Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(=O)CS.[H-].[Na+].FC(F)(F)C(O)=O.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[CH:20][C:21]2[NH:27][C:26](=O)[CH2:25][S:24][CH2:23][C:22]=2[CH:29]=1.FC(F)(F)C1C=CC(N)=CC=1.[AlH4-].[Li+]>>[F:31][C:17]([F:16])([F:30])[C:18]1[CH:19]=[CH:20][C:21]2[NH:27][CH2:26][CH2:25][S:24][CH2:23][C:22]=2[CH:29]=1
Reactant: O=C1CSCc2cc(C(F)(F)F)ccc2N1
Agent: COC(=O)CS
Agent: Nc1ccc(C(F)(F)F)cc1
Agent: [AlH4-]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc2c(c1)CSCCN2

Procedure:
This reaction is carried out by any method which makes it possible to convert from a ketone to an alcohol. The procedure is generally carried out by means of sodium borohydride, in an alcohol such as methanol or ethanol, at a temperature of between 0 and 25 degrees C. The synthesis method described above and in patent application WO99/05147 involves obtaining the methanesulfonate of dioxide-6,6 of 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine in 9 steps from the 4-trifluoromethyl-aniline according to the following reaction scheme (I) In order to obtain the product 2, the product 1 is protected according to standard methods with a BOC group with dicarbonate di tert-butyl in reflux THF. The product 2 is transformed in product 3 with tert butyl lithium, which is highly unstable. In order to obtain the product 4, the methyl function is brominated with N-bromosuccinimide. In order to obtain the intermediate 5, the sulfurated chain is reacted with methyl thioglycolate in the presence of sodium hydride. This intermediate is cyclised in the presence of trifluoroacetic acid. The amide function of the intermediate 6, i.e., 7-trifluoromethyl-1,5-dihydro-3H-[4,1]benzothiazepine-2-one, is reduced to the amine in the presence of lithium tetrahydroaluminate to obtain the intermediate 7, i.e., 7-trifluoromethyl-1,2,3,5-tetrahydro-[4,1]benzothiazepine. The third cycle is added in the presence of potassium and bromine thiocyanate in acetic acid. The key intermediate 8, i.e., 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine, is thus obtained in 7 steps. The intermediate 8 is reacted to obtain the final methanesulfonate product, 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine-6,6-dioxide, as well as the corresponding (R,S) 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine-6-oxide as well as its enantiomers. A recently developed improved synthesis directed to optimizing each of these steps is summarized in reaction scheme (II) below. In particular, this improved synthesis reduces the number of synthesis steps and makes use of other synthesis intermediates, as well as industrial reagents. It also allows a one-step cyclization and, at the same time, avoids the need for purification by chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](O)=[O:20])[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](=[O:20])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: CC(C(=O)O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(C(=O)Nc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 58 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-(1-carboxyethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (less polar) (100 mg, 0.28 mmol) and aniline (28 μL, 0.31 mmol) to give 70 mg of the title compound (58%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.00 (s, 1H), 7.52 (d, 2H, J=8 Hz), 7.29 (t, 1H, J=8 Hz), 7.19 (s, 1H), 7.17 (s, 1H), 7.05 (t, 1H, J=8 Hz), 5.19 (bd, 1H, J=9 Hz), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.67~2.84 (m, 2H, J=17.1 Hz), 2.01 (dm, 1H, J=13.5 Hz), 1.72~1.92 (m, 1H), 1.02 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([O:9][C@@H:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11](=[O:24])[CH2:12][CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:1]([O:9][C@@H:10]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11](=[O:24])[CH2:12][CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)[C@H](Cc1ccccc1)OCc1ccccc1
Reaction time: 7.5 h

Procedure:
A mixture of 1-[(5S)-5-(benzoyloxy)-1,4-dioxo-6-phenylhexyl]-L-proline (250 mg., 0.5 mmole), 10% palladium on carbon catalyst (50 mg.), and ethyl acetate (10 ml.) is stirred under hydrogen gas for 7.5 hours. The solution is filtered (millipore), and the solvent removed at reducted pressure. Ether is added to the residue and crystals form. The solution is filtered to give the desired product as a white hygroscopic solid which is dried under vacuum over P2O5 to give 150 mg. of 1-[(5S)-5-(benzoyloxy)-1,4-dioxo-6-phenylhexyl]-L-proline; Rf =0.40 [silica gel, ethyl acetate:pyridine:acetic acid:water (100:20:6:11)]; m.p. 114°-115°;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](\[C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=3[Cl:44])/[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and K3PO4 (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% methanol-dichloromethane. The product was further purified by reverse phase HPLC. Yield: 8 mg. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.38 (s, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.70 (m, 2H), 3.70 (m, 2H), 3.10 (m, 4H), 2.90 (s, 3H), 2.60 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[CH3:27][NH:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][NH2:31].C(=O)([O-])[O-].[K+].[K+].II>C(O)(C)(C)C>[CH3:27][N:28]1[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][N:31]=[C:1]1[C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: CNC(CN)c1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NCC(c4ccccc4)N3C)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step B) (0.8 g, 2.07 mmol) in tert-butanol (5 mL) was added N1-methyl-1-phenyl-1,2-ethanediamine (43.57 mg, 0.29 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, and then potassium carbonate (107.8 mg, 0.78 mmol) and iodine (43.57 mg, 0.33 mmol) were added. The reaction mixture was stirred at 70° C. for 3 h and then quenched by addition of saturated aqueous sodium sulfite solution until the iodine color almost disappeared. The reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative thin-layer chromatography on silica gel using a mixture of 94% ethyl acetate, 5% methanol and 1% triethylamine as eluant to give 64 mg of the title product, a compound of the present invention, as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:31])([F:43])[F:44])=[CH:39][CH:38]=3)[N:7]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 34 %

Procedure:
To a solution of 4-(6-chloro-4-pyrrolidin-1-yl-pyridin-2-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.27 mmol) in 1,4-dioxane (8 mL) was added 1N sodium carbonate solution (0.3 mL) and tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.013 mmol), followed by 4-trifluoromethoxyphenyl boronic acid (67.2 mg, 0.32 mmol). The resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound pale yellow solid (46 mg, yield 34%.).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: Nc1nc2ccc(F)cc2s1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-6-fluorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g,0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6fluorobenzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.Cl.Cl.[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CC(C)=O.O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:23])=[CH:17][CH:18]=2)[C:4](=[O:10])[CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: COc1ccc(O)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: NC1=CC(=O)C(Nc2ccc(N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.75 mole (10.5 g) of 3-amino-4-methoxy phenol is dissolved in 50 cc of acetone to which have been added 50 cc of ammonia (22° Be') and 250 cc of H2O2 (20 volumes). To this solution there is immediately added 0.05 mole (9.0 g) of paraphenylene diamine dihydrochloride in solution in 100 cc of water. The resulting reaction mixture is agitated for two hours at ambient temperature at which time the reaction mixture is filtered to recover the precipitate which has formed. After recrystallizing the precipitate in ethylacetate and washing the recrystallized product initially with a little methyl cellosolve and then with a little ether, 2-amino-5-[4'-(amino)anilino]-1,4-benzoquinone is obtained which is chromatographically pure and which melts with decomposition above 260° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:13][C@H:12]([NH:14][C:15]([C:17]2[C:18]3[N:19]([CH:28]=[CH:29][N:30]=3)[C:20]([CH2:23][O:24]COC)=[CH:21][CH:22]=2)=[O:16])[CH2:11]1.Cl>C1COCC1.CC(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@H:10]1[CH2:13][C@H:12]([NH:14][C:15]([C:17]2[C:18]3[N:19]([CH:28]=[CH:29][N:30]=3)[C:20]([CH2:23][OH:24])=[CH:21][CH:22]=2)=[O:16])[CH2:11]1
Reactant: COCOCc1ccc(C(=O)N[C@H]2C[C@H](Oc3cccc(Cl)c3Cl)C2)c2nccn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1)c1ccc(CO)n2ccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of N-{trans-3-[(2,3-dichlorophenyl)oxy]cyclobutyl}-5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxamide (598 mg, 1.328 mmol) in THF (5 mL) was added 5 to 6M HCl in 2-propanol (5 mL, 27.5 mmol) and a clear solution was observed. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. More 5-6M HCl in 2-propanol (0.5 mL) was added and stirring continued for another hour when HPLC indicated the reaction to be complete. The mixture was concentrated in vacuo to give a colourless gum (2.163 g). This material was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (2×15 mL). The organic phase was separated, washed with brine (15 mL), dried over magnesium sulphate and evaporated in vacuo to give the title compound as a yellow solid (537 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:28][N:29]1[C:33]([CH2:34]Cl)=[N:32][CH:31]=[N:30]1>CN(C=O)C.O>[CH3:28][N:29]1[C:33]([CH2:34][O:20][C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]3[N:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]=3[N:12]=2)=[N:32][CH:31]=[N:30]1
Reactant: Cn1ncnc1CCl
Reactant: O=c1nc2n(-c3ccccc3)[nH]nc-2c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(nnn2-c2ccccc2)c2ccccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.5 %

Procedure:
A mixture of 3-phenyl-1,2,3-triazolo[4,5-c]isoquinolin-5-one (0.10 g, 0.38 mmol), cesium carbonate (0.33 g, 1.0 mmol) and 2-methyl-3-chloromethyl-1,2,4-triazole hydrochloride (0.08 g, 0.48 mmol) in dry DMF (2 ml) was stirred at 60° C. for 5 h. The mixture was diluted with water (20 ml) and the white solid was collected, washing with water (10 ml) and diethyl ether (10 ml). The solid was dried to give 5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-c]isoquinoline (0.093 g, 68%), m.p. 188-190° C. Found: C, 63.48; H, 4.19; N, 27.14. C19H15N7O.0.1(H2O) requires C, 63.54; H, 4.27; N, 27.30. δH (360 MHz; CDCl3) 3.99 (3H, s), 5.83 (2H, s), 7.48-7.53 (1H, m), 7.61-7.70 (3H, m), 7.94-7.98 (2H, m), 8.20-8.22 (2H, m), 8.37 (1H, d, J=8) and 8.69 (1H, d, J=8); m/z (ES+) 358 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>ClCCl>[CH3:8][O:9][C:10]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([N+](=O)[O-])ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (5 eq) was added to a solution of tert-butyl 4-(2-methoxy-4-nitrophenoxy)piperidine-1-carboxylate (200 mg, 0.57 mmol, 1 eq) in dichloromethane, stirring at room temperature for 1 hour. The solvent was then evaporated, the residue was brought to pH 10 with sat. aq. Na2CO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the product 4-(2-methoxy-4-nitrophenoxy)piperidine as a light yellow solid (137.3 mg, 96%). LC/MS (m/z): 253.2 (MH+), Rt 1.81 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:12])([CH3:1])[CH2:11][CH2:10]2)=[O:19]
Reactant: CC1(C)CCc2ccccc2O1
Reactant: O=C(Cl)CCCCCl
Product: CC1(C)CCc2cc(C(=O)CCCCCl)ccc2O1

Procedure:
Using 2,2-dimethylchroman (19.7 g) and 5-chlorovaleryl chloride (20.7 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (22.0 g) having a melting point of 50 to 51° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([CH3:8])=O)#[N:2].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:6]([CH3:8])[CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:16]
Reactant: CC(=O)CCCC#N
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)CCCC#N
Reaction time: 10 h

Procedure:
A mixture of methyl 3-cyanopropyl ketone (55.5 g, 0.5 mole), ethyl cyanoacetate (56.5 g, 0.5 mole), acetic acid (6.0 g, 0.1 mole), ammonium acetate (3.85 g, 0.05 mole) and toluene (50 ml) was refluxed while azeotropically removing the water of reaction formed. After 10 hours the solution was vacuum distilled and a fraction (b.p. 145° C.-153° C., 0.5 torr) was collected. Total yield was 77.0 g or 74.7 percent. Analysis by infrared spectroscopy confirmed the product's identity as:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@H:73]1[C@@H:76]([CH2:77][OH:78])[NH:75][C:74]1=[O:79]>C(Cl)Cl.CN(C=O)C>[C:35]([O:34][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])[CH2:19][CH2:18]2)/[C:23]([NH:72][C@@H:73]2[C:74](=[O:79])[NH:75][C@@H:76]2[CH2:77][OH:78])=[O:24])[N:27]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N[C@@H]1CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CO)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (6.66 g, 12.38 mmol) at 0° C. in DCM (61.9 ml, ratio: 1) and DMF (61.9 ml, ratio: 1) were added DIPEA (6.49 ml, 37.2 mmol) and HATU (5.65 g, 14.86 mmol). After 20 min, (3S,4S)-3-amino-4-(hydroxymethyl)azetidin-2-one (1.44 g, 12.38 mmol) was added. After stirring for 2 h at rt, the reaction mixture was concentrated in vacuo and diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (4.4 g, 56%). LCMS: Rt=0.97 min, m/z=636.1 (M+1), Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6): 11.80 (br s, 1H), 9.08 (d, J=9.0 Hz, 1H), 8.41 (s, 1H), 7.48-7.32 (m, 5H), 7.32-7.15 (m, 6H), 6.84 (s, 1H), 5.20 (ddd, J=9.2, 5.1, 0.9 Hz, 1H), 4.77 (t, J=5.3 Hz, 1H), 3.76-3.70 (m, 1H), 3.62-3.48 (m, 1H), 3.47-3.33 (m, 1H), 1.56-1.33 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C.O>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH3:13])[CH:3]=1
Reactant: CI
Reactant: Brc1c[nH]c2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ncccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A mixture of 3-bromo-1H-pyrrolo[3,2-b]pyridine (450 mg) in DMF (5 mL) was treated with a NaH (60% in oil, 100 mg) and the resulting mixture stirred at room temperature for 5 min. The mixture was cooled to 0° C., treated with MeI (324 mg) then allowed to warm to room temperature over a period of 1 h. After this time, the reaction was diluted with water (100 mL) and extracted with AcOEt (3×50 mL). The combined organics were washed with water (50 mL), 5% LiCl aqueous solution (50 mL) then brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (heptane to AcOEt) to give the title compound (408 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:19](=O)[CH3:20])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C.C([BH3-])#N.[Na+]>COCCOC.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([CH:19]([NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])[CH3:20])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(=O)c1ccc(Cl)c(Br)c1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(N[C@H](C)c1cccc(Cl)c1)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65 %

Procedure:
A solution of (R)-1-(3-chlorophenyl)ethanamine 107 (0.701 g, 4.50 mmol), 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.00 g, 4.29 mmol), and triethylamine (1.79 mL, 12.9 mmol) in dry DME was chilled to −78° C. in a dry ice bath. Via syringe, titanium(IV) chloride (4.50 mL, 4.50 mmol) was added dropwise to the reaction mixture. The reaction was warmed to ambient temperature and it was stirred under N2 for 10 h. A solution of sodium cyanoborohydride (0.674 g, 10.7 mmol) in 4 mL of MeOH was then added slowly to the reaction mixture and the reaction solution was stirred for another 3 h. The reaction was quenched by the addition of saturated NH4Cl. The solution was diluted with ether and water, and the mixture was extracted with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 3% to 30% gradient of EtOAc in hexanes as the eluent. The desired fractions were combined and concentrated to give 1-(3-bromo-4-chlorophenyl)-N—((R)-1-(3-chlorophenyl)ethyl)ethanamine 108 (1.04 g, 65.0% yield) as a colorless oil.