobenzene (6.84 g, 31.07 mmol, 1.3 equiv.) were added as solids, under Ar, and the reaction mixture was stirred at room temperature for 15 min, then stirred at 100° C. for 2 days (LC-MS shows ratio of desired product/starting material approx. 8/1). The reaction mixture was cooled to room temperature, and the solvent removed in vacuo. The dark brown residue was dissolved in warm CH3COOH/EtOH (60 mL/60 mL), and then water (700 mL) was added. A dark yellow solid precipitated and was filtered under vacuum. A small portion of the dark yellow solid was purified by flash chromatography (silica gel, gradient elution with ethyl acetate/hexanes 1/1 to 3/1, then up to 20% methanol in 3/1 ethyl acetate/hexanes) to provide the desired compound as an orange solid. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 10.67 (br s, 1H), 8.80 (dd, 1H), 8.37 (dd, 1H), 6.85-6.80 (m, 1H), 4.39-4.30 (m, 1H), 3.81-3.73 (m, 1H), 2.67-2.44 (m, 2H), 2.18-2.14 (m, 2H), 1.92-1.88 (m, 2H), 1.56-1.41 (m, 2H); MS (EI) m/z 423.3 (MH)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=1)(=[O:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl.O>[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39]([O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][S:3]([C:2]([F:1])([F:14])[F:15])(=[O:5])=[O:4])[CH:12]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)CCCC(F)(F)F
Reactant: O=S(=O)(Oc1cc(O)ccn1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CCCC(F)(F)F)Oc1ccnc(OS(=O)(=O)C(F)(F)F)c1

Procedure:
Under argon, 550 mg (2.26 mmol) of 4-hydroxy-2-pyridinyl trifluoromethanesulfonate (Example 39A) are suspended in 15 ml of dichloromethane at room temperature. 2 ml of a 40% strength solution of tetrabutylammonium hydroxide in water are added dropwise to this. Then 476 mg (2.26 mmol) of 4,4,4-trifluoro-1-butanesulfonyl chloride are added and allowed to react for 20 minutes. Working up takes place by adding water, extracting with ethyl acetate, washing, drying and evaporating in a rotary evaporator. The residue is purified by chromatography on 20 g of silica gel (0.04-0.063 mm) with cyclohexane/ethyl acetate 2:1 to 1:1).
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCSc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1NCCSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of 5-methyl-2,3-dihydro-1,4-benzothiazepine (5.92 g, 33.40 mmol) in methanol (100 mL) was added a solution of sodium borohydride (3.16 g, 83.49 mmol) in water (60 mL). After being stirred at room temperature overnight, the reaction mixture was acidified with concentrated hydrochloric acid, and then stirred at room temperature for 30 minutes. After being adjusted to pH 9 with an aqueous solution of sodium hydroxide, the resulting mixture was extracted with ethyl acetate (60 mL×3). The combined organic layers were washed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 5.6 g of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, MS obsd. (ESI+) [(M+H)+] 180.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH:26]1[C:38]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][C:27]=1/[C:39](/[CH3:43])=[CH:40]/[CH2:41]O>C1C=CC=CC=1.O.C(OCC)(=O)C>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:41]/[CH:40]=[C:39](/[C:27]2[CH:28]=[CH:29][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:37][C:38]=3[CH:26]=2)\[CH3:43])=[CH:7][CH:6]=1
Reactant: C/C(=C\CO)c1ccc2c(c1)Cc1ccccc1-2
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.4 %

Procedure:
Under a atmosphere of nitrogen, methyl 4-hydroxyphenylacetate (183 mg, 1.1 mmol) was added to a stirred cooled solution of azodicarboxylic dipiperidide (378 mg, 1.5 mmol), tributylphosphine (304 mg, 1.5 mmol) and (E)-3-(9H-fluoren-2-yl)-but-2-en-1-ol (236 mg, 1.0 mmol) in dry benzene (30 ml), the mixture warmed to room temperature, and stirred for 17 h. The reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml each). The aqueous layer was collected and further extracted with ethyl acetate (2×50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (eluent: 15% ethyl acetate in toluene) to give 240 mg (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:33](=[O:34])[CH2:32][N:16]3[CH2:17][CH2:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]3=[O:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1ccc(N2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(5-chloropyridin-2-yl)piperazine (0.037 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.12 (dd, J=2.6, 0.7 Hz, 1H), 7.45 (dd, J=9.0, 2.7 Hz, 1H), 7.18-7.38 (m, 10H), 6.54 (dd, J=9.1, 0.7 Hz, 1H), 4.24 (s, 2H), 3.67-3.72 (m, 2H), 3.54 (t, J=6.6 Hz, 2H), 3.51-3.56 (m, 2H), 3.44-3.50 (m, 2H), 3.36-3.42 (m, 2H), 2.82 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 475 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([N+:30]([O-:32])=[O:31])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])#[N:29]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c([N+](=O)[O-])c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.85 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.50 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, the aforementioned 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (4.60 g, 82%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([C:21]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37](O)=[O:38])=[O:31])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C@H:33]3[CH2:34][CH2:35][CH2:36][N:32]3[C:30]([C@@H:26]3[CH2:27][CH2:28][CH2:29][N:25]3[C:23](=[O:24])[CH2:22][C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[O:31])=[O:38])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1CCN(CC2CCCCC2)CC1
Reactant: O=C(O)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(NC1CCN(CC2CCCCC2)CC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by a method similar to Step 5 of Example 1, using 1-cyclohexylmethyl-4-piperidinamine (JP 52122378) and (2R)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxylic acid. The compound was obtained as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[CH:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCCl>[CH:15]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:8]3[CH2:9][C:10]4[N:4]([CH:3]=[CH:2][CH:1]=4)[CH2:5][C:6]4[N:14]=[CH:13][CH:12]=[CH:11][C:7]3=4)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ncccc21
Yield: 39.4 %

Procedure:
A mixture of the 9,10-dihydro-4H-3a, 5,9-triaza-benzo[f]azulene of Step D (4.67 mmol), 4-cyclohexylbenzoyl chloride (4.90 mmol) and triethylamine (5.1 mmol) in 1,2-dichloroethane was refluxed for three days under nitrogen. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 20% of ethyl acetate in hexane to provide the title compound as a tan solid (0.684 g), m.p. 150–152° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:17][CH:18]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N3c4ccccc4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
The obtained 9,10-dihydroacridine (11.8 g, 65.2 mmol) and 4-bromobiphenyl (18.2 g, 78.2 mmol) were dissolved in toluene (500 mL). Then, Pd2(dba)3 (1.4 g, 1.3 mmol) was added thereto under a nitrogen atmosphere. Then, NaOBut (9.4 g, 97.8 mmol) was added thereto, and (t-Bu)3P (1.6 ml, 2.6 mmol) was introduced to the resultant solution. The resultant mixture was reflux-stirred for 5 hours. The completion of the reaction was identified by a TLC. After the reaction was completed, the mixture was cooled to room temperature. The resultant solution was poured onto a thin silica pad so as to perform a short chromatography, and then was washed with MC. The filtrate was evaporated under a reduced pressure to remove the solvent. The residue was then purified by silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain 10-(biphenyl-4-yl)-9,10-dihydroacridine compound (pale yellow solid, 15.3 g, yield 70%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(N=NC(C#N)(C)C)(C#N)C.[CH2:21]([SnH:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
A solution of 10.0 g (0.0908 mol) of 1-octyne, 60 ml of anhydrous toluene, 230 mg of azobisisobutylonitrile (AIBN), and 25 ml (0.0943 mol) of tri-n-butyltin hydride is refluxed under an argon atmosphere for 3 hours. The reaction mixture is cooled to ambient temperature and concentrated in vacuo. The resulting yellow liquid is distilled (bulb to bulb) to give 36.29 (99%) of the stannyl octene as a pale yellow liquid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(O)C.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 20.3 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.52 g.), 10% palladium carbon (1.3 g.) ethanol (13 ml.), tetrahydrofuran (25 ml.), acetic acid (0.22 ml.) and water (2.2 ml.) were treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.4 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][CH:23]1[O:27][C:26](=O)[C:25]2[S:29][CH:30]=[CH:31][C:24]1=2.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:26]1[C:25]2[S:29][CH:30]=[CH:31][C:24]=2[CH:23]([CH3:22])[O:27]1
Reactant: CC1OC(=O)c2sccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1OC(=C2C(=O)Nc3ccc(F)cc32)c2sccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one in THF is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 4-methyl-4H-thieno[2,3-c]furan-6-one (0.15 mmol), in THF is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution. The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (35% EtOAc-Hexanes) to give the title compound as a yellow solid (38 mg, 87%).
Reaction SMILES: [CH3:1]I.[NH:3]1[C:10](=[O:11])[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[S:5]>CCO.[OH-].[Na+].O>[CH3:1][S:5][C:4]1[N:6]=[C:7]([OH:8])[CH:9]=[C:10]([OH:11])[N:3]=1
Reactant: CI
Reactant: O=C1CC(=O)NC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (32.64 g, 220 mmol) was added dropwise to a suspension of thiobarbituric acid (29 g, 200 mmol) in EtOH (300 ml) and 2M NaOH solution in water (110 ml) at room temperature. The mixture was stirred at room temperature overnight and then stirred for two hours at 60° C. The ethanol was removed, water was added and the mixture was allowed to stay for 2 hours on an ice bath. The solid title compound was filtered of, washed with ice cold water and dried (30 g, 95%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>O1CCOCC1.O.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>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5]1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccccn2)c(=O)n(C)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
Methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (57 mg, 0.23 mmol), 2-(tributylstannyl)pyridine (85 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol, Strem) were stirred in 1.5 mL of dioxane at 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were washed 1× with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (4 g pre-packed column, elution 0-30% EtOAc/Hexanes) gave the title compound (22 mg, 39%) as a light yellow solid. MS m/z: 245 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: Nc1c(F)c(N2CCC(c3ccncc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.10 g, 3.7 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.75 g, 48%) as a yellow solid, mp 236°-238° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:29][C@@H:30]1[CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>C1COCC1>[CH3:29][C@@H:30]1[C@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[N:31]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC[C@@H](C)CCC(=O)O
Reactant: C[C@H]1NC(=O)OC1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL) and cooled to 0° C. Triethylamine (19.74 mL, 141.6 mmol) was added dropwise, followed by dropwise addition of trimethylacetyl chloride (6.98 mL, 56.64 mmol). The thick white suspension was stirred at 0° C. for 90 minutes. LiCl (1.86 g, 41.54 mmol), (4R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one (6.824 g, 38.51 mmol), and THF (70 mL) were added, and the reaction warmed to room temperature overnight. The solvent was evaporated. The solids were taken up in EtOAc, filtered off, and washed generously with EtOAc. The filtrate was washed with water (2×50 mL), and brine. The organics were dried over MgSO4, filtered, and rotovapped. The crude material was chromatographed on silica eluting with 10% EtOAc/hexanes to give 155 as an oil (10.974 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44–7.35 (m, 3H), 7.31–7.26 (m, 2H), 5.66 (d, J=7.33 Hz, 1H), 4.76 (quint, J=7.03 Hz, 1H), 3.04–2.96 (m, 1H), 2.93–2.86 (m, 1H), 1.74–1.66 (m, 1H), 1.52–1.47 (m, 1H), 1.46–1.36 (m, 2H), 1.27–1.16 (m, 2H), 0.92–0.87 (m, 8H); [α]D=+34.1 (c1 in CHCl3).