Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:26]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(OCCCC)(OCCCC)OCCCC.[CH2:28]([NH2:30])[CH3:29].[OH-].[Na+]>>[CH2:28]([NH:30][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:29]
Reactant: Oc1cccc2ccccc12
Reactant: CCN
Agent: CCCCOP(OCCCC)OCCCC
Agent: [Na+]
Agent: [OH-]
Product: CCNc1cccc2ccccc12
Yield: 85 %

Procedure:
288 parts of α-naphthol, 10 parts of tributyl phosphite and 110 parts of ethylamine gas are heated for 20 hours at 240° C, whilst stirring. After cooling and letting down the autoclave, the mixture is stirred for 20 minutes with 1,000 parts of 2.5 percent strength by weight aqueous sodium hydroxide solution at 70° C. The organic phase is separated off, washed with 2,000 parts of water at 30° C, separated off and distilled. 290 parts of N-ethyl-α-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 85% of theory.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](=[O:13])[C@H:10]([OH:12])[CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O1CCCC1.C(OCC)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]([CH3:11])[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:13])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: C[C@@H](O)C(=O)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCOCC2)cc1
Yield: 57 %

Procedure:
To a suspension of sodium hydride (60% in paraffin liquid) (8.41 g, 210 mmol) in tetrahydrofuran (120 ml was dropped (2R)-1-morpholin-4-yl-1-oxopropane-2-ol (32.1 g) in tetrahydrofuran (150 ml) under stirring, ice cooling and an atmosphere of nitrogen. The mixture was then stirred for 30 minutes at 50° C. After being ice-cooled, thereto was dropped a solution of p-toluenesulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 ml), and the mixture was stirred for 4 hours at room temperature. Thereto was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the oily residue. Thereto was added diethyl ether and the resulting precipitate was taken by filtration, washed with diethyl ether and dried under reduced pressure to give the subject compound as a white solid (36.1 g, 115 mmol, 58%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C1CC1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (3 mL), and triethylamine (0.38 mL) and 3-cyano-5-cyclopropyl-4-methoxybenzoyl chloride were added to the solution, and then stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (e).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:18][CH:19]=[CH2:20])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:18][CH:19]=[CH2:20])[C:9]2[C:14]([C:15]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(Cl)c2ccc(C)nc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCn1c(=O)c(C(=O)OCC)c(N2CCCC2)c2ccc(C)nc21

Procedure:
A stirred mixture of 0.49 g. (0.0016 mole) of 1-allyl-4-chloro-1,2-dihydro-7-methyl-2-oxo-1,8-naphthridine-3-carboxylic acid ethyl ester, 0.11 g. (0.0016 mole) of pyrrolidine and 0.16 g. (0.0016 mole) sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.2 g. of the title compound, m.p. 97°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([CH:8]=1)[NH2:7].[CH3:15][S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([NH:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=1
Reactant: CN(C)CCOc1ccc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)CCOc1ccc(Br)cc1NS(C)(=O)=O
Yield: 84.2 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 5-bromo-2-(2-(dimethylamino)ethoxy)aniline (1.8 g, 6.94 mmol) was mesylated with methanesulfonyl chloride (875 mg, 7.63 mol), pyridine (822 mg, 10.4 mmol), DCM (20 mL) to afford 1.97 g (83.12% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.71-7.0 (d, 1H), 7.2-7.16 (dd, 1H), 6.92-6.89 (d, 1H), 4.07-4.04 (t, 2H), 2.92 (s, 3H), 2.56-2.53 (t, 2H), 2.35 (s, 6H).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10](=O)[C:4]2=[N:3][CH:2]=1.Cl.[NH2:17][OH:18].CC([O-])=O.[Na+]>CO>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10](=[N:17][OH:18])[C:4]2=[N:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCc2ccccc2-n2ccnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCc2ccccc2-n2ccnc21
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Under a nitrogen atmosphere, charge a reactor with 42 kg of (5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one), 15.5 kg of hydroxylamine hydrochloride, 21.5 kg of sodium acetate anhydrous, and 171 kg of methanol. Heat the resulting brown suspension to 60 to 70° C. for 20 h (in process HPLC<3% 5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one). Cool the reaction to 23 to 25° C. and stir for 8 h. Isolate the solid by centrifugation, rinsing with 33 kg of cold methanol. Transfer the resulting solid into a reactor and slurry with 210 kg of water at 85 to 90° C. for 2 h. Isolate the solid by centrifugation, rinsing the solid with 85 kg of water. Dry the resulting solid to give 39.65 kg of 5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-one oxime. MS=214 (M+1).
Reaction SMILES: [C:1]([S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH:16]OS([O-])=O.[K+]>CO>[C:1]([S:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)Sc1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 156.7 %

Procedure:
4-(tert-Butylthio)benzoic acid (3.18 g, 15.1 mmol) was dissolved in methanol (78.70 mL) followed by the addition of water (7.9 mL) and OXONE (4.65 g, 7.56 mmol). The reaction mixture was stirred at room temperature for 45 minutes before it was filtered using methanol. The solvent was evaporated under reduced pressure. Water (35 mL) was added to the residue and the mixture was basified using solid NaOH and was washed with ethyl acetate (3×50 mL). The aqueous layer was acidified with 1N HCl before it was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-(tert-butylsulfinyl)benzoic acid (2.68 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.12-8.08 (m, 2H), 7.73-7.69 (m, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([I:25])[C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1sc(N)c(C#N)c1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate (4.50 g, 9.53 mmol) in dichloromethane (100 mL) at room temperature was added trifluoroacetic acid (22.5 mL, 292 mmol). The mixture was then stirred at room temperature for 10 minutes. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude material was diluted with ethyl acetate, then treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate five times and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 88%). LCMS: (FA) ES+, 323. 1H NMR (400 MHz, d6-DMSO) δ: 8.18 (s, 2H), 4.20-4.16 (m, 2H), 2.50-2.48 (m, 3H). To a suspension of 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 8.85 mmol) in acetonitrile (46.2 mL) under argon was added diiodomethane (2.49 mL, 31.0 mmol). The mixture was heated to 38° C. for 30 minutes, then amyl nitrite (2.59 g, 22.1 mmol) was added dropwise over 5 minutes. The reaction was slowly allowed to cool to room temperature then the mixture was concentrated and column chromatography was performed to yield the title compound (3.20 g, 79%). LCMS: (FA) ES+, 434. 1H NMR (400 MHz, d6-DMSO) δ: 4.33-4.27 (m, 2H), 2.51-2.47 (m, 3H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Li])[CH2:18][CH2:19]C.BrCC#C>O1CCCC1.CCCCCC>[CH2:19]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)[C:18]#[CH:17]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCN1c2ccccc2C(=O)Nc2cccnc21

Procedure:
To a suspension of 7.4 g (0.035 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 150 ml of anhydrous tetrahydrofuran, 44.8 ml (approx. 0.07 mol) of a 15% solution of n-butyl-lithium in n-hexane was added dropwise with stirring at a reaction temperature of from 0° to +10° C. After it had all been added, the mixture was stirred for 30 minutes at ambient temperature before a solution of 4.16 g (0.035 mol) of 3-bromo-prop-1-yne in 25 ml of anhydrous tetrahydrofuran was added dropwise. The resulting mixture was stirred for a further 2 hours at ambient temperature, added to 1 liter of saturated aqueous saline solution and the resulting mixture was extracted exhaustively with ethylacetate. The combined ethylacetate extracts were washed twice more with 100 ml of saturated saline solution, dried over sodium sulphate with the addition of 1 g of activated charcoal and evaporated down in vacuo. The residue was purified on silica gel by chromatography using dichloromethane/ethyl acetate 95/5 (v/v) as eluant. 8.5 g (97% of theory) of colourless crystals were obtained, m.p. 199° C. (decomposition).
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][NH2:16])[CH3:13].O.Cl>C(OCC)C>[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][N:16]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1)[CH3:13]
Reactant: CCCCC(CC)CN
Reactant: O=C(Cl)c1ccccc1SCl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCC(CC)Cn1sc2ccccc2c1=O
Reaction time: 8 h
Yield: 64 %

Procedure:
2-chlorosulphenylbenzoyl chloride (10.35 parts; 0.005M) was slowly added to a stirred solution of 2-ethylhexylamine (29.8 parts; 0.23M;) in diethylether (150 ml) at below 5° C. The reactants were then stirred overnight, allowing the temperature to rise to 18° to 20° C. Iced water was then added and the mix made just acid to Congo red by dropwise addition of of concentrated hydrochloric acid, keeping the temperature below 5° C. The ether layer was then separated and dried over magnesium sulphate. The solution was then filtered and the ether evaporated leaving a syrupy oil. This was boiled with petroleum ether (bp 60°-80° C.), the ether layer decanted from some tarry material and then evaporated to dryness leaving a dark yellow oil. This oil was purified by high vacuum distillation in a Kugelrohr and 8.4 parts pale yellow liquid obtained (Yield 64% theory).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4[C:52](C#N)=[CH:51][S:50][CH:49]=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[N:55]1([CH2:60][CH2:61][CH2:62][NH:63][C:64]2C3SC=C(C4C=CC(O)=CC=4)C=3[N:67]=[CH:68][N:69]=2)[CH2:59][CH2:58][CH2:57][CH2:56]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[C:52]5[N:67]=[CH:68][N:69]=[C:64]([NH:63][CH2:62][CH2:61][CH2:60][N:55]6[CH2:56][CH2:57][CH2:58][CH2:59]6)[C:51]=5[S:50][CH:49]=4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: Oc1ccc(-c2csc3c(NCCCN4CCCC4)ncnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4csc5c(NCCCN6CCCC6)ncnc45)cc3)s1)CC2

Procedure:
The title compound 78 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 78B: 1H NMR (DMSO-d6): δ 12.82 (s, 1H), 9.53 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 8.03-8.07 (m, 1H), 8.01 (d, J=7.98 Hz, 1H), 7.69 (d, J=8.59 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67 (d, J=7.36 Hz, 1H), 7.32-7.49 (m, 4H), 7.01 (d, J=8.9 Hz, 2H), 4.84 (s, 2H), 4.04 (t, J=6.29 Hz, 2H), 3.73 (t, J=5.83 Hz, 2H), 3.18-3.24 (m, 4H), 3.01-3.05 (m, 4H), 1.78-2.07 (m, 6H). ESI (+)/MS: 831 (M+H)+.
Reaction SMILES: [C:1]([N:6]([CH2:8][C:9]([NH2:11])=[S:10])[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[C:1]([N:6]([CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N(C)CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(CN(C)C(=O)OCC)n1

Procedure:
To a solution of (N-carbethoxy-N-methylamino)thioacetamide (30.7 g; 0.17 mole) [prepared in Step B] in 180 ml of absolute ethanol was added a solution of ethyl bromopyruvate (25.0 ml; 0.20 mole) in 130 ml of absolute ethanol. The reaction mixture was heated at reflux temperature for 17 hours and then evaporated under reduced pressure, and the residue was partitioned between ether and water. The organic layer was washed with water and saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to give an oil which was placed on silica gel and chromatographed using diethyl ether as the eluting solvent. The appropriate fractions yielded the title compound as an oil; TLC [Silica/CH2Cl2 :CH3 --CN (85:15)] gave Rf=0.50. The NMR spectrum (60 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 8.49 (s, 1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H); 1.30 (q, 6H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:30]([CH3:38])[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:34][CH2:33][CH:32]([CH2:31][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:38])[CH2:37][CH2:36]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(Cc1ccccc1)CC1CCNCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(Cc1ccccc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and benzyl-methyl-piperidin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (56%, colourless crystals). HPLC-MS m/z=500.2 (M+1), Rt: 3.18 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:21][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Reaction time: 18 h
Yield: 79 %

Procedure:
Benzyl bromide (9.98 g, 58.3 mmol) was added to a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (15.0 g, 58.3 mmol) and K2CO3 (3.5 g, 58.3 mmol) in DMF (300 mL) and stirred for 18 hours. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (500 mL). Sat'd NaHCO3 soln (20 mL) was added and the aqueous layer extracted with ethyl acetate (2×) and the combined organic layers were washed with brine and dried and filtered. Concentration gave Example J5, benzyl 4-(4-bromophenyl)-4-oxobutanoate 16 g (79%) which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.35-7.34 (m, 5H), 5.14 (s, 2H), 3.27 (t, J=6.7 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H). HRMS: Anal. C17H16BrNO3 Calcd. 347.0277; found: 347.0283 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH2Cl2 (25 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol), triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and then partitioned between Et2O and water. The water layer was extracted with Et2O. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to yield [1-(methoxy-methyl-carbamoyl)-cyclopropyl]carbamic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32].O>O1CCCC1>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until C02 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified to a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).