Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([F:25])[C:18]([CH2:23]Br)=[C:19]([CH2:21]Br)[CH:20]=1>CN(C=O)C>[Br:14][C:15]1[CH:20]=[C:19]2[C:18]([CH2:23][N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH2:21]2)=[C:17]([F:25])[CH:16]=1
Reactant: Fc1cc(Br)cc(CBr)c1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)cc(F)c3C2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1.17 g of about 60% sodium hydride was suspended in 30 ml of DMF, to which was added 15 ml of DMF solution of 2.50 g of p-toluene sulfonamide, and the resulting mixture was stirred at 60° C. for 1 hour. 15 ml of DMF solution of 5.02 g of 5-bromo-1,2-bis(bromomethyl)-3-fluorobenzene (3-13) was dropped thereto and the resulting mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water and the precipitated crystal was separated by filtering to obtain 5.10 g of 6-bromo-4-fluoro-2-(p-toluensulfonyl)isoindoline (3-14).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: CCOC(=O)C=CN1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced into the reaction mixture. Triethylamine (5.2 g, 51 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml) and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.6 g; purity according to GC: 85.5%; yield: 85.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:9]2([CH3:17])[CH3:10]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A 200 ml round-bottomed flask equipped with a stir bar and a reflux condenser was charged with a solution of bromobenzene (109 mmol, 17 ml) and 2,5-dichloro-2,5-dimethyl hexane (10 grams, 54.6 mmol) in dichloromethane (30 ml). Aluminum chloride (1.45 grams, 10.9 mmol) was added to the solution slowly, until spontaneous reflux subsides. After stirring for 10-15 minutes at room temperature, the reaction was poured into ice water (30 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (5×20 ml). The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated, to yield a 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 108.2 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in dioxane/water (300 mL:200 mL) was purged with nitrogen for 1 hour. [1,-bis(Diphenylphosphino) ferrocene]dichloropalladium [II] (4.5 g, 5.5 mmol) was added. The reaction mixture was heated to 100° C. with vigorous stirring for 3.5 hours, then cooled and filtered through Celite® (Celite Corp., Santa Barbara, Calif.). The cake was washed with ethyl acetate (500 mL). The combined organic phases were washed with 1N sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium carbonate, and concentrated in vacuo to afford a dark oil (28.6 g). Purification by flash chromatography using 2% ethyl acetate in hexanes as solvent provided the title compound (24.7 g, 93%) as a pale yellow oil. MS [(+)ESI, m/z]: 241 [M+H]+ HRMS [(+)ESI, m/z]: 241.12205 [M+H]+. Calcd for C16H17O2: 241.12286 Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.67; H, 6.61.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[BH4-].[Na+].O>C1COCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (125 g, 0.67 mol) in anhydrous THF (400 mL) was added NaBH4 (28 g, 0.74 mol) in portions at 0° C. The mixture was stirred for 1 h at 0° C., then poured into 500 mL of water. The mixture was extracted with ethyl acetate (200 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol as colorless oil (120 g, 95%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>OP(O)(O)=O>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:17][C:18](=[O:19])[O:5]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Product: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Temperature: 85 °C

Procedure:
A mixture of resorcinol (20 g), ethyl benzoylacetate (23.8 mL) and O-phosphoric acid (130 mL) was heated at 85° C. with care for 1 hr. The solution was cooled, poured onto H2O, extracted (3x EtOAc/THF), washed twice with H2O, and then twice with brine. The organic phase was dried and evaporated. Trituration with Et2O followed by filtration afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[CH:6][N:7](C)C)[CH3:2].O1CCOCC1.Cl.NO>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:21][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnoc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
Ethyl-2-(2'-trifluoromethylbenzoyl)-3-dimethylaminopropenoate (3.14 g.; 0.01 mol.) was dissolved in 15 ml. of dioxane. To this solution was added a solution of hydroxylamine hydrochloride (1.05 g.; 0.015 mol.) in 5 ml. of water. The resulting solution was stirred for 14 hours at 25° C. Extraction with water and diethyl ether yielded ethyl-5-(2'-trifluoromethylphenyl)-4-isoxazolecarboxylate as an oil (1.6 g.; 56.2% yield) having the following analysis:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)CCCCCCCCCCCBr
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCOc1ccc(F)cc1
Yield: 106.4 %

Procedure:
12-Bromododecanoic acid (1 g) was stirred in 10% hydrochloric acid-methanol for 4 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was dried with anhydrous sodium sulfate to give the methyl ester of 12-bromoundecanoic acid (1.01 g). To para-fluorophenol (0.38 g) dissolved in dimethylformamide (DMF) was added 60NaH (0.40 g), and the mixture was stirred. To this mixture was added 12-bromododecanoic acid (1 g), and the mixture was stirred for 12 hours. The reaction mixture, after having been concentrated and adjusted to a weak acidic range of pH by adding citric acid, was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give 12-para-fluorophenoxydodecanoic acid (1.12 g). The product was dissolved in a mixed solvent of ethanol-water (1:1), and potassium hydroxide (0.6 g) was added to the solution. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with water (80 ml), adjusted to acidic range of pH by adding citric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-para-fluorophenoxy-dodecanoic acid (1.03 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>CCCCCC>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(OCC)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To 41.15 g (0.3 Mol) of p-phenetidine in 90 ml of hexane, 64.9 g (0.3 Mol) of diethyl ethoxymethylenemalonate was added dropwise with stirring at room temperature. After an additional hour of stirring at room temperature, the reaction mixture was cooled with an ice bath and the product crystallized spontaneously. The crude solid material was isolated by filtration and washed with hexane to give 78.3 g of the title product; white solid melting at 55-56° C. UV 329 nm (E=802).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (5 mmol). Chromatograph on silica gel eluting with 10% methanol/dichloromethane to give the title compound: Rf =0.28 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].O.[OH-].[Na+]>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic anhydride (25.0 g) was heated at reflux for two hours. The reaction mixture was then cooled and poured into water (750 ml) with stirring. After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered, washed with water and dried to give 26.5 g (85%) of the title product as a white flaky solid. mp 175-176° C. 1H NMR (CDCl3): δ=8.29 (d, 1H); 8.12 (d, 1H); 7.96 (br, 1H); 7.78 (d of d, 1H); 2.19 (s, 3H). MS (EI): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Fc1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC/C=C/c2ccc(F)cc2)c(C)c(C)c1NC=O
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-fluorobenzene, the title compound was synthesized according to Reference Example 17b. Yield: 52%. Melting point: 196-198° C. (Ethyl acetate-hexane)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+]>C(O)=O.C(N(CC)CC)C.[C].[Pd]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: c1cnc2c(c1)CCN2
Temperature: 70 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and 10% palladium-carbon (500 mg) were dissolved in a mixture of formic acid (10 mL) and triethylamine (10 mL), and the solution was stirred at 70° C. for 17 hours. To this reaction mixture was further added 10% palladium-carbon (270 mg), and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, then an aqueous solution of 5N sodium hydroxide was added thereto, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1), and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614 mg, 5.11 mmol, 60%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:25][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-methoxyphenyl)(p-tolyl)methanone, 32-b. (3 g, 13.3 mmol) in CCL4 (30 ml) was added NBS (2.8 g, 16 mmol) and AIBN (50 mg), the reaction mixture was then stirred for 3 h under refluxed. The resulting mixture was cooled to ambient temperature, filtered, and filtrate was concentrated under reduce pressure. Purified by column chromatography on silica gel (petroleum ether/ethyl acetate=6:1), the pure product, 32-c, was obtained as a colorless oil (3 g, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.49 (s, 2H), 6.90-6.94 (m, 2H), 7.43-7.61 (m, 2H), 7.67-7.79 (m, 4H). LC-MS 305 [MH]+.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:18][CH2:17][C:13]2([CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[C:27]3=[O:35])[CH2:14]2)[CH2:17][CH2:18]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride from Example 7F (0.237 g, 0.749 mmol), the product from Example 14D (0.248 g, 0.749 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 ml, 1.123 mmol) and N-methylmorpholine (0.247 ml, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv 40 gm silica gel column and the product was eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[NH3:14]>>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:14][CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Bromo-2-bromomethyl-benzoic acid methyl ester (0.5 g, 16.2 mmol) is treated with methanolic ammonia (10 mL, 7 N NH3 in MeOH) for 5 minutes at 90° C. After cooling to room temperature a precipitate is formed, collected by filtration and washed with a small amount of methanol to afford the title compound as a colourless solid (224 mg, 65%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 4.41 (2H, s), 7.64 (1H, d), 7.70 (1H, d), 7.87 (1H, s), 8.67 (1H, br s). LCMS: Rt 2.49 min, (99.6%), m/z (APCI) 212 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([CH2:17][OH:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])([CH2:17][O:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][O:7]1
Reactant: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
100 mg (0.369 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 4.0 mL of pyridine and cooled to 0° C., 77.3 mg (0.406 mmol equivalents) of p-toluenesulfonyl chloride was then added thereto, and the mixture was stirred at room temperature (25° C.) for 1 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 115 mg (0.270 mmol equivalents) of 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[S:1]([Cl:14])(=[O:3])=[O:2])#[N:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: N#Cc1ccccc1S(=O)(=O)Cl

Procedure:
heating saccharin and phosphorus pentachloride under conditions and for a time sufficient to provide 2-cyanobenzenesulfonyl chloride; and
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene (5.0 g, 33.7 mmol), N-bromosuccinimide (5.7 g, 32.0 mmol) and dibenzoylperoxide (0.25 g, 1.01 mmol) in tetrachloromethane was heated to reflux for 2 hours. It was cooled to room temperature and left for 16 hours. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane (1:10) as eluent, to give 6.37 g (83%) of 5-bromomethylbenzo[b]thiophene.
Reaction SMILES: [OH2:1].C([O:6]C([NH:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:20][CH2:19]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12])=O)(C)(C)C.Cl.[OH-].[Na+]>C(O)C>[OH2:6].[OH2:1].[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:19][CH2:20]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](N)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Charge water (32 mL, 8 volumes) and (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (3.99 g, 10.4 mmol) to a reactor followed by concentrated HCl (1.80 mL, 2.0 equivalents) and then heat the reaction to 45-55° C. until the reaction complete (monitor by HPLC). Cool the reaction mixture to 20-30° C. and adjust the pH to approximately 3.6 with 5 N NaOH. Add absolute ethanol (15 mL, 3.75 volumes) over at least 30 minutes between 20-30° C. to the resulting slurry. Allow the resulting slurry to granulate between 20-30° C. for at least 12 hours. Cool the mixture between −5-5° C. and allow it to granulate for at least 60 minutes. Filter the resulting solids and wash the cake with 30% absolute ethanol in water (2×9 mL, 2.25 volumes). Dry the solids under reduced pressure at 35° C. for at least 12 hours, and then allow the resulting solids to stay on the balance until no additional weight change for at least 2 hours to provide the title compound as a white solid (2.71 g, 8.51 mmol, 81.6%). 1H NMR (D2O, 400 MHz): δ 3.90 (q, J=7.2, 1H), 2.56 (dd, J=6.5, 2.9, 1H), 1.74-1.66 (m, 2H), 1.62-1.54 (m, 2H), 1.39 (d, J=7.1, 3H), 0.61-0.56 (m, 1H), 0.55-0.49 (m, 1H), 0.40-0.30 (m, 2H).