Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O.C1(C)C=CC=CC=1>[C:17]1([CH2:16][O:15][C:13]([NH:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer and internal thermometer, sodium hydroxide (61.65 g, 1.541 mol) was dissolved in distilled water (1000 ml). To this solution, L-methionine (100.0 g, 0.670 mol) was added at room temperature. The solution was cooled in an ice bath (internal temperature 3° C.) and benzyl chloroformate (110 ml, 0.737 mol) was added over 10 minutes. After a 15 minute induction period, the internal temperature rose from 3° C. to 12° C. over 30 minutes and then dropped to 0° C. over 15 minutes. The reaction was stirred at 0° C. for 2 hours, during which time the initially cloudy reaction mixture became homogeneous. The ice bath was removed, and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separatory funnel and washed with hexane (2×300 ml). The aqueous layer was acidified with 6N hydrochloric acid to pH 5 and diluted with ethyl acetate (600 ml). The mixture was further acidified to pH 2. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×600 ml). The organic extracts were combined and washed with brine (750 ml), dried (magnesium sulfate), filtered and concentrated in vacuo to produce a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml), and the solution was concentrated to half of its volume. A second portion of toluene (750 ml) was added, and concentrated again such that 630 ml of toluene remained. This solution was stored at 5° C. overnight, during which time some of the product crystallized from solution. The solid was redissolved by warming to room temperature. Toluene (134 ml) was then added (a few seed crystals remained). With mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time). At this point, the product started to crystallize from solution. An additional portion of heptane (1020 ml) was added over 1.5 hours, and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with 1:2 toluene:heptane (3×150 ml) and heptane (3×500 ml) and air-dried to give 158.6 g of title product as a white solid; m.p. 66° C.; [α]D =-1.5° (c=1, 95% ethanol). TLC (ethanol:water, 3:1) Rf =0.78.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][C:11]=1[CH3:16]
Reactant: COC(=O)CBr
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(OCC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 g (8.9 mmol) of the title B compound, (4-amino-3-methylphenoxy)-acetic acid t-butyl ester and 2.44 g (17.7 mmol) of potassium carbonate in 8 mL of DMF are added 1.76 g (11.5 mmol) of methyl bromoacetate. The mixture is stirred at 60° C. for 1 h, then allowed to cool to RT. The mixture is poured into water and extracted with EtOAc. The organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue is chromatographed using CH2Cl2 as the eluant to afford (4-t-butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methyl ester as an oil (contaminated with approx 25% of dialkylated product): 1H-NMR (CDCl3) δ 6.76-6.64 (m, 2H), 6.40 (d, J=8.46, 1H), 4.43 (s, 2H), 3.91 (s, 2H), 3.78 (s, 3H), 2.19 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=[O:15])[C:6]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(C)=O.CC(C)([O-])C.[K+].[C:26]1([S:32](Cl)(=O)=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[C:8]1([C:6]2([CH3:14])[C:5](=[O:15])[N:4]([S:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:3]([S:2][CH3:1])=[N:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1Sc1ccccc1
Reaction time: 1 h

Procedure:
0.6 g (2.7 mmol) of 2-methylthio-4-methyl-4-phenyl-2-imidazolin-5-one in solution in 50 ml of anhydrous tetrahydrofuran (THF) is charged to a 10 0 ml, three-necked, round-bottomed flask under an inert atmosphere. The solution is stirred with a magnetic stirrer and is cooled to 0° C. (ice bath+acetone). 0.30 g (1 molar equivalent) of potassium tert-butoxide is added and the mixture is stirred for 10 minutes at 0° C. A solution containing 0.40 g of phenylsulfonyl chloride (phenylthio chloride) and 10 ml of anhydrous THF is then run in. The mixture is then left to return to more temperature for one hour. The reaction mixture is run into 100 ml of water. Extraction is carried out with 100 ml of ethyl acetate. The organic phase is washed 4 times with water and dried over sodium sulfate.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:16]N1CCOCC1>>[CH2:1]([C:5]1[C:13]([Cl:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)O)c(OC)c1
Reactant: ClN1CCOCC1
Product: CCCCc1cc(OC)c(C(=O)O)cc1Cl

Procedure:
4-n-Butyl-2-methoxybenzoic acid (0.5 g; 2.9 mmol) and N-chloromorpholine (356 mg; 2.9 mmol) were treated in a similar manner to that described in Preparation 24 to give the title compound as a white soid (0.4 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.Cl>C(OCC)C.CCCCCC.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[CH:3][C:4]=1[CH2:9][CH3:10]
Reactant: CCc1cc(Br)ccc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCc1cc(C=O)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 4.319 g of 4-bromo-1-chloro-2-ethyl-benzene (20 mmol) in 50 ml diethylether, cooled to 0° C., were added dropwise 12.3 ml of 1.6M n-BuLi in hexane. After 30 min. stirring at 0° C. and 2 h at RT, a solution of 2.43 ml DMF (31 mmol) in 10 ml diethylether was added dropwise (temperature raised from 20 to 28° C.). After 1 h additional stirring at RT, the reaction mixture was acidified with 2N HCl, diluted with 150 ml water and extracted with diethylether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by flash column chromatography (heptane/AcOEt: 95/5) to yield 2.1 g of a colorless oil. MS (ISP) 168.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([Cl:11])[CH:3]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:34]([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43]C2C=CC([N+]([O-])=O)=CN=2)[N:30]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:34]([C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43][C:13]3[N:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[N:30]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Br)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(4-bromo-2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-bromo-2-chlorobenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: CNN(NC)CC(O)=O.Cl.[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12].C(C1(NC(C(N[C:69]([N:71]2[CH2:76]C[O:74][CH2:73][CH2:72]2)=O)CC(C)(C)C)=O)CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N>>[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:21])[CH2:14][CH2:15][N:16]([C:73](=[O:74])[CH2:72][N:71]([CH3:76])[CH3:69])[CH2:17][CH2:18]1)#[N:12]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: CNN(CC(=O)O)NC
Agent: Cl
Product: CN(C)CC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound was prepared from N,N-dimethylaminoglycine and morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride using the coupling method described in Example 1-part (d). The product was purified by reverse phase preparative HPLC to give the title compound as an off-white solid; MS, m/z 477=M+1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23]6(OCC[O:24]6)[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ncn3cc4c(cc23)CCCC2CC3(CCC42Cc2ccccn2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
rac-(4aR,13bS)-9-(4-Fluorophenyl)-13b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13b-octahydro spiro[benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (148, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.380 g, 0.786 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was treated with 6 N hydrochloric acid (0.52 mL, 3.1 mmol) then stirred at rt for about 4 h. Water (1 mL) was added and the mixture was stirred for about 12 h. Sat. aq. NaHCO3 (˜10 mL) and EtOAc (20 mL) were added to the mixture then the layers were separated. The organic layer was washed with brine (˜15 mL) then dried over MgSO4, filtered and concentrated to yield rac-(4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3(2H)-one (149, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.323 g, 94%); LC/MS, method 3, Rt=2.30 min, MS m/z 440 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.38-8.36 (m, 1H), 8.18 (s, 1H), 7.96-7.90 (m, 3H), 7.75 (s, 1H), 7.43-7.39 (m, 1H), 7.27-7.19 (m, 2H), 7.08-7.04 (m, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.70 (d, J=13.6 Hz, 1H), 3.45-3.38 (m, 2H), 3.20-3.02 (m, 2H), 2.69-2.62 (m, 1H), 2.29-1.87 (m, 7H), 1.72-1.63 (m, 1H), 1.46-1.32 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 198-200° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (dd, J=7.8, 7.5 Hz, 1H), 7.32-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.17 (s, 1H), 5.27 (d, J=15.6 Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.49 (td, J=8.7, 0.7 Hz, 2H), 3.15 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 155.2, 154.9, 148.6, 142.1, 138.3, 132.1, 129.1, 128.9, 127.6, 124.0, 123.7, 123.3, 122.3, 109.7, 107.2, 104.0, 80.1, 71.8, 58.6, 45.5, 30.4; MS (ES+) m/z 370.9 (M+1).
Reaction SMILES: Cl[Si:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH:28]1([Na])[CH:32]=[CH:31][CH:30]=[CH:29]1.C1CC=CC=1.[H-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.O>[CH:31]1([Si:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:30]=[CH:29][CH:28]=[CH:32]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)C1c2ccccc2-c2ccccc21
Reactant: [Na]C1C=CC=C1
Agent: C1=CCC=C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C1=CC([Si](c2ccccc2)(c2ccccc2)C2c3ccccc3-c3ccccc32)C=C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
80 g (0.21 mol) of (2a) were added at 10° C. to an about 2 molar solution of cyclopentadienylsodium in tetrahydrofuran (THF), prepared from 27.8 g (0.42 mol) of freshly cracked cyclopentadiene and 16.7 g (0.42 mol) of 60% strength sodium hydride (as an oil suspension) in 200 ml of THF and the reaction mixture was stirred at room temperature for 3 hours. 300 ml of water and 400 ml of toluene were subsequently added. After phase separation, extraction with a further 250 ml of toluene and drying over magnesium sulfate, the solvents were removed and the residue was taken up in 240 ml of n-heptane. The solid was filtered off, washed with n-heptane and dried under reduced pressure. 57 g (65%) of 2b were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]2[CH2:64][CH2:63][NH:62][CH2:61]2)=[CH:56][CH:55]=1>C(#N)C>[F:53][C:54]1[CH:55]=[CH:56][C:57]([CH:60]2[CH2:64][CH2:63][N:62]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:61]2)=[CH:58][CH:59]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (36 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (8 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16F4N2O2: 404.1148, found 404.1152.
Reaction SMILES: [OH:1][CH2:2]/[C:3](=[C:14]1\[C:15](=[O:20])[NH:16][C:17](=[O:19])[S:18]\1)/[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[N:16]([CH3:21])[C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)/C(=C(\CO)c2cccc3ccccc23)S1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)SC(=C(CO)c2cccc3ccccc23)C1=O
Yield: 74.9 %

Procedure:
(E)-5-[2-Hydroxy-1-(1-naphthalenyl)ethylidene]-2,4-thiazolidinedione (1.49 g, 5.22 mmol) was added to suspension of potassium carbonate (7.22 g, 52.2 mmol) in acetone. After 30 minutes iodomethane (0.65 mL, 10.4 mmol) was added. After 30 min the mixture was filtered, and concentrated to give a brown oil which was dissolved in chloroform. The resulting solution was washed with water then dried over magnesium sulfate and concentrated in vacuo to give an oil which was chromatographed on silica gel (chloroform/acetonitrile) to give a glass (1.17 g). Recrystallization from carbon tetrachloride/hexane/ether gave analytically pure E isomer of the title compound as yellow needles (0.90 g).
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:16]([CH3:26])[CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>ClCCl>[Br:15][C:9]1[C:8]2[N:7]3[C@H:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:20])[C:6]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2cccc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CNC(=O)c2cc3cccc(Br)c3n21
Temperature: 25 °C

Procedure:
A solution of 6.10 g (14.3 mmol) (R)-7-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester in 65 ml dichloromethane was cooled down to 0° C. and treated dropwise with 32 ml (28.7 mmol) trifluoroacetic acid. The cooling bath was removed and after 45 min. stirring at room temperature all volatile components were removed at a rotary evaporator and the remaining oil was dissolved in 35 ml methanol. To this solution, 7.93 g (57.4 mmol) potassium carbonate was added and the reaction was stirred for 16 h. The suspension was poured onto water and ethyl acetate; the organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane, tert-butyl methyl ether was added and the solution was concentrated at a rotary evaporator until a white precipitate began to form. The suspension was filtered, the solid material was washed with tert-butyl methyl ether and dried under high vacuum to give the desired compound as white crystalline solid. ISP-MS: m/e=2381.1 ([M+H+1]).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1c2ccccc2CNc2ccc(Br)cc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC1c2ccccc2C=Nc2ccc(Br)cc21
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-bromo-6,11-dihydro-11-methyl -5H-dibenzo[b,e]azepine (4, R8=Br; 32 g, 0.11 mol) in DCM, MnO2 (manganese oxide)(96.6 g, 1.11 mol) was added and the reaction mixture was allowed to stir overnight. The reaction mixture was filtered over decalite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=8:2) to give 2-bromo-11-methyl-11H-dibenzo[b,e]azepine (5, R8═Br; 29.4 g, 92%). Data: (m/z)=286/288 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:8])[O:5]CC)C.CO.O>C(Cl)(Cl)(Cl)Cl>[CH2:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:19]1[NH:18][CH:9]([P:10](=[O:11])([OH:14])[OH:17])[P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCOP(=O)(OCC)C(NC1C=CCCCC1)P(=O)(OCC)OCC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: O=P(O)(O)C(NC1CCCCCC1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34.8 %

Procedure:
2.5 ml of trimethylsililiodide was added dropwise to an ice-cold solution of 1.55 g of tetraethyl(2-cycloheptenyl)aminomethylenebis(phosphonate) in 25 ml of carbon tetrachloride. Then, the mixture was stirred at room temperature for 2.5 hours. 2 ml of methanol and 1 ml of purified water were added to the ice-cold reaction solution and it was concentrated under reduced pressure. To the obtained residue were added methanol and acetone to give a white solid. The residue was recrystallized from water-methanol to give 0.39 g of (2-cycloheptyl)aminomethylenebis(phosphonic acid) as colorless crystals in the form of needles.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([O:45]C(C)(C)C)=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-].[Na+].C(OC([NH:59][CH2:60][C:61]1[CH:62]=[N:63][N:64]([CH2:86][CH2:87][O:88]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:65]=1[NH:66]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:41])[CH3:42])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:63]4[N:64]([CH2:86][CH2:87][OH:88])[C:65]([NH2:66])=[C:61]([CH2:60][NH2:59])[CH:62]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (5.82 g) in N,N-dimethylformamide (12 ml) was added sodium iodide (1.44 g). After stirring at room temperature for 1 hour, 4-(tert-butoxycarbonylaminomethyl)-5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazole (14.8 g) was added to the mixture. The stirring was continued at 35° C. for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and added to diisopropyl ether (500 ml) dropwise. The resulting precipitate was collected by filtration. The filter cake was washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The solid (15.6 g) was dissolved in dichloromethane (47 ml), and to the solution were added anisole (16 ml) and trifluoroacetic acid (32 ml) successively. After stirring at room temperature for 3 hours, the reaction mixture was poured into diisopropyl ether (500 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The crude product was dissolved in a phosphate buffer (pH 7.0) and purified by preparative HPLC (eluent: pH 7.0 phosphate buffer and acetonitrile). The eluate was subjected to column chromatography on Diaion® HP-20 (Mitsubishi Chemical Corporation) and freeze-dried to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (940 mg).