Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.C(O)C.C(O)(=O)C.[OH-].[Na+]>[Fe].O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)ccc1-n1cnc(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Iron powder-325 mesh (4.6 g, 82 mmol) was added to a 500 mL round bottom flask charged with a mixture of 4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 20.5 mmol), absolute ethanol (100 mL), and glacial acetic acid (50 mL). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 100° C. with vigorous stirring for 30 min. The reaction mixture allowed to cool to rt and was added to a chilled and stirred solution of 3 M NaOH (291 mL). The resulting mixture was poured into a separatory funnel and extracted with EtOAc (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (4.57 g, 97% yield) as a solid. LC-MS (M+H)+224.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (d, J=1.22 Hz, 1H) 7.00 (d, J=8.24 Hz, 1H) 6.99 (d, J=1.53 Hz, 1H) 6.32 (d, J=2.44 Hz, 1H) 6.29 (dd, J=8.24, 2.44 Hz, 1H) 3.88 (br. s., 2H) 3.78 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[S:8][CH:9]=1)=[O:4].CO.[OH-].[Na+]>O>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][CH2:10][C:7]2[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)=[O:26])=[CH:16][CH:17]=1
Reactant: COC(=O)c1csc(CNC(=O)COc2ccc(OC(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NCc1nc(C(=O)O)cs1
Reaction time: 12 h
Yield: 85.8 %

Procedure:
2-{[2-(4-Trifluoromethoxy-phenoxy)-acetylamino]-methyl}-thiazole-4-carboxylic acid methyl ester (8.6 g, 22 mmol) was mixed with methanol (110 mL). NaOH (1.3 g, 33 mmol) was dissolved in water (110 mL) and added to the methanol solution. The reaction mixture was stirred for 12 hours. The mixture became homogenous after three hours. The methanol was removed in vacuo and the resulting slurry was acidified with 1 N HCl. The resulting slurry was extracted with EtOAc ×3. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was recrystallized from methanol to afford the title compound (7.1 g, 86%). 1H NMR (400 MHz, d6-DMSO): 9.08 (t, 1H), 8.33 (s, 1H), 7.31 (d, 2H), 7.06 (d, 2H), 4.63 (s, 2H), 4.61 (d, 2H); MS (ESI-LCMS) for C14H12F3N2O5S: 377 (MH+).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]1=2.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([O:12][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[N:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: Oc1cccc2sccc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sccc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (0.104 g, 2.6 mmol, 60% suspension in mineral oil, Aldrich) was added in small portions to a solution of benzo[b]thiophen-4-ol (0.3 g, 2 mmol, prepared according WO 01/68653) in DMF (4 mL) and the mixture was stirred at room temperature for 0.5 h. (4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.776 g, 3 mmol) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc (50 mL), washed with 1 N NaOH and water, dried over MgSO4, and filtered. The filtrate was evaporated under vacuum and the residue purified by silica gel chromatography (10% EtOAc in hexanes) to give the title compound. Mp: 122.3–122.4° C. MS (ESI, pos. ion) m/z: 373.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH:14][C:6]2[CH:5]=[CH:4][CH:3]=[C:22]3[C:23]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 40 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (0.60 g, 4.16 mmol), 4-chlorosulfonyl-3-nitro-benzoic acid methyl ester (Intermediate 438) (1.5 g, 5.41 mmol), DMAP (cat), pyridine (6 ml) and DCM (3 ml) gave the title compound (0.65 g, 40%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][C:10](=[CH2:12])[CH3:11].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CCOCC>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:4]
Reactant: C=C(C)C
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.0 mm of (+)-2-bromo-3-methylbutyric acid is dissolved in a solvent consisting of 100 ml of ether, 100 ml of isobutylene, and 0.5 ml of sulfuric acid. The resulting solution is shaken for approximately 72 hours in an autoclave at room temperature. The solution is then neutralized with sodium bicarbonate, dried with magnesium sulfate, and then evaporated to yield (+)-t-butyl 2-bromo-3-methylbutyrate.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH2:25])[C:9]([NH2:24])=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:17][CH:18]=1)#[N:2].CO[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)=N>>[C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:10][C:9]2[NH:24][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[CH:36][N:35]=3)=[N:25][C:8]=2[CH:7]=1)#[N:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1
Reactant: COC(=N)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2C#N)cn1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyano-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 221 (step 3) and methylpyrazin-2-imidate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.CCN(C(C)C)C(C)C.N1C=CC=CC=1.[C:29](Cl)([Cl:31])=[O:30]>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:29]([Cl:31])=[O:30])[CH2:8][C:7]=2[CH:13]=1
Reactant: Brc1ccc2c(c1)CNCCO2
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCOc2ccc(Br)cc2C1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (3.0 g, 11.34 mmol) was suspended in dichloromethane (30 mL) followed by addition of DIPEA (3 mL, 34 mmol) and pyridine (4 mL, 49 mmol) and the resulting partially heterogeneous mixture was added portionwise over 5 minutes to a 0° C. cooled solution of phosgene (20 W % in toluene, 15 mL, 28 mmol) in dichloromethane (15 mL). The resulting mixture was then allowed to slowly warm to room temperature over 30 minutes then concentrated. The residue was partitioned with ethyl acetate and water and the organic phase washed twice with 1M aqueous hydrochloric acid then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carbonyl chloride (3.35 g) as a pale yellow oil. MS (EI) for C10H9BrClNO2: 292 (MH+).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:17][CH:16]=[CH:15][CH2:14][N:13]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]1[C:29](=[O:45])[NH:30][O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.O>[CH:32]([O:31][N:30]1[C:9](=[O:8])[CH:11]2[CH:12]([N:13]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH:15]=[CH:16][CH2:17]2)[C:29]1=[O:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC=CCC3C(=O)N(OC(c4ccccc4)c4ccccc4)C(=O)C32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-benzhydryloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-3-carboxylic acid benzyl ester (430 mg, 0.69 mmoL) was dissolved in a THF:H2O (1:1, 10 mL) mixture and was then treated with LiOH (35 mg, 0.82 mmoL). This solution was stirred overnight at ambient temperature. The THF was removed in vacuo and the resulting mixture was acidified with 2 M aqueous citric acid. The product was extracted into diethyl ether, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% methanol in chloroform) to give 7-benzhydryloxy-1-(4-methoxybenzenesulfonyl)-2,5,5a,8a-tetrahydro-1H-pyrrolo[3,4-b]azepine-6,8-dione; MS: (M+H)+ 519.
Reaction SMILES: O=[C:2]([CH2:24][CH2:25][C:26](=O)[C:27]1[S:28][C:29]([CH2:32][O:33]C2CCCCO2)=[CH:30][N:31]=1)[CH:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C.C(OCC)(=O)C>[OH:33][CH2:32][C:29]1[S:28][C:27]([C:26]2[NH:45][C:2]([CH:3]([C:11]3[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=3)[CH2:4][CH:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:24][CH:25]=2)=[N:31][CH:30]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-[2,5-dioxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-5-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}pentyl]benzoate (2.24 g) in acetic acid (15 mL) was added ammonium acetate (4.85 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was m washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.30 g, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 469 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)=[CH:8][C:7]=1[F:13]
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-fluoro-phenyl}-2-ethoxy-propionic acid methyl ester as light yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[CH:2]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:25])([CH3:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:1]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(CO)cc3ccccc13)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.36 g (1 mmol) of 5'-hydroxymethyl-1,3,3-trimethylspiro[indoline-2,3'-[3H]-naphtho[2,1-b][1,4]oxazine] in 30 ml of dichloromethane is added to 0.42 g (1 mmol) of Dess-Martin reactant prepared according to the method published in J. Org. Chem., 1983, 48, 4155, in solution in 60 ml of anhydrous dichloromethane. The mixture is then stirred for 1 hour at ambient temperature. 100 ml of ethyl ether are then added. The solution is then filtered and then evaporated. The product is purified by chromatography on a column of silica (CH2Cl2 eluent).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O1CCOC1CCCCCCCCOC1C=C(C=CC=1)C=O>>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(OCCCCCC2OCCO2)c1
Reactant: Fc1cccc([Mg]Br)c1
Agent: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Product: OC(c1cccc(F)c1)c1cccc(OCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-fluorophenylmagnesium bromide and 3-((5-(1,3-dioxolan-2-yl)pentyl)oxy)benzaldehyde replacing 2-thienylmagnesium bromide and 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde respectively.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CS(C)=O.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (50.0 g) and 3-formylphenylboronic acid (24.5 g, 1.05 eq) were dissolved in dimethyl sulfoxide (500 mL), and 10% Pd—C (PE type) (725.0 mg, 0.2 mol %) and 1,1′-bis(diphenylphosphino)ferrocene (171.6 mg, 0.2 mol %) were added. After nitrogen substitution, a deaeration operation was performed under reduced pressure three times, and the mixture was stirred at inside temperature 80±5° C. for 1 hr. A solution of separately prepared tripotassium phosphate (66.1 g, 2.0 eq)/water (250 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at the same temperature for 4.5 hr. After cooling to 60° C., the mixture was partitioned. To the organic layer was added ethyl acetate (175 mL), and the mixture was cooled to 30° C. Pd—C was filtered off, and washed with ethyl acetate (125 mL). To the filtrate was added 10% brine (300 mL), and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined and washed with 10% brine (300 mL×2). The organic layer was concentrated to about 150 mL, to the residue was added ethyl acetate (300 mL), and the mixture was concentrated to about 150 mL. To the residue were added ethyl acetate (250 mL) and activated carbon Shirasagi A (5 g), and the mixture was stirred for 30 min. The activated carbon was filtered off, and washed with ethyl acetate (150 mL). The filtrate was concentrated to about 150 mL, and the mixture was stirred at room temperature overnight. Heptane (750 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The crystals were filtered, and washed with ethyl acetate/heptane (25 mL/125 mL). The crystal was dried at 60° C. under reduced pressure to give the title compound (46.9 g, yield 90.0%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8].[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(Cl)(Cl)Cl.O>CN(C=O)C>[C:14]1(=[O:24])[N:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: C#CCOC(=O)CCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C#CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
Prop-2-ynyl 6-bromohexanoate (0.606 g, 2 mmol, 1 eq.) was added to a solution of phthalimide potassium salt (0.441 g, 2.4 mmol, 1.2 eq.) in 50 mL of DMF and stirred overnight under argon. CHCl3 was added to the solution flask and was transferred to a separatory funnel containing water. The aqueous layer was separated and twice extracted with CHCl3. The combined organic layers were twice extracted with water then the solvent was removed on a rotary evaporator. Remaining solvent was removed under high vacuum overnight to yield a brown oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: c1ccc(CC2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 1-(3-benzylazetidin-1-yl)-4-phenylbutan-1-one are collected and the solvent is removed in vacuo to give 479 mg of colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Cl:23].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:16]([Cl:23])=[CH:17][C:18]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][C:20]=1[Cl:21]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)Cc1c(Cl)cc(N)cc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1c(Cl)cc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 46.5 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (5.0 g, 31.4 mmol), (4-amino-2,6-dichloro-phenyl)-acetic acid methyl ester (7.8 g 33.3 mmol), and a 4 N solution of HCl in dioxane (12 mL, 48.0 mmol, 2.9 equiv) in MeOH/dioxane (60 mL; 1:1, v/v) is stirred for 46.5 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 4:1), followed by trituration in diethyl ether, provides the title compound: ES-MS: 355.9/357.9 [M+H]+; tR=5.33 min (System 1); Rf=0.25 (Hexane/EtOAc, 4:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH2:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([N:28]([CH3:36])[C:29](=[O:35])[C@@H:30]3[CH2:34][C@@H:31]32)=[CH:26][C:25]=1[CH:37]=O.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH:15][CH2:37][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][C:24]=3[O:23][CH3:22])[C@H:31]3[CH2:34][C@H:30]3[C:29](=[O:35])[N:28]4[CH3:36])([CH2:11]2)[C@@H:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)[C@@H]1C[C@H]21
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CN)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1CNC[C@@]13C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H]3c1ccccc1)N(C)C(=O)[C@@H]1C[C@H]21
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Racemic Intermediate 21, one enantiomer being (1R,2S,5S)-1-aminomethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.055 g, 0.19 mmol) was combined with (1aR,7bS)-6-methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde (0.046 g, 0.20 mmol) in methylene chloride (3 mL) and the mixture was stirred for 3.0 hours. APCI mass spec showed complete imine formation (m+1: 503). Methanol (1.0 mL) and sodium triacetoxyborohydride (0.053 g, 0.25 mmol) were added and the reaction allowed to stir for 16 hours. The solvent was removed at reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and methylene chloride, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (0.10 g, quantitative crude yield). This material was used without further purification.