Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:11][CH2:12][C:13](Br)=[O:14].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C.O>[Br:11][CH2:12][C:13]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: NOCc1ccccc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CBr)NOCc1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a 0° C. solution of O-benzylhydroxylamine hydrochloride (1.6 g, 10 mmol) in THF (40 mL) was added bromoacetyl bromide (871 μL, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol). The reaction mixture was warmed to room temperature overnight and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography with ethyl acetate-hexane to give 1.27 g (52%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>ClCCCl.CCOCC>[OH:22][C:15]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: O=C1C2=NCCCN2c2ccccc21
Reactant: COCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ether (60 ml) and 4-bromo-1-methoxy-butane (10.2 g) were added to magnesium turnings (1.46 g). After formation of the Grignard reagent, the mixture was cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml) and the mixture was stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound or the free base (3.55 g), m.p. 128°-139° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 178°-179° C.
Reaction SMILES: C([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])(=O)C.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:8]2[NH:4][C:5](=[O:18])[N:6]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[F:17])[C:7]2=[O:9])=[CH:22][CH:21]=1
Reactant: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Reactant: Cc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C=C2NC(=O)N(c3cc(F)ccc3F)C2=O)cc1
Yield: 89.2 %

Procedure:
N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (2.1 g, 8.2 mmol), 4-methylbenzaldehyde (1.05 g, 8.7 mmol) and triethylamine (1.7 g, 16.5 mmol) were heated under reflux in DMF (20 mL) for 4 hours. The solution was cooled diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 2.3 grams of 5-(4-methylbenzylidene)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione, m.p. 218°-224° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.20 g, 5.6 mmol), 2-chloro-4,6-dimethyl-pyrimidine (1.03 g, 7.2 mmol), Cs2CO3 (2.12 g, 6.5 mmol) and DMF (15 mL) were combined and heated to 100° C. for 24 hours. The reaction was then allowed to cool and water and EtOAc were added. The products were extracted into EtOAc, dried over Na2SO4, and concentrated. The resulting crude mixture was purified by flash column chromatography (EA/hex) to give the title compound (1.27 g, 71%). MS (ESI) mass calcd. for C17H26N4O2, 318.42; m/z found, 319.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.25 (s, 1H), 3.85-3.75 (m, 2H), 3.69-3.46 (m, 4H), 3.38-3.20 (m, 2H), 2.94 (br s, 2H), 2.29 (s, 6H), 1.44 (s, 9H).
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]=[O:14].[C-:15]#[N:16].[K+]>O.C(O)C>[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]([OH:14])[C:15]#[N:16]
Reactant: [C-]#N
Reactant: C[C@@H]1C=CCC[C@H]1C=O
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1C=CCC[C@H]1C(O)C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Sodium bisulfite (10.4 g., 0.1 mole) was dissolved in 50 ml. H2O. Absolute ethanol (50 ml.) and trans-2-methyl-3-cyclohexene-1-carbaldehyde (85%, 8.6 g., 0.07 mole) were added and the mixture heated in an oil bath at 63°-65° C. for 1.5 hours, then cooled to 15° C. in an ice-water bath. KCN (13 g., 0.2 mole) in 50 ml. H2O was added at 15°-18° C. The reaction mixture was stirred at room temperature 0.5 hour and extracted with 150 ml. ether. The ether was back-washed with 75 ml. H2O and concentrated in vacuo to yield title product as an oil, 5.5 g. Based on pnmr, the product contained 85% trans isomer (doublet at 4.6 ppm, J=4) and 15% cis isomer (doublets at 4.2 and 4.35, J=2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90.4 mg, 0.20 mmol), 3-bromo-benzonitrile (37.5 mg, 0.21 mmol), and Pd[P(Ph)3]4 (15.9 mg, 6.9 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 11.7 mg. MS: 426.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.80-2.04 (m, 3H), 2.15-2.36 (m, 1H), 3.39-3.58 (m 2H), 4.32-4.43 (m, 1H), 4.89-5.14 (m, 2H), 7.03-8.07 (m, 13H), 10.13-10.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[C:18]#[N:19]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(O)c2ccccc12
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Preparation 82, 4-hydroxynaphthaldehyde and 3,4-difluorobenzonitrile were converted to the title compound: RT=3.90 min; m/z (ES+)=292.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1.C(O)(=O)C>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2ncnc(Oc3ccc(N)c(N)c3)c2cc1OC
Reaction time: 18 h

Procedure:
4-(6,7-Dimethoxyquinazolin-4-yloxy)-2-nitro-phenylamine (Step A, 1 g, 2.9 mmol) was dissolved in EtOH (200 mL) and glacial acetic acid (10 mL) and placed under nitrogen. Pd/C was added, the reaction mixture blanketed with H2, the mixture was shaken under H2 for 18 h at 55 psi. The catalyst was removed by filtration through Celite® and the solution was concentrated in vacuo. The residue was dissolved in MeOH/H2O and NH4OH was added to adjust to PH 10, and the solvent evaporated. Purification of the residue by column chromatography using a gradient of 0-100% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) afforded the title compound as a orange solid. MS(MH+)=N/A; Calc'd 312.32 for C16H16N4O3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(NS(C)(=O)=O)cc(OC)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
N-(3,5-Dimethoxyphenyl)methanesulfonamide (1.7 g, 6.53 mmol) was dissolved in dichloromethane (28 ml). A solution of boron tribromide (1 M in dichloromethane, 33 mL, 33 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Boron tribromide (1M in dichloromethane, 10 ml, 10 mmol) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 344 mg (26% yield) of the title compound. Purity 99%.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)([CH3:14])[CH3:13].[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:24])[CH:22]=[CH2:23])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Production in a way similar to: D. A. Evans, K. T. Chapman, J. Bisha J. Am. Chem. Soc. 1988, 110, 1238; A Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185. 6.88 ml of a 1.6M solution of n-BuLi in hexane (11.0 mmol) is slowly added to a solution of 1.299 g (10.0 mmol) of (S)-4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF at -78° C. The solution is stirred for 30 minutes at -78° C.; 1.22 ml (15.0 mmol) of acrylic acid chloride is added drop by drop; it is allowed to reach room temperature and hydrolyzed with 50 ml of saturated NH4Cl solution. It is extracted three times with 50 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (10:1), 1.63 g (8.9 mmol, 89%) of 20 is obtained.
Reaction SMILES: [I-].[K+].Cl[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCCC1>[CH:26]1([NH:29][CH2:4][C:5]2[N:9]3[C:10]4[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=4[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])=[N:13][CH2:14][C:8]3=[N:7][N:6]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nnc(CNC3CC3)n2-c2ccccc21

Procedure:
In the manner given in Example 1, potassium iodide and 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 1-[(cyclopropylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)Cl>C(N(CC)CC)C>[CH3:9][S:10]([O:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH:2]([CH3:3])[CH3:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(O)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(OS(C)(=O)=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 5.81 g (50 m.mols) of 2,4-dimethyl-3-pentanol, 6.30 g (55 m.mols) of methane sulfonyl chloride, and 50 ml of methylene chloride were placed and cooled to 0° C. To the cooled mixture, 7.59 g (75 m.mols) of triethyl amine was added dropwise over a period of one hour with the reaction temperature retained meanwhile. The reactants in the resultant reaction mixture were left reacting at 0° C. for one hour. After the reaction, the reaction mass was thrown into 50 ml of ice water to obtain an organic layer by separation. The organic layer thus obtained was washed with 50 ml of a diluted aqueous hydrochloric acid solution, 50 ml of water, 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and 50 ml of a saturated saline solution. Then, by removing the solvent from the organic layer, 8.94 g (46 m.mols) of (2,4-dimethyl-3-pentyl) methanesulfonate was obtained as the product aimed at.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>C1COCC1>[CH3:1][S:2]([CH2:5][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([I:11])[CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: BrCc1cccc(I)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)CCc1cccc(I)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl sulfone (1 eq.) in 60 mL of anhydrous THF (0.2 M) was added, at −78° C., n-butyl lithium (1.6 M hexane solution, 1.2 eq.) over a period of 10 min. The resulting mixture was stirred at −78° C. for 1 h. To the now yellow solution was added, at −78° C., 3-iodobenzyl bromide (I eq.). The reaction mixture was then slowly warmed to RT over 16 h. The reaction was carefully quenched with 10% aq. HCl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a viscous oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) followed by trituration with hexanes afforded the title compound as a white crystalline solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25](I)[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29](=[O:31])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25]([CH:29]([OH:31])[CH3:30])[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: Cc1c(I)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cc1c(C(C)O)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl 1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized according to general procedure P, 200 mg, 0.38 mmol) was placed in a 10 mL 2-neck flask and the flask was evacuated and purged with N2 three times. To the solid was added THF (1.9 mL) and the solution was lowered to −78° C. PhMgBr (0.21 mL, 1.8 M) was added to the solution and it was stirred for 15 minutes. n-BuLi (0.19 mL, 2.0 M) was subsequently added and the reaction was stirred an additional 30 minutes. Acetaldehyde (0.085 mL, 1.5 mmol) was added to the reaction and it was warmed to 0° C. The solution was subsequently quenched with 10% HCl and the aqueous layer was extracted three times with EtOac. The combined organics were dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to afford 4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide as a white solid: MS (ES) M+H expected 449.1, found 449.1.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][CH:39]1[CH2:40][O:41]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), potassium carbonate (125 mg), and epibromohydrin (124 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (62 mg, yield 53%).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH:30]=[O:31])[CH:22]=2)[CH2:17][C@H:16]1[O:32][CH3:33])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>C1COCC1>[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH:30]([OH:31])[CH3:1])[CH:22]=2)[CH2:17][C@H:16]1[O:32][CH3:33])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A solution of methylmagnesium bromide (0.97 mol/L) in THF (1.59 mL, 1.54 mmol) was added to a solution of methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-3-formylthiophene-2-carboxylate obtained in Example (246c) (333 mg, 0.77 mmol) in THF (8 mL) at 0° C., and the mixture was stirred at room temperature for five hours. Saturated ammonium chloride solution was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 223 mg of the title compound as a pale yellow solid (65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:39]=[CH:38][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C([O-])(=O)C.[NH4+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:39]=[CH:38][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-alanine was dissolved in methanol (1.5 ml). Sodium borohydride was added and the mixture was stirred for 30 minutes. An ammonium acetate/H2O solution (2 ml) was added and the methanol was evaporated. The product was purified by preparative HPLC (CH3CN/0.1% ammoniumacetate buffer 20:80-100:0). The fractions containing product were lyophilized and 27 mg (48%) of the title product was obtained. M/z: 555.0 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl[C:18]1[C:19]([N+:45]([O-:47])=[O:46])=[C:20]([C:30]2[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][C:33]([N+:39]([O-:41])=[O:40])=[CH:32][C:31]=2[N+:42]([O-:44])=[O:43])[C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].CO>CC(C)=O>[N+:8]([C:7]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH2:1][C:22]1[C:21]([N+:27]([O-:29])=[O:28])=[C:20]([C:30]2[C:31]([N+:42]([O-:44])=[O:43])=[CH:32][C:33]([N+:39]([O-:41])=[O:40])=[CH:34][C:35]=2[N+:36]([O-:38])=[O:37])[C:19]([N+:45]([O-:47])=[O:46])=[CH:18][C:23]=1[N+:24]([O-:26])=[O:25])([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2[N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CO
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])c2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
The reaction of 4.5 g (0.02 mole) of TNT with 4.6 g, (0.01 mole) of 3-chloro-2,2',4,4',6,6'-hexanitrobiphenyl was carried out as above. After extracting the crude reaction product with methanol until the extracts were light colored, the somewhat gummy residue was dissolved in acetone, an equal volume of methanol was added and the solution was heated, with magnetic stirring, on a hot plate. A light yellow crystalline material separated, was filtered off and dried. It weighed 1.7 g, 25% of the theoretical yield. Recrystallized from acetone methanol formed faintly yellow rod-like crystals, mp 255°-256°. Anal. Calcd for C19H7N9O18 : C, 35.1; H, 1.1; N, 19.4. Found: C, 34.9, 34.2; H, 1.6, 1.2; N, 19.2, 18.8.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:20]([N:19]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: ClCCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20° C. dibenzyl amine (442 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 324 g (53% yield) of the title compound was isolated as a yellow oil.