Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([F:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([F:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-fluoro-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:19])[CH:17]=2)=[O:25]
Reactant: Cc1c(F)cncc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (161.4 mg; 0.6372 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (80.3 mg; 0.772 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (496.9 mg; 0.9149 mmol), N,N-diisopropylethylamine (0.30 mL; 1.7 mmol), 4-(dimethylamino)pyridine (0.06372 mmol) and N,N-dimethylformamide (5 mL; 64.4 mmol) was heated at 40° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 30-90% ethyl acetate in dichloromethane) followed by preparatory reverse-phase HPLC to yield 124 mg (57%) of the title compound. LCMS (ESI): RT (min)=8.33, M+H=340.2, method=G; 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.21 (s, 1H), 8.55 (d, J=4.5 Hz, 2H), 8.42 (s, 1H), 8.13 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.78 (dd, J=8.5, 1.6 Hz, 1H), 5.06-4.85 (m, 1H), 2.34-2.27 (m, 1H), 2.26 (d, J=1.9 Hz, 3H), 1.75-1.65 (m, 1H), 1.25-1.16 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.CON(C)[C:13](=[O:24])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:15])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Temperature: -20 °C
Yield: 65.5 %

Procedure:
To 11.0 g of 2-bromo-3,5-dichloropyridine in 5 ml of tetrahydrofuran, 36.4 ml of a 1.3 M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 15 minutes. Then, to the reaction mixture, 5.0 g of (S)—N-methoxy-N-methyl-2-(tert-butoxycarbonylamino)propionamide in 36 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of saturated aqueous ammonium chloride and 10 ml of water and extracted with ethyl acetate (40 ml×2), the resulting organic layers were combined, washed with water (40 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 10:0 to 3:7) to obtain 4.5 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]([C:19]([OH:21])=O)=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][CH:13]=1)=[O:21])[CH3:27]
Reactant: COc1cccc(C(=O)O)c1-c1ccccc1OC(C)C
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(OC)c1-c1ccccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111.3 %

Procedure:
Prepare a stirred solution of 2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid (1.432 g, 0.0050 mole) in methylene chloride (50 mL) at -50° C. and under argon. Warm to ambient temperature then add thionyl chloride (0.8415 g, 0.516 mL). Continue stirring for about 45 minutes, observing the color change to light brown. Cool to 0° C. and dropwise add diethylamine (6.00 mL, 4.242 g, 0.058) mole, keeping the temperature of the reaction below 26° C. Continue stirring for about 30 minutes once the addition is complete. Dilute to 150 mL with additional methylene chloride. Wash the methylene chloride layer with water, separate, and extract twice with 100 mL 5% sodium bicarbonate. Separate, wash again with brine , separate and dry over MgSO4. Filter through celite and condense on a rotary evaporator to a light brown, viscous liquid. Elute via chromatography with 30% ethyl acetate/70% hexane to give a clear viscous liquid (1.90 g). Concentrate under high vacuum to give a waxy solid of the title compound. (1.40 g, 82%).
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]\[CH2:18][N:19]2[CH:23]=[CH:22][CH:21]=[C:20]2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([CH3:7])[C:3]([O:5]C)=[O:4].CO.[OH-].[Li+]>C1COCC1.O>[CH3:7][C:2]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]\[CH2:18][N:19]2[CH:23]=[CH:22][CH:21]=[C:20]2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)OCc1ccc(/C=C\Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccn2C/C=C\c2ccc(COC(C)(C)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To the compound of Example 1-1 (410 mg, 0.95 mmol) in THF (4 ml) were added methanol (4 ml) and 1N aqueous lithium hydroxide solution (4 ml), followed by stirring for 8 hours at room temperature. The reaction mixture was diluted with water and washed with diethyl ether. To the aqueous layer was added 5% aqueous potassium hydrogen sulfate solution and the solution was adjusted around pH3 and extracted with ethyl acetate. The organic layer was washed with water, saturated brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (262 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19](CNC)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37].O.[CH3:39][N:40](C)[CH:41]=O>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:34][CH2:35][CH2:36][OH:37])=[CH:20][C:21]=3[CH2:39][NH:40][CH3:41])[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: CN(C)C=O
Reactant: CNCc1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
5.0 g (0,013 Mol) of trans-N-(4-chlorobenzoyl)-N-methyl-4-(4-methylaminomethylphenyl)cyclohexylamine, 2.1 g (0.0148 Mol) of potassium carbonate and 2.1 g (0.015 mol) of 3-bromo-1-propanol are stirred together in 30 ml of dimethylformamide at ambient temperature for 40 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. After washing with water and saturated saline solution the mixture is evaporated down and the residue is purified by column chromatography (aluminium oxide, ethyl acetate/methanol=70:1 to 40:1, v:v). 3.8 g (68% of theory) of the title compound are obtained, melting point 98°-100° C. 1H-NMR spectrum (200 MHz, CDCl3); signals at ppm: 1.35 (m, 1H) , 1.6-2.1 (m, 9H) , 2.2 (2s, 3H) , 2.35-2.55 (m, 1H), 2.6 (t,2H), 2.8-3.1 (m,3H), 3.45 (s,2H), 3.75 (t,2H), 3.6+4.6 (t+m, 1H), 7.0-7.5 (m,8H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH2:28][OH:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:32])[CH3:31])[S:24]2)[C@H:20]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH:28]=[O:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:32])[CH3:31])[S:24]2)[C@H:20]1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A solution of DMSO (14.6 g, 187 mmol) in dichloromethane (300 mL) was treated with oxalyl dichloride (17.7 g, 140 mmol) at −78° C. for 1 hour, then a solution of ((3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (10 g, 23 mmol) in dichloromethane (30 mL) was added slowly. The resulted solution was kept for 4 hours at −20° C., followed by the addition of triethylamine (28.3 g, 280 mmol) at −78° C. After additional 1 hour at −50° C., the reaction was quenched by water (300 mL) and extracted with dichloromethane (2×200 mL). The organic layers combined, washed with brine (3×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrates were concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 20% ethyl acetate in dichloromethane to give compound 95 as a yellow syrup (8.1 g, 80%). (ES, m/z): [M+H]+ 426.7; 1H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 7.28-7.39 (m, 10H), 6.27-6.34 (m, 1H), 4.41-4.84 (m, 6H), 4.10-4.17 (m, 1H), 3.86-3.94 (m, 1H), 3.02 (s, 6H).
Reaction SMILES: ClCCl.[I-].[C:5]([O:9][C:10]([N:12]([CH2:25][C@@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][N:28]([C:37]([N:39]2[CH:43]=[CH:42][N+](C)=[CH:40]2)=[O:38])[CH2:27]1)[C@@H:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.N1CC[CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54]C1>C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]([CH2:25][C@@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][N:28]([C:37]([N:39]2[CH2:43][CH2:42][CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54][CH2:40]2)=[O:38])[CH2:27]1)[C@@H:13]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][CH:24]=1)[CH3:14])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2cc[n+](C)c2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A 6.0 ml dichloromethane solution of 250 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}-3-methyl-1H-imidazol-3-ium iodide and 31 mg of triethylamine was mixed with 48 mg of ethyl 4-piperidine-carboxylate and stirred overnight at room temperature. The reaction solution was mixed with ethyl acetate and washed with water. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 106 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylate as a white amorphous substance.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B2OC3C=CC=CC=3O2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:32][CH:31]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1ccc(B2Oc3ccccc3O2)cc1
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Yield: 59 %

Procedure:
The title compound (82 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 332 mg of 2-(4-chloro-phenyl)-benzo[1,3,2]dioxaborole. MS (ESI): exact mass calculated for C16H20ClN3, 289.13. found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.44-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.81-2.76 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1N.[BH3-][C:18]#[N:19].[Na+]>CO>[CH2:1]([NH:16][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]1[NH:19][CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: [BH3-]C#N
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN[C@@H]2CCCC[C@H]2NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Benzaldehyde (12.72 g, 120 mmol) was added dropwise over a period of 2 minutes to a solution of (R,R)-cyclohexane-1,2-diamine (6.84 g, 60 mmol) in 100 mL of anhydrous MeOH at refluxing temperature. After stirring for 30 min, the solution was allowed to cool to room temperature and NaBH3CN (4.8 g, 126 mmol) was added in portions. After the vigorous effervescence subsided down, the mixture was brought to refluxing and stirred for 20 min. The reaction was quenched by water and extracted with dichloromethane. The organic phase was dried and concentrated to give 16.95 g of crude product (yield 96%) which was used in the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([Mg]Cl)[CH3:11].C1COCC1.B(F)(F)F.CCOCC>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([NH2:6])[CH2:11][CH2:10]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC[Mg]Cl
Reactant: N#Cc1cccc(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2cccc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-chlorobenzonitrile (1 g, 7.27 mmol) and titanium (IV) isopropoxide (2.34 mL, 8 mmol) in Et2O (35 mL) at −78° C. was added ethyl magnesium chloride in THF (5.71 mL, 15.99 mmol). The solution was stirred for 10 min at −78° C. then at 25° C. for 1 h. BF3.Et2O (1.82 mL, 14.54 mmol) was added and the solution was stirred for 1 h at 25° C. The reaction mixture was quenched with 1N HCl (22 mL) Et2O was added (100 mL). Then 10% aq. NaOH (70 mL) was added and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 5% CH3CN/H2O 2.5 min, 5-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound. MS (UPLC-MS): 170 [M+H]+, 168 [M−H]−; tR (HPLC conditions f): 1.22 min.
Reaction SMILES: C[CH:2]1[CH2:8][CH:7]2[CH:3]1[N:4]([C:13](=[O:15])[CH3:14])[C:5](=[O:12])[N:6]2[C:9](=[O:11])[CH3:10].CC1(C)CC2C1N([C:28](=[O:30])[CH3:29])C(=O)N2C(=O)C.C(C1CC2C1N(C(=O)C)C(=O)N2C(=[O:45])C)(C)(C)C.CC1(C)C(C)(C)C2C1N(C(=O)C)C(=O)N2C(=O)C.C=C1CC2C1N(C(=O)C)C(=O)N2C(=O)C.COC1CC2C1N(C(=O)C)C(=O)N2C(=O)C>>[C:28]([O:30][CH:2]1[CH2:8][CH:7]2[CH:3]1[N:4]([C:13](=[O:15])[CH3:14])[C:5](=[O:12])[N:6]2[C:9](=[O:11])[CH3:10])(=[O:45])[CH3:29]
Reactant: CC(=O)N1C(=O)N(C(C)=O)C2C1CC2(C)C
Reactant: CC(=O)N1C(=O)N(C(C)=O)C2C1CC2C(C)(C)C
Reactant: CC(=O)N1C(=O)N(C(C)=O)C2C(C)CC21
Agent: C=C1CC2C1N(C(C)=O)C(=O)N2C(C)=O
Agent: CC(=O)N1C(=O)N(C(C)=O)C2C1C(C)(C)C2(C)C
Agent: COC1CC2C1N(C(C)=O)C(=O)N2C(C)=O
Product: CC(=O)OC1CC2C1N(C(C)=O)C(=O)N2C(C)=O
Yield: 40 %

Procedure:
The following cycloadducts are accessible analogously: 6-methyl-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, boiling point0.25 111°-115° (77%); 6,6-dimethyl-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, boiling point0.4 103°-104° (67%); 6-tert.-butyl-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, melting point 85°-86° (54%); 6,6,7,7-tetramethyl-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, melting point 79°-81° (78%); 6-methylene-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, melting point 109°-111° (71%); 6-methoxy-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, boiling point1 120-124 (68%), stereoisomers; 6-acetoxy-2,4-diacetyl-2,4-diaza-bicyclo[3,2,0]heptan-3-one, melting point 151°-153° (single stereoisomer) (82% total yield); 8,10-diacetyl-8,10-diaza-tricyclo[5,3,0,02,6 ]decan-9-one, melting point 148°-150° (single stereoisomer, yield: 40%); and 2',4'-diacetyl-spiro[cyclopropane-1,6'-diaza-(2',4')-bicyclo[3,2,0]heptan-3'-one], melting point 63° (74%).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7](=[O:25])[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)C.[OH-].[K+:28]>C(O)C>[OH2:3].[K+:28].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[N:9]([CH2:8][C:7]([NH:6][CH2:5][C:4]([O-:26])=[O:3])=[O:25])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C([O-])CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 115.5 %

Procedure:
A mixture of N-[[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-y1]acetyl]glycine ethyl ester (4.0 g, 0.0108 mole), potassium hydroxide (0.62 g, 0.011 mole), and 100 ml of 95% ethyl alcohol was heated at reflux for 2 hrs. The hot solution was filtered and allowed to cool to initiate crystallization. The solid was diluted with 95% ethyl alcohol, filtered, and washed with a little 95% ethyl alcohol. The solid was dried under high vacuum at room temperature overnight to give 2.5 g (55%) of title compound, m.p. >300° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([OH:16])=O)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.[CH3:30][N+:31](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN.C(O)C>CN(C)C=O>[CH3:30][NH:31][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][CH2:12]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reaction time: 1 h
Yield: 42.4 %

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid (0.044 g. 0.15 mmol) in N,N-dimethylformamide (3 mL) was combined with N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [Oakwood #: 023926](160 mg, 0.42 mmol) and N,N-diisopropylethylamine (100 μL, 0.6 mmol) at room temperature. 3.0 M methylamine in ethanol (0.2 mL, 0.6 mmol) was added, and the resulting mixture was stirred for 1 h, at which time the mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1 N HCl, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide solid (0.020 g. 30%). LCMS calculated for C15H15N4O4 (M+H)+: m/z=315.1. found: 315.0.
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]([CH2:15][OH:16])[OH:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CC[O:19][CH2:20][CH3:21].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:22]([O:14][CH:13]([CH2:15][O:16][C:20](=[O:19])[CH2:21][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:12][O:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CO)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)OC(=O)CCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.7 ml of stearoyl chloride dissolved in 50 ml of anhydrous stearoyl chloride were added dropwise within 1 hour to 46 mmoles of 1-O-tosyl-glycerol dissolved in 100 ml of anhydrous chloroform containing 4.25 ml of anhydrous pyridin at 0° C., according to the method of De HAAS and Van DEENEN Recueil. Trav. Chim. Pays-Bas 80 (1961)(951-970). After 24 hours at room temperature the reaction mixture was diluted by 150 ml of ether and poured in 150 ml of ice-cold 0.5 NH2SO4. The organic phase obtained was washed with ice-cold solutions of HN2SO4 and of half-saturated aqueous solutions of NaCl, then dried on Na2SO4 and concentrated. Ether was added to the syrup obtained and left overnight at -10° C. After filtration there were obtained 3.2 g of 1-tosyl-glycerol-2,3-distearate (III): MP=55°-57° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16].O>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[CH2:14][CH:13]([OH:17])[CH3:12])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CCC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/CC(C)O)cc1[N+](=O)[O-]
Yield: 77.3 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (2.16 g, 10.0 mmol), 4-penten-2-ol (904 mg, 10.5 mmol), palladium(II) acetate (22 mg, 0. 10 mmol) and tri-o-tolylphosphine (122 mg, 0.400 mmol) was diluted with triethylamine (3 mL) and acetonitrile (6 mL) and refluxed under nitrogen for 28 h. The mixture was poured into water (30 mL) and extracted with chloroform (2×30 mL). The chloroform extracts were dried (Na2SO4) and evaporated, and the residue was column chromatographed on 100 g of Merck silica gel 60 (70-230 mesh) with 20-40% (v/v) ethyl acetate, 20% (v/v) chloroform in hexane. This gave 1.71 g (77.4% yield) of yellow oil.