Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(Br)cc1F
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (7.6 g, 32.8 mmol) dissolved in anhydrous CH2Cl2 (300 mL) at 25° C. was added triethylsilane (7.8 mL, 49.1 mmol), followed by trifluoroacetic acid (25 mL, 328 mmol). The resulting solution was stirred at that temperature for 45 min. The solvent was removed in vacuo and the residue was purified by flash column chromatography (0–10% EtOAc in hexanes) to give the desired product (5.7 g, 80% yield).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7](C)[CH:6]=1>C(OCC)C>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][CH:6]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNc1ccc(Br)cc1
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-methylaniline (Aldrich Chemical Company) (19.15 g, 103.4 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere. The reaction was filtered, and the filtrate was concentrated in vacuo at room temperature to give 4-bromophenylcyanamide (8.5 g, 92%) as an off white solid. HRMS: calcd for C8H7BrN2, 209.97926; found (EI, M+), 209.9788.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH:22]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][CH2:6]1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCCC1C1CCNCC1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(C2CCCN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of tert-butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxylate (400 mg, 1.57 mmol) in dry DMF (2.0 mL) at 0° C., was added NaH (132 mg, 3.30 mmol, 60% in mineral oil) in small portions. The reaction mixture was then warmed to room temperature with stirring for another 1 h. 2-iodopropane (2.0 mL) was added. The resulting mixture was stirred at room temperature for 24 h and then poured into the ice-water (20 mL). The resultant mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel chromatography using 5-10% MeOH in DCM as eluant to afford the desired product (302 mg, 65% yield). LCMS m/z [M+H]+ 297.2.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[NH2:16][NH2:17].[Cl-].[NH4+]>>[NH2:16][N:17]1[CH2:13][CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(N)CC1

Procedure:
Under an inert atmosphere at ambient temperature, 15.3 g of the product of Step A and 80 ml of hydrazine hydrate were mixed together and then 150 ml of a saturated aqueous solution of ammonium chloride were added. Extraction was done with methylene chloride and the organic phase was washed with an aqueous solution of ammonium chloride, dried, and the solvent was eliminated under reduced pressure. After chromatography on silica (eluent:methylene chloride - methanol, 100/7) 5 g of the expected product were obtained.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:13]([CH3:45])([CH3:44])[C:14]([N:16]([CH3:43])[C:17]2[C:18]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29]OS(C)(=O)=O)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:48][S-:49].[Na+].[OH-].[Na+]>CN(C=O)C>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:45])([CH3:44])[C:14]([N:16]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29][S:49][CH3:48])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH3:43])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:8]=1
Reactant: C[S-]
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(COS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSCC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 0.29 g (0.42 mmol) methanesulfonic acid 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl ester and 44 mg (0.63 mmol) sodium methanethiolate in 8 ml DMF was heated at 80° C. for 30 min. After cooling to room temperature the reaction mixture was treated with a 1 N aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.25 g (92%) of the title compound as a white solid.
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[CH2:26][N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:8][C:7]=1[F:34]>C(O)C>[ClH:5].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH2:26][N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:8][C:7]=1[F:34]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2ccccc2=O)C1
Agent: Cl
Solvent: CCO
Product: O=c1ccccn1C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 199.3 %

Procedure:
14 N Hydrogen chloride-ethanol solution (1 mL, 14.00 mmol) was added to a solution (3 mL) of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-[(2-oxopyridin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (267 mg, 0.61 mmol) in ethanol, and the mixture was stirred at room temperature for 3 hr. The residue was concentrated, diethyl ether was added, and the mixture was stirred for a while. The insoluble material was collected by filtration to give the title compound (227 mg, 0.608 mmol, 100%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (40 mg, 0.095 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30 mg, 0.14 mmol), and potassium carbonate (39 mg, 0.28 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.5 mL) was degassed and refilled with argon (3×) prior to addition of (1,1′-bis(diphenylphosphino)-ferrocene) palladium dichloride (7.0 mg, 0.0095 mmol). The reaction mixture was degassed and refilled with argon (2×) and stirred at 100° C. for 30 min in a CEM microwave. LC-MS showed completion of the reaction. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by mass-directed purification to give the title compound as a brown oil (15.9 mg). 1H NMR (CDCl3, 400 MHz): δ=1.91 (d, J=6.8 Hz, 3H), 4.00 (s, 3H), 5.93 (br s, 2H), 6.65 (q, J=6.8 Hz, 1H), 7.09 (dd, J=9.1, 7.8 Hz, 1H), 7.31 (dd, J=9.1, 4.8 Hz, 1H), 7.58 (s, 1H), 7.64 (s, 1H), 7.71 (s, 1H), 8.03 (s, 1H). MS (ES+): 421.00/423.02 [MH+].
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8](=[O:12])[C:9](Cl)=[O:10])[CH3:6].[CH:13]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:12])[C:9]([C:20]1[CH:21]=[CH:22][C:17]([S:16][CH:13]([CH3:15])[CH3:14])=[CH:18][CH:19]=1)=[O:10])[CH3:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)Sc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
In a round bottom flask was placed methylene chloride (70 mL) and aluminum trichloride (6.09 g, 45.65 mmol) and it was cooled to 0° C. in an ice bath. To this was then added dropwise chloro-oxo-acetic acid ethyl ester (3.98 mL, 35.79 mmol) keeping the temperature of the solution below 5° C. and it was then stirred for 30 min at 0° C. After this time a solution of isopropylsulfanyl-benzene (5.00 g, 32.84 mmol) in methylene chloride (5 mL) was added dropwise while keeping the temperature of the solution below 5° C. The ice bath was then removed and the reaction allowed to warm up to 25° C. and stirred for 3 h. The reaction was then cooled back down to 0° C. in an ice bath and added dropwise ice water (20 mL) keeping the temperature of the solution below 20° C. It was then stirred for 15 min and then transferred to a separatory funnel and separated. The organic phase was then washed with water (2×25 mL), saturated aqueous sodium bicarbonate solution (2×25 mL) and water (25 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford (4-isopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (5.85 g, 71%) as a yellow oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.B(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.[Cl:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:29][C:30]1[N:35]=[C:34]([C:9]2[S:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1cccc2ccsc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: Clc1nccc(-c2cc3cccc(Cl)c3s2)n1
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
A solution of 7-chlorobenzo[b]thiophene (10.0 g, 59.3 mmol) in THF (100 mL) is cooled to −70° C. and triisopropyl borate (12.3 g, 65.2 mmol) is added. n-Butyl lithium (n-BuLi) (40.8 mL, 40.8 mmol, 1.6 M in hexane) is added dropwise via syringe over 40 minutes. After stirring 10 minutes at −75° C., the cold bath is removed and the mixture is allowed to warm to room temperature over 30 minutes. After 3 hours, to the mixture is added 2,4-dichloropyrimidine (8.83 g, 59.3 mmol), 2M Na2CO3 (60 mL, 120 mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.64 g, 2.96 mmol) and palladium acetate (666 mg, 2.96 mmol) and the mixture is heated to reflux for 18 hours. The cooled mixture is concentrated under reduced pressure, extracted from water with 10% MeOH/CHCl3 (2×200 mL) and concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel eluting with dichloromethane in hexanes 0-100%, to provide the title compound as a light yellow solid (6.95 g, 42% yield).
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9](=[O:13])(=[O:12])[CH2:10][CH2:11][N:6]2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[O:21]1[CH2:26][CH2:25][O:24][C:23]2[CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=[CH:30][C:22]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]=[S:9]1(=[O:13])[CH2:10][CH2:11][N:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:33][C:31]([C:28]3[CH:29]=[CH:30][C:22]4[O:21][CH2:26][CH2:25][O:24][C:23]=4[CH:27]=3)=[O:32])[C:7]2=[N:8]1
Reactant: NC(=O)c1ccc2c(c1)OCCO2
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1=CC=CN2CCS(=O)(=O)N=C12)c1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 5 h
Yield: 18.5 %

Procedure:
To a solution of 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in DMF (1 mL) were added toluene (2 mL), 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (74.9 mg), cesium carbonate (248 mg), 9,9-dimethyl-4,5-(diphenylphosphino)xanthene (33.0 mg) and tris(dibenzylideneacetone)dipalladium(0) (34.8 mg) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 100° C. for 5 hr, and purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from (methanol/diisopropyl ether) to give the title compound (25.4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([OH:21])(=[O:20])[C:14]([CH2:16][C:17](O)=[O:18])=[CH2:15]>O>[O:18]=[C:17]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)[CH2:15][CH:14]([C:13]([OH:21])=[O:20])[CH2:16]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: O
Product: O=C1COc2ccc(N3CC(C(=O)O)CC3=O)cc2N1
Yield: 95.6 %

Procedure:
A mixture of 6-amino-2H-1,4-benzoxazin-3(4H)-one (4.93 g, 30.0 mmol), itaconic acid (4.06 g, 31.2 mmol) and water (80 ml) was heated under reflux overnight. The reaction solution was cooled, and the insoluble material was collected by filtration and washed with water and diethyl ether. The filtrate was dried at 50° C. under reduced pressure to yield 7.92 g (96%) of the title compound in the form of a brownish solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN(CC)CC.[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:35])[N:24]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]3=[N:26]2)=[CH:21][CH:20]=1>O=S(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:35])[N:24]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]4=[N:26]3)=[CH:21][CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc2c(=O)n3c(nc2c1)CCCCCC3
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc2c(=O)n3c(nc2c1)CCCCCC3)c1ccc(F)cc1
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A solution of 4-fluorobenzoic acid (100 mg, 0.71 mmol) in SOCl2 (2 mL) was stirred at reflux for 1 h. Excess SOCl2 was removed and the residue was dissolved in THF (10 mL). The solution was added to a mixture of Et3N (1 mL) and 3-amino-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one (22 mg, 0.09 mmol). After stirring for 1 h, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product (2 mg). MS (ESI): 366 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.70 Hz, 1H), 7.96-7.91 (m, 4H), 7.75-7.71 (dd, J=8.72 Hz, 2.12 Hz, 1H), 7.24-7.19 (t, J=8.60 Hz, 2H), 4.34 (broad, 2H), 3.06-3.02 (m, 2H), 1.99-1.87 (m, 4H), 1.68-1.66 (m, 2H), 1.47-1.46 (d, J=4.32 Hz, 2H). mGluR5 PAM EC50: +.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)=O.[C:16]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>>[O:23]=[C:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: O=C1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(C=C2CCCCCC2=O)cc1
Yield: 39.7 %

Procedure:
To a mixture of 5.15 g of ethyl 2-(p-formylphenyl)propionate and 4.2 g of cycloheptanone were added dropwise at room temperature 30 ml of an aqueous solution of 2.6 g of sodium hydroxide and the resulting mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was extracted twice with ethyl acetate, an aqueous layer was made acidic with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off to leave an oily substance, which was then subjected to a silica gel column chromatography and elution was effected with benzene-ethyl acetate 5:1 to yield an yellow oily substance. The substance was distilled under reduced pressure to give 2.7 g of the desired product as a pale yellow oily substance having a boiling point of 210°-215° C./0.3 mmHg (bath temp.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH3:34]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:33][CH3:34])[CH2:22]3)=[O:20])[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCCNC2)CC1
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-(piperidin-3-ylcarbonyl)piperazine-1-carboxamide hydrochloride (200 mg) in dimethylformamide (10 mL) was added potassium carbonate (138 mg) and ethyl bromide (0.035 mL). The reaction mixture was stirred overnight. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (94 mg, 48%).
Reaction SMILES: F[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9].[C:19]([Si](C)(C)C)#[N:20]>C[N+]([O-])=O>[C:19]([C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9])#[N:20]
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(F)c1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#N
Solvent: C[N+](=O)[O-]
Product: N#Cc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Yield: 82 %

Procedure:
A solution of 5-fluoro-1,3-diamino-2,4,6-trinitrobenzene (F-DATB) (5.22 g, 20 mmol) and cyanotrimethylsilane (4.96 g, 50 mmol) in CH3NO2 (100 ml) was refluxed for two hours and then evaporated under vacuum to leave a solid residue. Recrystallization from acetonitrile (100 ml) gave 5-cyano-1,3-diamino-2,4,6-trinitrobenzene (4.4 g, 82%) as orange-brown crystals: mp 212°-217° C. dec. An additional recrystallization gave the analytical sample: mp 220°-221° C.; mass spectrum (CI, CH4) m/z 269 (M+1, 100).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH2:27][C:28](O)=[O:29]>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Product: Cc1ccc(C)c(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1

Procedure:
The product of Example 1B and 2-(2,5-dimethylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.02-8.04 (m, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.99 (d, J=7.7 Hz, 1H), 3.81-3.84 (m, 4H), 3.62 (s, 2H), 3.05-3.11 (m, 4H), 2.29 (s, 3H), 2.26 (s, 3H); MS (ESI+) M/Z 393 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)CCN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCNc1cc(Br)ccc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.5 mol), methyl 3-aminopropanoate hydrochloride (6.4 g, 45.5 mol) and K2CO3 (19 g, 136.5 mol) in THF (250 mL) was heated at 100° C. for 4 hrs. The mixture was extracted with ethyl acetate (100 mL), washed with brine (150 mL), dried and concentrated to give the residue, which was purified by CombiFlash (PE:EA=2:1) to give methyl 3-((5-bromo-2-nitrophenyl)amino)propanoate (12 g, yield 88%). 1H NMR (300 MHz, CDCl3) δ 2.70-2.75 (t, J=6.6 Hz, 2H), 3.58-3.65 (m, 2H), 3.74 (s, 3H), 6.76-6.80 (m, 1H), 7.02-7.03 (d, J=2.1 Hz, 1H), 8.01-8.04 (d, J=9.0 Hz, 2H), 8.20-8.22 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12])=[CH:4][CH:3]=1.[OH-:13].[K+].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12])=[CH:6][CH:7]=1.[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])(=[O:22])=[O:13])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [OH-]
Agent: OC/C=C\Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Dissolve 7.3 g (0.04 mole) of (Z)-4-(4-chlorophenyl)but-2-en-ol in 100 ml of anhydrous ether. Add 3.2 g (0.05 mole) of powdered 86% KOH. Stir and cool the mixture in ice bath while adding a solution of 8.4 g (0.044 mole) of p-toluenesulfonyl chloride in 50 ml of anhydrous ether. Slowly warm the reaction mixture to room temperature and stir at room temperature for 16 hours. Remove the solid by filtration. Wash the filtrate with saturated aqueous sodium bicarbonate, H2O. Dry, evaporate, and recrystallize from cyclohexane to yield the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][N:20]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:22][CH3:23])[CH2:3]1.CCN(CC)CC.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][N:20]([CH2:19][C@@H:4]2[CH2:3][C@H:2]([NH:1][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:7][CH2:6][C@H:5]2[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22][CH3:23])=[CH:32][CH:31]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](N)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](NC(=O)C(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of benzyl(1R,2S,4R)-4-amino-2-(((3-(4-fluorophenyl)propyl)(propyl)-amino)methyl)-cyclohexylcarbamate (1.1 g, 2.4 mmol) and Et3N (0.3 g, 3 mmol) in CH2Cl2 (50 ml) was cooled in an ice bath and treated drop-wise with pivaloyl chloride (0.32 g, 2.6 mmol). The solution is stirred for 30 minutes and then washed successively with saturated sodium bicarbonate, 0.5 N NaOH, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. This chromatographed on silica gel to (0.3:2.7:97 NH4OH/MeOH/CH2Cl2) to give 0.85 g of white solid. MS: (M+H)+=540.38.