Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:36])[CH3:35].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([N:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:34](=[O:36])[CH3:35])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: OC(c1cccc(C(F)(F)F)c1)C(NC1CCCC1)c1ccnc(F)c1
Reactant: CC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N(C1CCCC1)C(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2-(2-fluoro-pyridin-4-yl)-2-cyclopentylamino-1-(3-trifluoromethyl-phenyl)-ethanol (6) (1.0 g, 2.7 mmol) and diisopropylamine (0.95 mL, 5.4 mmol) in methylene chloride (10 mL) was placed under argon and cooled to −10° C. Acetyl chloride (0.21 mL, 3.0 mmol) in methylene chloride (1.0 mL) was slowly added to the reaction mixture. After 2 hrs, ethyl acetate was added (200 mL) followed by aqueous citric acid (50 mL of a 10% solution). The organic layer was then washed with aqueous sodium bicarbonate (50 mL of a sat. solution) and water (50 mL), dried (sodium sulfate), filtered, and concentrated. The crude residue was passed though a pad a silica gel (50% ethyl acetate in hexane) to remove minor impurities, and taken to the next step. Colorless oil (95%): 1H NMR (300 MHz, CDCl3) d 8.54 (d, J=5.1 Hz, 1 H, Pyr), 7.49 (m, 4 H, Ar), 6.81 (d, J=5.0 Hz, 1 H, Pyr), 6.72 (s, 1 H, Pyr), 5.63 (s, 1 H, OH), 5.46 (s, 1 H, PhCHOH), 4.34 (s, 1 H, CHCHN), 4.16 (m, 1 H, CH2CHCH2), 2.32 (s, 3 H, COCH3), 1.90 (m, 1 H, CH2), 1.60 (m, 7 H, CH2).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17](N(CC)CC)C.[N+]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)([O-])=O.CC1CCC(N)CC1>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:34]([NH:33][CH:30]2[CH2:31][CH2:32][CH:27]([CH3:17])[CH2:28][CH2:29]2)=[O:35])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1nn(C[C@H]2CCCO2)c(=N)s1
Reactant: CCN(CC)CC
Agent: CC1CCC(N)CC1
Solvent: C1CCOC1
Product: CC1CCC(NC(=O)/N=c2\sc(C(C)(C)C)nn2C[C@H]2CCCO2)CC1
Temperature: 50 °C

Procedure:
To a solution of Example 67C (33 mg, 0.14 mmol) in tetrahydrofuran (0.3 mL), was added triethylamine (28 mg, 0.27 mmol). After shaking a solution of p-nitrophenyl carbamoyl chloride (28 mg, 0.14 mmol) was added in tetrahydrofuran (0.3 mL). A precipitate was formed and after shaking for 30 minutes a solution of 4-methylcyclohexanamine (21 mg, 0.19 mmol) in tetrahydrofuran (0.6 mL) was added. The mixture was heated to 50° C. overnight. The mixture was cooled to ambient temperature, and filtered through Si-Carbonate cartridge, washed with methanol checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/Methanol and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to afford the title compound. 1H NMR (500 MHz, DMSO/D2O) δ ppm 0.83-0.93 (m, 3H), 0.93-1.01 (m, 1H), 1.15-1.25 (m, 1H), 1.26-1.35 (m, 10H), 1.41-1.99 (m, 10H), 3.59-3.67 (m, 2H), 3.75-3.80 (m, 1H), 3.96-4.08 (m, 1H), 4.19-4.32 (m, 2H); MS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[O-]CC.[Na+].[N+:14]([CH3:17])([O-:16])=[O:15].Cl.C(O)(C)C>C1(C)C=CC=CC=1.C(O)C>[N+:14]([CH2:17][C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CN2CCC1CC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC1(O)CN2CCC1CC2

Procedure:
Quinuclidin-3-one (125 g., 1 mole) was dried by azeotropic distillation (40% w/w in toluene) and placed in a 3 l. flask equipped with a mechanical stirrer, 1 l. methanolic sodium ethoxide was added and the clear solution was stirred at 15°-20° C. Nitromethane, 61 g. (1.0 mole), dissolved in 500 ml. absolute ethanol was then added over 0.5 hour while keeping the temperature below 20° C. The solution was acidified to pH=1 using HCl-isopropanol, filtered and dried to yield 160 g. crude product which was used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl.CCOC(C)=O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:7][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.617 mmol) and N,N-diisopropylethylamine (159.5 mg, 215 μL, 1.234 mmol) in 5 mL CH2Cl2 was treated with phenyl chloroformate (106 mg, 85 μL, 0.68 mmol) and left to stir for 3 h at rt. Solution was diluted with EtOAc and washed twice with 1 N HCl and 1 time with brine. The organic layer was dried (Na2SO4) and concentrated to provide a white solid. Tituration with 10% EtOAc in hexanes gave 120 mg (69%, 0.42 mmol) of the above compound as a white solid. 1H-NMR (DMSO-d6) δ 11.26 (s, 1H), 8.70 (s, 1H), 8.22 to 8.16 (m, 1H), 7.99 (d, J=8 Hz, 1H), 7.45 to 7.40 (m, 2H), 7.30 to 7.20 (m, 3 H)
Reaction SMILES: C(OC(=O)[NH:7][CH:8](C)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:41])[NH:17][CH:18]([CH:30]1[CH:37]2[CH2:38][CH:33]3[CH2:34][C:35]([OH:40])([CH2:39][CH:31]1[CH2:32]3)[CH2:36]2)[C:19]([N:21]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH:22]1[C:27](=O)[NH2:28])=[O:20])=[O:10])(C)(C)C.N1C=C[CH:47]=[CH:46][CH:45]=1.[F:50][C:51]([F:62])([F:61])[C:52]([O:54]C(=O)C(F)(F)F)=[O:53]>C1COCC1>[F:50][C:51]([F:62])([F:61])[C:52]([OH:54])=[O:53].[C:27]([CH:22]1[N:21]([C:19](=[O:20])[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH2:7])[CH:46]([CH3:47])[CH3:45])=[O:41])[CH:30]2[CH:31]3[CH2:32][CH:33]4[CH2:34][C:35]([OH:40])([CH2:36][CH:37]2[CH2:38]4)[CH2:39]3)[CH2:26][CH:25]2[CH:23]1[CH2:24]2)#[N:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC(C(=O)N1CC2CC2C1C(N)=O)C1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(N)C(=O)N1CCCC1C(=O)NC(C(=O)N1CC2CC2C1C#N)C1C2CC3CC1CC(O)(C3)C2
Product: O=C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
Analogously to example 23 the solution of 1.7 gm of (2-{2-[2-(2-Carbamoyl-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(5-hydroxy-adamantan-2-yl)-2-oxo-ethylcarbamoyl]-pyrrolidin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester in THF was added into the mixture of pyridine (1.0 ml) and Trifluoro acetic anhydride (0.95 ml). The reaction mixture was stirred at room temperature. THF was evaporated and residue was taken into MeOH and 10 ml 10% K2CO3 solution was added. MeOH was evaporated and aq. layer was extracted with EtoAC. The combined EtoAC layers were washed with 1N HCl and aq. NaHCO3, dried over sodium sulphate and concentrated in vacuum to give crude product. The crude product was purified by column chromatography to get pure Trifluoro acetic acid salt of 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [2-(2-cyano-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(5-hydroxy-adamantan-2-yl)-2-oxo-ethyl]-amide of formula 37. (Yield: 0.7 gm)
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH3:17])(=O)C.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.N1CCCC1.O>C1(C)C=CC=CC=1>[CH2:11]([C:10]1[CH:9]=[C:8]2[C:7]([C:14](=[O:16])[CH2:15][C:18]3([O:13]2)[CH2:21][CH2:20][CH2:19]3)=[C:6]([CH3:17])[C:5]=1[OH:4])[CH3:12]
Reactant: O=C1CCC1
Reactant: CCc1cc(O)c(C(C)=O)c(C)c1OC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: O
Product: CCc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Yield: 15.2 %

Procedure:
A mixture of 3-acetyl-6-ethyl4-hydroxy-2-methylphenyl acetate (5.18 g), cyclobutanone (4.5 g) and pyrrolidine (1.5 mL) in toluene (50 mL) was stirred at refluxing temperature with a Dean Stark. After 8 hours it was poured into water and the toluene was separated, dried, and evaporated. The residue was dissolved in MeOH (50 mL) with LiOH (2 g), stirred at room temperature for 3 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate was washed, dried, and evaporated. The residue was purified by silica gel column eluting with 15% ethyl acetate in hexane, giving 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one as a light brown oil (0.82 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:14]([CH3:25])[NH:15][CH:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:10]2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(#N)C>[C:33]([N:15]1[CH:14]([CH3:25])[CH:11]2[CH:10]([C:9](=[O:26])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]2=[O:13])[CH:16]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC1NC(c2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C12
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N1C(C)C2C(=O)N(Cc3ccccc3)C(=O)C2C1c1ccc(C#N)cc1
Reaction time: 1.5 h
Yield: 83 %

Procedure:
4.B)c) A solution of 3.46 g (10 mmol) of (1RS,3SR,3aRS,6aSR)-4-(5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile in acetonitrile (10 ml) was treated with pyridine (20 mmol). Acetic anhydride (20 mmol) was slowly added dropwise while cooling with ice. The cooling was removed and the reaction mixture was stirred for a further 1.5 hours. Thereafter, the reaction mixture was poured into saturated NaCl solution and extracted with dichloromethane. The solvent was removed and the residue was separated chromatographically (hexane:ethyl acetate=1:1). (1RS,3SR,3aRS,6aSR)-4-(2-Acetyl-5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (83%) was isolated as a colourless solid. M.p.: 107°-109° C. EI-MS: 387 ([M]+, 72); 344 (35); 320 (28); 254 (18); 183 (16); 169 (17); 158 (53); 91 (86); 43 (100).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[I-].[K+].C(N(CC)CC)C.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[CH3:25]>C1(C)C=CC=CC=1.O>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])=[CH:20][C:19]=1[CH3:25]
Reactant: Cc1cc(N)ccc1Br
Reactant: CN(C)CCCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(NCCN(C)C)ccc1Br
Temperature: 110 °C
Reaction time: 17 h
Yield: 18.1 %

Procedure:
2-Chloro-N,N-dimethylethylamine hydrochloride (372 mg, 2.58 mmol), potassium iodide (428 mg, 2.58 mmol) and triethylamine (0.719 ml, 5.16 mmol) were added to a solution of 4-bromo-3-methylaniline (400 mg, 2.15 mmol) in toluene (5.0 ml), and the mixture was heated with stirring at 110° C. for 17 hours. The reaction mixture was cooled and water was then added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give N′-(4-bromo-3-methyl-phenyl)-N,N-dimethyl-ethane-1,2-diamine (100 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6](Br)[CH:5]=1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:18][CH:19]=1>C1(C)C=CC=CC=1.CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]=2)[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cn2)c1

Procedure:
A mixture of 3-bromo-5-hydroxy-benzoic acid methyl ester (1.47 g, 6.36 mmol), 5-methyl-2-(tributylstannyl)pyridine (3.0 g, 7.85 mmol), tetrakis(triphenylphosphine)-palladium(0) (300 mg, 0.26 mmol) in toluene (20 mL) and DMF (2 mL) was subjected to microwave irradiation at 110° C. for 1 hour. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)=[CH2:14].[CH2:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](F)=[O:34])=[CH:31][CH:30]=1)[CH2:27][CH3:28]>C1COCC1>[CH2:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:20]2[C:19](=[O:25])[C:18]3[C:23](=[CH:24][C:15]([CH:13]=[CH2:14])=[CH:16][CH:17]=3)[O:22][CH2:21]2)=[O:34])=[CH:36][CH:37]=1)[CH2:27][CH3:28]
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Reactant: CCCc1ccc(C(=O)F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)OCC(C(=O)c1ccc(CCC)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a flame-dried 10 mL round-bottom flask under nitrogen charged with butyllithium (2.5 M in hexanes) (0.875 mL, 2.19 mmol) in THF (1 mL) at 0° C. was added diisopropylamine (0.312 mL, 2.19 mmol) dropwise. The solution was stirred at 0° C. for 20 min. The solution was then cooled to −78° C., and 7-vinylchroman-4-one (Preparation 2D, 1.79 M in THF) (1.02 mL, 1.82 mmol) was added dropwise via syringe. The mixture was stirred for 20 min. at −78° C. 4-propylbenzoyl fluoride (0.303 g, 1.823 mmol) in 1 mL of THF was then added dropwise via syringe, and the reaction mixture was stirred at −78° C. for 60 min. and then warmed to room temperature. The reaction was quenched with 1N aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The yellow residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12%) to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.179 g, 0.559 mmol, 31% yield). The compound was triturated with methanol with sonication, filtered, washed with methanol, and dried to give 3-(4-propylbenzoyl)-7-vinylchroman-4-one (0.125 g, 0.390 mmol, 21% yield) as a yellow solid. LC/MS M+1=321.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (t, 3H), 1.58-1.68 (m, J=7.42, 7.42, 7.42, 7.42, 7.21 Hz, 2H), 2.65 (t, J=7.63 Hz, 2H) 4.71-4.77 (m, 1H), 4.78-4.83 (m, 1H), 5.20 (dd, J=9.16, 4.99 Hz, 1H), 5.47 (d, J=11.10 Hz, 1H), 6.05 (d, J=17.76 Hz, 1H), 6.73-6.82 (m, 1H), 7.17 (s, 1H) 7.24 (dd, J=8.18, 1.25 Hz, 1H), 7.38 (d, J=8.32 Hz, 2H), 7.73 (d, J=8.05 Hz, 1H), and 7.96 (d, J=8.32 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccc5ccccc45)c2)c1=O)CCCC3
Yield: 29 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 1-naphthalenesulfonyl chloride (33 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 14 mg, yield 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1N(C)C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (127 mg, 0.50 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of ((3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-yl)-methyl-amine (the preparation of which is described herein above) (135 mg, 0.48 mmol) and ethyl-diisopropyl-amine (0.12 ml, 0.72 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.18 g (75%) of the title product as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:12]#[N:13])=[C:6]([CH2:19][CH3:20])[N:5]([CH2:21][CH2:22]O)[N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:47]C(=O)C2=CC=CC=C12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>O1CCCC1>[NH3:4].[NH2:47][CH2:22][CH2:21][N:5]1[C:6]([CH2:19][CH3:20])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:12]#[N:13])[C:3]([CH2:1][CH3:2])=[N:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(C#N)cc(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn(CCN)c(CC)c1Oc1cc(C#N)cc(OC)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 152.2 %

Procedure:
The alcohol from Example 202 (87 mg, 0.28 mmol), triphenylphosphine (220 mg, 0.84 mmol) and phthalimide (124 mg, 0.84 mmol) were dissolved in tetrahydrofuran (5 ml) at 0° C. under nitrogen and diisopropylazodicarboxylate (165 μl, 0.84 mmol) dissolved in tetrahydrofuran (1 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (6 ml) and hydrazine hydrate (68 μl, 1.40 mmol) was added. The slurry was stirred for 48 hours at room temperature under nitrogen, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through an SCX column eluting with methanol to remove impurities, then 2M ammonia in methanol solution to elute the product. The product was then purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5) then dichloromethane:methanol:0.88 ammonia (90:10:1, by volume) to provide the title compound (67 mg) as an oil.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=O)[CH2:17]CCCCCCC>>[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:16][CH3:17]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C1COCCN1C(=O)c1ccccc1
Product: CCCCCCCCC(=O)N1CCOCC1=O

Procedure:
Synthesized as for N-benzoyl-3-oxomorpholine (Example I) using nonanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].Cl[C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=2)[N:43]=[N:42][CH:41]=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:31])([CH3:30])[CH3:32])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[N:43]=[N:42][CH:41]=2)[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1CC1(NC(=O)C1CC(O)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Reactant: COc1ccc2c(Cl)cnnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1CC1(NC(=O)C1CC(Oc2cnnc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
To 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (210 mmg, 0.46 mmol) at 0° C. (external temperature, ice bath) was added KOt-Bu (1 m in THF, 2.3 mL, 2.3 mmol, 5 equiv.) and 4-chloro-7-methoxy-cinnoline (95 mg, 0.49 mmol, 1.06 equiv.) in THF (3 mL). The reaction was stirred at 0° C. for 2.5 h and diluted with EtOAc. The solution was washed with aqueous HCl (1M), resulting a precipitation of the crude product. The organic layer was dried over Na2SO4 and combined with the precipitate. The crude product was purified by column chromatography (0→15% MeOH/CH2Cl2) to provide 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-cinnolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (161 mg, 57%).
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([NH:19][S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH3:18]>>[CH2:16]([NH:19][S:20]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:22])=[O:21])[CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCN
Reactant: CCCNS(=O)(=O)Cl
Product: CCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 55 %

Procedure:
The title compound was prepared following the method described Example 6. The starting reactants are 0.10 g (0.5 mmol) of N-tetradecylamine and 0.076 g (0.5 mmol) of N-propylsulfamoyl chloride. 0.092 g of a white solid are obtained. Yield 55%; m.p. 105-107° C.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(#N)C.[O:16]=[O+][O-].Cl.[NH2:20][C:21]12[CH:28]3[C:23]4(N)[CH:24]5[C:27]3(N)[CH:26]1[C:25]5(N)[CH:22]24.[OH2:32]>>[N+:20]([C:21]12[CH:28]3[CH:23]4[CH:24]5[CH:27]3[CH:26]1[CH:25]5[CH:22]24)([O-:16])=[O:32]
Reactant: O=[O+][O-]
Reactant: O
Reactant: NC12C3C4(N)C1C1(N)C2C3(N)C41
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])C12C3C4C5C3C1C5C42
Reaction time: 2 h

Procedure:
Potassium monopersulfate (4.0 g), water (50 ml), and acetonitrile, (15 ml), were mixed together to form a solution. Then, ozone was added until the solution was saturated. A second solution of 1,3,5,7-tetra-aminocubane hydrochloride in water, 200 mg in 15 ml, was slowly added to the first solution while ozone was slowly bubbled through the first solution. The reaction temperature was 0 degrees C. The addition of ozone was stopped after 2 hours; the reaction mixture was stirred overnight and 10 ml of acetone were added.