Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(C=CC2C=CC=CC=2)=C(C=CC2C=CC=CC=2)C=CC=1)=CC1C=CC=CC=1.[CH2:31]([O:43][C:44]1[CH:45]=[C:46](/[CH:63]=[CH:64]/[C:65]2[CH:70]=[C:69](/[CH:71]=[CH:72]/[C:73]3[CH:78]=[C:77]([O:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89]CC)[CH:76]=[C:75]([O:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102]CC)[CH:74]=3)[CH:68]=[C:67](/[CH:105]=[CH:106]/[C:107]3[CH:112]=[C:111]([O:113][CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH2:123]CC)[CH:110]=[C:109]([O:126][CH2:127][CH2:128][CH2:129][CH2:130][CH2:131][CH2:132][CH2:133][CH2:134][CH2:135][CH2:136]CC)[CH:108]=3)[CH:66]=2)[CH:47]=[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]CC)[CH:49]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CC>>[CH3:102][CH2:101][CH2:100][CH2:99][CH2:98][CH2:97][CH2:96][CH2:95][CH2:94][CH2:93][O:92][C:75]1[CH:74]=[C:73](/[CH:72]=[CH:71]/[C:69]2[CH:70]=[C:65](/[CH:64]=[CH:63]/[C:46]3[CH:47]=[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH:49]=[C:44]([O:43][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:45]=3)[CH:66]=[C:67](/[CH:105]=[CH:106]/[C:107]3[CH:108]=[C:109]([O:126][CH2:127][CH2:128][CH2:129][CH2:130][CH2:131][CH2:132][CH2:133][CH2:134][CH2:135][CH3:136])[CH:110]=[C:111]([O:113][CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH3:123])[CH:112]=3)[CH:68]=2)[CH:78]=[C:77]([O:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH:76]=1
Reactant: CCCCCCCCCCCCOc1cc(/C=C/c2cc(/C=C/c3cc(OCCCCCCCCCCCC)cc(OCCCCCCCCCCCC)c3)cc(/C=C/c3cc(OCCCCCCCCCCCC)cc(OCCCCCCCCCCCC)c3)c2)cc(OCCCCCCCCCCCC)c1
Agent: C(=Cc1cccc(C=Cc2ccccc2)c1C=Cc1ccccc1)c1ccccc1
Product: CCCCCCCCCCOc1cc(/C=C/c2cc(/C=C/c3cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c3)cc(/C=C/c3cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c3)c2)cc(OCCCCCCCCCC)c1

Procedure:
The employed network molecule is derived from tristyrylbenzene, i.e. (1,3,5-tris[(E)-2-(3,5-didodecyloxyphenyl)-ethenyl]benzene). (TSB35), it has also been provided with (1,3,5-tris[(E)3,5-didodecyloxyphenyl)-ethenyl]benzene) (OC12H25 lateral arm). The latter has been solubilised in a solvent (phenyl-octane or tetradecane) at approximately 10−4 mol/L concentration. A drop of the solution has been then deposited on the freshly dived sample. The 2-D sieve thus obtained has been characterized using an STM microscope, operating directly in the liquid, whereof the tip is immersed in the drop.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].S(=O)(=O)(O)N.[BH4-].[Na+].Cl>C(O)C>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2ccccc12
Agent: Cl
Agent: NS(=O)(=O)O
Agent: [BH4-]
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Thianaphthene-3-carboxaldehyde (5 g, 30.8 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (12.22 g, 123.30 mmoles) and sulfamic acid (0.29 g, 3.08 mmoles) were added and the reaction mixture heated to 45° C. for 18 h. The reaction mixture was then cooled to room temperature. Sodium borohydride (1.2 g, 30.8 mmol) was added and the reaction mixture was stirred for 1 hour. 1N HCl (30 mL, 30 mmol) was added and the reaction mixture was filtered through Celite. The filtered solution was then diluted with water (100 mL). The precipitate was filtered to yield the title compound as a off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11]OS(C3C(C)=CC=CC=3)(=O)=O)[CH2:8][C:7]=2[CH:23]=1.[CH3:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11][N:33]3[CH2:34][CH2:35][C:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([CH3:24])=[CH:38][CH:37]=4)([OH:36])[CH2:31][CH2:32]3)[CH2:8][C:7]=2[CH:23]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc2c(c1)C[C@@H](COS(=O)(=O)c1ccccc1C)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(C)cc3)CC1)O2
Temperature: 110 °C
Yield: 87.2 %

Procedure:
(S)-Toluenesulfonic acid 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (2.30g, 6.88 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (1.62 g, 7.9 mmol) and Na2CO3 (1.10 g, 10.3 mmol) were suspended in DMF and heated at 110° C. for 1 hr. After cooling to ambient temperature distilled H2O and EtOAc were added (100 ml) and the mixture shaken, the organic phase was then separated and the aqueous phase extracted with EtOAc (10 ml). The combined organic extracts were then washed with satd. NaCl solution (100 ml) and the organic phase dried with Na2SO4, filtered and evaporated to afford a yellow oil. This foam was chromatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2, and then with CH2Cl2—MeOH (97:3) to afford (S)-1-(5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (2.20 g, 6.0 mmol, 87% yield) as a yellow oil MS: m/e=368.2 (M+H+) [α]=+45.8° (c=1.0, CHCl3).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:17]C=O)([CH3:16])/[CH:5]=[CH:6]/[CH2:7][P:8]([O:13]CC)([O:10]CC)=[O:9].O>Cl>[NH2:17][C:4]([CH3:16])(/[CH:5]=[CH:6]/[CH2:7][P:8]([OH:13])([OH:10])=[O:9])[C:3]([OH:20])=[O:2]
Reactant: CCOP(=O)(C/C=C/C(C)(NC=O)C(=O)OC)OCC
Agent: Cl
Solvent: O
Product: CC(N)(/C=C/CP(=O)(O)O)C(=O)O

Procedure:
14.5 g of E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester are heated for 32 hours under nitrogen at 100°-105° in 500 ml of 4.35N hydrochloric acid. Working up as in Example 11 yields E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, m.p. 225°-226° (from water).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[C:7]1=[O:17])[CH3:2].[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[C:7]1=[O:17])[CH3:2]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)c2ccc(OC3CCCCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a mixture of (5-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (8.0 g) in anhydrous tetrahydrofuran (160 ml) was added cyclohexanol (3.2 g), diethylazadicarboxylate (6.9 g) and then triphenyl phosphine (12.6 g). Resulting mixture was stirred at room temperature overnight and concentrated. Residue was partitioned between water and ethyl acetate. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over magnesium sulfate and filtered. Filtrate was concentrated and purified by silica gel chromatography (eluting with 5% ethyl acetate in methylene chloride) to give the title compound (6.2 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (dd, J=8.2, 0.8 Hz, 1H), 7.30 (br s, 1H), 7.12 (m, 1H), 4.38 (m, 3H), 4.21 (q, J=7.1 Hz, 2H), 2.02 (m, 2H), 1.82-1.25 (m, 13H).
Reaction SMILES: C([Mg]Cl)(C)C.[Mg].ClC(C)C.Cl[CH2:12][CH2:13][CH2:14][OH:15].BrCC(Br)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>O1CCCC1>[NH2:33][CH:32]([C:28]1([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31]1)[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: OCCCCl
Agent: CC(Br)CBr
Agent: CC(C)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: NC(CCCO)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of isopropylmagnesium chloride [prepared by the reaction of magnesium (2.4 g) and 2-chloropropane (10 ml) in tetrahydrofuran (30 ml)] was added dropwise under argon at -20° C. to a solution of 3-chloropropan-1-ol (9.45 g) in tetrahydrofuran (100 ml). Magnesium (3.6 g) was added and the mixture was allowed to stand for twenty minutes and was then heated under reflux in the presence of 1,2-dibromopropane for 40 minutes. 1-(4-Chlorophenyl)cyclobutanecarbonitrile (8 g) was added and the mixture was heated under reflux for 16 hours. The mixture was cooled and the supernatant liquid decanted from excess magnesium metal and treated with sodium borohydride (3 g) and propan-2-ol (100 ml). The mixture was heated under reflux for 5 hours. The reaction mixture was cooled, added to water and excess concentrated hydrochloric acid was added. The resulting solution was washed with toluene, basified and extracted with toluene. The extracts were dried and evaporated to give a residue which was distilled in a Buchi Kugelrohr apparatus (140°/0.4 mm) to give 4-amino-4-[1-(4-chlorophenyl)-cyclobutyl]butan-1-ol.
Reaction SMILES: [OH:1][C@:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH:7]([CH3:9])[CH3:8])[CH2:3][C:4]([OH:6])=[O:5].Cl.C[C@@H](N)C1C=CC=CC=1>>[OH:1][C@@:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH:7]([CH3:8])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@](O)(CCc1ccccc1)CC(=O)O
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Product: CC(C)[C@@](O)(CCc1ccccc1)CC(=O)O
Temperature: 25 °C

Procedure:
The mother liquor from the isolation of diastereomeric salt G-10 (S) was treated with 1N HCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to liberate the free β-hydroxy acid. HPLC analysis indicated the isolated material was 73% (R):27% (S). β-Hydroxy acid G-10 (1 equiv.) was dissolved in 600 mL EtOAc and treated with (R)-α-methylbenzylamine (0.74 equiv.). The resulting suspension was placed on a steam bath and heated to reflux. The solution was allowed to cool to room temperature slowly and then cooled to 0° C. in an ice bath. The resulting solids were filtered off and washed with cold EtOAc followed by Et2O to yield the title compound. The free acid was obtained by treating the salt with 1N HCl followed by extraction with EtOAc. The organic phased was washed with brine, dried (MgSO4), filtered and concentrated to afford the resolved β-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (OD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA:+0.1% Formic acid)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Na+].[Na+].F[C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2cc(Br)ccc2c1
Reaction time: 0.17 h
Yield: 227.1 %

Procedure:
To 6-bromo-2-naphthol (8.43 g) in 80 ml DMF at room temperature was added sodium carbonate (8.0 g) portionwise, and after the addition was complete, the mixture was stirred for 10 minutes, and then a solution of 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 40 ml DMF was added dropwise. The reaction mixture was then stirred for six hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution and dried over Na2SO4. The filtrate was concentrated to yield a solid (31 g). This material was triturated with methanol to yield a solid, 10.0 g, m.p. 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:34]1[NH:39][CH2:38][CH2:37][N:36]2[CH2:40][CH2:41][CH2:42][C@H:35]12>ClCCl.CN(C)C=O.ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:39]2[CH2:38][CH2:37][N:36]3[CH2:40][CH2:41][CH2:42][C@@H:35]3[CH2:34]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)N2CCN3CCC[C@@H]3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 3-amino-4-fluorobenzoic acid (0.621 g, 4 mmol) and 1-hydroxybenzotriazole hydrate (0.613 g, 4 mmol) in dichloromethane/N,N-dimethylformamide (10:1, 60 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.621 g, 4 mmol). After 5 minutes, (R)-octahydropyrrolo[1,2-α]pyrazine (0.505 g, 4 mmol) in dichloromethane (1 mL) was added. The mixture was stirred at room temperature overnight. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give (R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-α]pyrazin-2(1H)-yl)methanone: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.60-2.10 (m, 6H), 2.70-3.10 (m, 4H), 3.55-3.70 (m, 1H), 4.40-4.60 (m, 1H), 5.30 (s, 2H), 6.50 (m, 1H), 6.77 (m, 1H), 7.00 (m, 1H); MS (ESI) m/z 264 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH:20]1([N:19]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:18]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)/C(C)=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(-c2ccc(O)cc2)n(C2CCCCC2)n1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a solution 4.1 (83 mg, 0.187 mmol) in CH2Cl2 (2 ml) at −50° C. was added a 1M solution of BCl3 in CH2Cl2 (933 μL, 0.933 mmol) followed by stirring at −50° C. for 15 min, and quenched with MeOH. The mixture was diluted with EtOAc, washed with H2O, sat. NaHCO3, brine, and dried (Na2SO4). Filtration through a 1″ pad of SiO2 and concentration to provided 4.3, 67 mg (100%). MS (ESI) 355.3 (MH+), 353.3 (MH−).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:27])([F:28])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH2:1][CH3:2])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-difluoro-acetic acid and benzyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>C(#N)C.CN(C)C1C=CN=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:9])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Temperature: 68 °C
Reaction time: 8 h

Procedure:
To 5-Bromo-pyridine-2-carbonyl chloride (69, 0.76 g, 3.4 mmol) in acetonitrile (29.0 mL) were added p-chloroaniline (53, 0.702 g, 5.50 mmol), 4-dimethylamino-pyridine (0.12 g, 0.96 mmol) and pyridine (2.9 mL, 0.036 mol). The reaction was stirred at 68° C. overnight, then poured into water, acidified with 1 N HCl to pH around 1 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane to give a white solid (70, 0.75 g, 70.0%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[NH4+].[Cl-]>C1COCC1>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Yield: 82.1 %

Procedure:
To a solution of oxazolidone (2) (30.2 g, 0.234 mol) in 400 mL THF at −78° C. was added n-BuLi (2.5 M in hexanes, 96.0 mL, 0.240 mol) dropwise over a period of 30 min. The solution was stirred at −78° C. for an hour. Heptanoyl chloride (37.15 g, 0.250 mol) was gradually added by syringe and the resulting solution stirred at −78° C. for 1 h and then warmed to 0° C. A saturated aqueous solution of NH4Cl (100 mL) was added and the mixture gradually warmed to room temperature. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed by a rotary evaporation and the yellowish residue chromatographed on a silica gel column using Hexane/EtOAc (8:1) as the eluant to give 4 as a colorless oil (46.272 g, 0.192 mol, 82%). 1H NMR (400 MHz, CDCl3) δ0.87 (t, J=7.2 Hz, 3 H), 0.88 (d, J=16.9 Hz, 3 H), 0.90 (d, J=16.9 Hz, 3 H), 1.24-1.39 (m, 6 H), 1.59-1.69 (m, 2 H)2.31-2.43 (m, 1 H), 2.81-3.02 (m, 2 H), 4.19-4.29 (m, 2 H), 4.41-4.45 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ13.9, 14.5, 17.9, 22.4, 24.3, 28.3, 28.7, 31.4, 35.4, 58.3, 63.2, 154.0, 173.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:22]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: COc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Yield: 50 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 60° C. for 72 hours yielding tert-butyl 1-(4-methoxy-2-nitrophenyl)piperidin-3-ylcarbamate (50%). LCMS (m/z): 352.1 (MH+); LC Rt=3.27 min.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([F:20])[C:12]=2[CH3:21])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH2:10])=[N:4]1>C1COCC1.[Pd]>[NH2:17][C:15]1[CH:14]=[C:13]([F:20])[C:12]([CH3:21])=[C:11]([C:3]2([CH:2]([F:1])[F:22])[CH:9]3[CH:7]([CH2:8]3)[O:6][C:5]([NH2:10])=[N:4]2)[CH:16]=1
Reactant: Cc1c(F)cc([N+](=O)[O-])cc1C1(C(F)F)N=C(N)OC2CC21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(F)cc(N)cc1C1(C(F)F)N=C(N)OC2CC21
Temperature: 18 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
5-(Difluoromethyl)-5-(3-fluoro-2-methyl-5-nitrophenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (200 mg, 0.634 mmol) was dissolved in THF (20 ml). 10% palladium on carbon (135 mg, 0.127 mmol) was added and the reaction mixture was put under a balloon of H2 and stirred at 18° C. for 4 h. The mixture was filtered through a pad of celite, washing well with ethyl acetate. The filtrate was concentrated under vacuum to yield crude 5-(5-amino-3-fluoro-2-methylphenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (140 mg, 0.491 mmol, 77% yield) as a gray foam. LC/MS (ESI+) m/z=286.2 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.N[C@H:23](C1C=NC=C(Br)C=1)[C@@](C1C=C(F)C=CC=1F)(O)C>>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])([CH3:23])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: C[C@@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Product: C[C@]1(c2cc(F)ccc2F)OC(=O)N[C@@H]1c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J=2.4 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.46 (ddd, J=10.9, 9.1, 4.4 Hz, 1H), 7.40-7.33 (m, 1H), 7.25 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 5.15 (d, J=1.5 Hz, 1H), 1.85 (s, 1H) 1.25 (s, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11]3.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]3
Reactant: O=C=Nc1ccccc1
Reactant: CN1C(=O)Cc2cc3ccccc3cc2S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(=O)C(C(=O)Nc2ccccc2)c2cc3ccccc3cc2S1(=O)=O
Reaction time: 20 h
Yield: 36.8 %

Procedure:
To a solution of 1.3 g (5 mmol) 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 0.7 ml (5 mmol) triethylamin dissolved in 10 ml DMSO at room temperature was added 0.6 g (5 mmol) phenylisocyanate. After stirring for 20 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 1.9 g crude product. This material was recrystallized from ethanol followed by recrystallization from ethylacetate to give 0.7 g 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C@@H:14]([NH:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1>C(Cl)Cl>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH2:27])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1
Reactant: COc1ccccc1CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of (R)-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino) propanamide (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 3-(1H-indol-3-yl)-2-amino-N-(2-methoxybenzyl)propanamide (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.