Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>CO>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To 800 ml of a methanol solution having dissolved therein 34 g (0.514 mol) of potassium hydroxide were added 100 g (0.512 mol) of 4-hydroxy-4'-cyanobiphenyl and 93 g (0.512 mol) of 6-bromo-1-hexanol, and the mixture was heated at reflux for 13 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was concentrated under reduced pressure by the use of an evaporator, and the residue was purified by column chromatography using Wakogel C-200 as a carrier and hexane/THF, i.e., tetrahydrofuran as a developing solution to obtain 65 g (yield: 40%) of 4-(6-hydroxyhexyloxy)-4'-cyanobiphenyl.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.10 g, 6.81 mmol), triethylamine (1.21 mL, 8.67 mmol) in DCM (25.2 mL) was cooled in an ice/water bath and treated with methanesulfonyl chloride (675 μL, 8.67 mmol) added dropwise under an atmosphere of nitrogen. The mixture was stirred at 25° C. overnight. The mixture was treated with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2×50 mL). The extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo leaving a beige oil which was recrystallized from hexanes (22 mL) to give 1.59 g (98%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.61-1.68 (m, 2H), 1.82-1.90 (m, 2H), 1.94-2.08 (m, 4H), 3.02 (s, 3H), 3.91-4.00 (m, 4H), 4.82-4.88 (m, 1H); MS (ESI): 237.10 [M+H]+; HPLC tR=2.54 min.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under cooling with ice, 1-benzhydrylazetidin-3-ol (718 mg) in tetrahydrofuran (8 mL) was added dropwise to a suspension of 60% sodium hydride (144 mg) in N,N-dimethylformamide (8 mL), and the resultant mixture was stirred for 20 minutes. Methyl iodide (0.23 mL) was added to the reaction mixture, followed by stirring at room temperature overnight. The reaction mixture was partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (680 mg, 90%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C1COCC1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:19][NH:20][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccsc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (500 mg, 2.077 mmol) in DCM (20 ml), methanamine 2N solution in THF (4.155 ml, 8.31 mmol) was added and the reaction was stirred for 1 hour at RT. The mixture was partitioned between 2N HCl and DCM and the aqueous phase was extracted with DCM. The combined organic layers were dried over sodium sulfate and the solvent was removed affording methyl 3-(N-methylsulfamoyl)thiophene-2-carboxylate (Int. 32) (430 mg, 1.828 mmol, MS/ESI+235.8 [MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:22]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCCc1cc(C(=O)OC)ccc1O
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 L three necked 24/40 round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a dropping funnel was first added a solution of 36.0 g (0.185 mol) of methyl 4-hydroxy-3-n-propylbenzoate dissolved in 700 mL of anhydrous DMF followed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged with nitrogen and the reaction mixture was stirred at room temperature for 2 hours. A solution of 58.5 g (0.204 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate dissolved in 100 mL of DMF was then added via an addition funnel over a 15 minute period. The reaction mixture was stirred an additional 1 hour at room temperature then quenched by addition to 5 L of a 5% aqueous citric acid solution. The organic product was extracted into diethylether (2×4 L), the organic layers were separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated. The residue was applied to a silica gel (2 kg; 70-230 mesh) column equilibrated in 10% CH2Cl2 -hexane. The column was then eluted successively with 12 L of 10% CH2Cl2 -hexane, 12 L of 5% EtOAc-hexane, 4 L of 7.5% EtOAc-hexane, 12 L of 10% EtOAc-hexane, and finally 8 L of 20% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 76.3 g (74.2 theoretical) of the title compound as a pale yellow oil which was used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>C(#N)C.CCOCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCOCC
Solvent: CC#N
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
1,2,3,4-tetrahydroquinoline (1.7 g, 12.8 mmol) was dissolved in acetonitrile (25 mL) and cooled to 0° C. N-Bromosuccinimide (2.16 g, 12.2 mmol) was added in 4 portions over 30 minutes and the mixture was stirred for 3 hours. The mixture was diluted with ether and washed with sodium bisulfite, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-30% ethyl acetate in hexane) afforded 6-bromo-1,2,3,4-tetrahydroquinoline (1.5 g). MS (ES) m/z 211.8; HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>O>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][OH:12]
Reactant: Clc1ccccn1
Reactant: CNCCO
Solvent: O
Product: CN(CCO)c1ccccn1
Temperature: 25 °C

Procedure:
2-chloropyridine (12 g) and 2-(methylamino)ethanol (100 ml) are stirred under nitrogen at 120° C. for 18 hours. Cool to room temperature and then pour into iced water (250 ml). Extract with ethyl acetate (2×200 ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The crude product is distilled in vacuo to give 10.3 g of N-methyl-N-(2-pyridinyl)-2-aminoethanol, boiling at 110° C./1.0 mmHg.
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17]>O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[C:9]([OH:17])[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(Cl)c(O)c1

Procedure:
A suspension (about 600 ml) containing 100 g of reduced iron, 5 g of ammonium chloride, 500 ml of isopropyl alcohol, and 100 ml of water was refluxed with vigorous stirring. To this suspension was added 100 g of 2-chloro-5-nitrophenol in portions. After completion of the addition, the mixture was heated for an additional 1 hour. This suspension was filtered when hot with the aid of Celite and the filtrate was washed with about 500 ml of hot isopropyl alcohol and then concentrated to about one-fifth its original volume under reduced pressure. To the concentrate was added 1 l of ice water and the resulting crystalline precipitate was collected by filtration and washed with water.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[CH:21]=1>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[C:21]=1[I:8]
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 43.2 %

Procedure:
NIS (6.75 g, 30.0 mmol) was added to a solution of 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (6.61 g, 30.0 mmol) in DMF (50 mL). The reaction mixture was stirred at ambient temperature for about 35 min and then partitioned between DCM and water. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and triturated with Et2O to give the title compound (4.49 g, 43%): LC/MS (Table 1, Method a) Rt=3.18 min; MS m/z: 347.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 32.4 g of α,α,α-trifluoro-m-cresol, 27.62 g of p-fluoroacetophenone, 55.2 g of potassium carbonate and 250 ml of N,N-dimethylacetamide is heated under Argon overnight with vigorous stirring at 150°-155° C. After cooling the mixture is added to 500 ml of water and extracted with benzene. The combined extracts are washed with two 100 ml portions of 5% NaOH, 100 ml of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid which is distilled to give the product as a pale yellow oil (bp 122°-142° C. @ 0.2 mm).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:9]([OH:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O>[CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:9]1[O:12][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0.976-g portion of the product obtained in Example 1, namely t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate, was suspended in 8 ml of acetone, then 2 ml of 10% sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and the organic layer was concentrated to dryness to give t-butyl [1(S)-benzyl-2(S),3-epoxypropyl]carbamate. After purification by preparative TLC, the optical purity (99.8% ee) was confirmed using a chiral column.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[OH-:10].[Na+:11].C.OO>O>[Na+:11].[CH2:1]([P:3]([OH:4])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCP(=O)(O)CCCO
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Temperature: 70 °C
Yield: 93 %

Procedure:
15.2 g (0.1 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 5) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Ft and 1% Bi is added, the suspension is heated to 70° C. and 30% strength hydrogenperoxide solution is passed into the suspension at a flow rate of 1 mol equivalent per hour while the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, the filter residue is washed and the water is distilled off in vacuo to obtain 19.3 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt (colorless solid).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reaction time: 1 h
Yield: 97 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (8.62 g, 19.91 mmol) was diluted with DCM (40 ml) followed by the portion wise addition of TFA (30 ml). After stirring for 1 hour, the reaction was concentrated and placed under vacuum over the weekend. The residue was taken up in DCM and washed with saturated bicarbonate and 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to yield the desired compound (7.278 g, 19.32 mmol, 97.00% yield) as a nice white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:30])[CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc4c(N)ncnn34)cc2)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (1.20 g, 3.04 mmol) in tetrahydrofuran (15 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (435 mg, 1.21 mmol) in four portions over 15 min. The mixture stirred at −20° C. for 3 h. Saturated, aqueous Na2SO3 (20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes. 1H-NMR indicated the presence of residual hydantoin side product, thus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL). The layers were separated and the organic layer was further washed with 5% aqueous K2CO3 (2×25 mL). The combined aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 340 mg (23%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91-7.83 (m, 3 H), 7.09 (s, 1 H), 7.00 (d, 2 H), 3.50-3.42 (m, 4 H), 3.20-3.14 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 473.0 [M+H]+, HPLC RT (min) 3.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: OCCC1CCCC1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2CCCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 115 mg, 60%). mp 100-101° C. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)+; (APCI−) m/z 509 (M+Cl)−. Anal. calc. for C24H24F2N2O4S.0.25H2O: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5.76.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=S(Cl)[Cl:14]>>[C:1]([Cl:14])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccccc1
Product: O=C(Cl)C=Cc1ccccc1

Procedure:
Cinnamic acid (25 g, 168.74 mmol) was treated with SOCl2 (150 ml) for 2 hours at 70° C. in a round-bottomed flask. The volatiles were distilled out under vacuum to afford cinnamoyl chloride as a yellow oil (25.2 g, crude), which was used in the next step without further purification.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[CH:14]1[CH:15]=[C:10]([S:9][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccn1
Reactant: O=C1NC(=O)C(Br)S1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Sc2ccccn2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of 5-bromo-thiazolidine-2,4-dione (28.24 g, 0.144 mol) and 2-mercaptopyridine [(II), 16.0 g, 0.144 mol] in dry THF (200 mL) at -78° C. was added lithium bis(trimethylsilyl)amide (1.0M in hexanes, 317 mL, 0.317 mol) dropwise over a 40 min period. After 30 min. the reaction mixture was warmed to room temperature. After an additional 3 hr, 10% HCl was added to pH=1. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried (MgSO4) and concentrated to provide the title compound as a green solid (30.45 g, 93%): mp 118°-120° C.; NMR (DMSO, d 6): δ12.35 (s, 1H, NH), 8.39 (d, J=5.3 Hz, 1H, PyrH), 7.69 (dd, J=7.3, 8.3 Hz, 1H, PryH), 7.42 (d, J=8.3 Hz, 1H, PyrH), 7.19 (dd, J=5.3,7.3 Hz, 1H, PyrH), 6.31 (s, 1H, CH), MS(EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (C8H6N2O2S2): C, H, N.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]2[CH2:16][N:15]([C:17]([C@@H:19]3[CH2:23][C@H:22]([S:24][C:25]4[C@H:26]([CH3:49])[C@@H:27]5[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]5[C:29]=4[C:30]([O:32]CC4C=CC([N+]([O-])=O)=CC=4)=[O:31])[CH2:21][N:20]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:18])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:65].[H][H]>O1CCCC1.O.[Pd]>[ClH:65].[NH2:12][CH:13]1[CH2:14][N:15]([C:17]([C@@H:19]2[CH2:23][C@H:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([OH:32])=[O:31])[CH2:21][NH:20]2)=[O:18])[CH2:16]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N)C4)C3)[C@H](C)[C@H]12

Procedure:
216 mg of 4-nitrobenzyl (1R,5S,6S)-2-((2S,4S)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 10 ml of a 3:2 by volume mixture of tetrahydrofuran and water. 250 mg of a 10% w/w palladium-on-carbon catalyst and 239 μl of 1N aqueous hydrochloric acid were then added to the resulting solution, after which the mixture was hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous phase was then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 18 ml). Of the fractions obtained by elution with water, the one containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried to give 46 mg of the title compound as a powder.