Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:21](=[O:32])[NH:22][CH2:23][C:24]2[O:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=2)[CH2:14]1.ON1C2C=CC=CC=2N=N1.Cl.C(N)C.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([NH:3][C:29]([C:27]1[O:28][C:24]([CH2:23][NH:22][C:21]([NH:20][CH2:19][C@@H:15]2[O:16][CH2:17][CH2:18][N:13]([CH2:12][C:11]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:9]([Cl:8])[CH:10]=3)[CH2:14]2)=[O:32])=[CH:25][CH:26]=1)=[O:30])[CH3:2]
Reactant: O=C(NCc1ccc(C(=O)O)o1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 41 in N,N-dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (0.0159), and ethylamine hydrochloride (0.042 g). To the suspension was added N,N-diisopropylethylamine (0.09 ml) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.02 g). After stirring at room temperature for 16 h, further amounts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.030 g), ethylamine hydrochloride (0.02 g) and N,N-diisopropylethylamine (0.09 ml) were added. The mixture was stirred for a further 3 h at room temperature. The mixture was partitioned between ethyl acetate (60 ml) and 2N sodium hydroxide (20 ml) The phases were separated and the organic phase washed with 2N sodium hydroxide (20 ml) and water (20 ml), dried (MgSO4), and filtered. The solvent was removed in vacuo. The residue was dissolved in methanol and applied onto a sulphonic acid ion exchange cartridge (1 g Isolute SCX, pre-treated with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia in methanol. The solvent was removed from the basic fraction by evaporation under a stream of nitrogen. The residue was purified by mass directed preparative HPLC to give the title compound as a colourless gum (0.0064 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[OH:15][CH2:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (5 g, 19.3 mmol) in anhydrous diethyl ether was chilled in an ice bath and 1 M LiAlH4 in diethyl ether (38 mL, 38.6 mmol) was added dropwise under an N2 atmosphere. The reaction was allowed to warm to room temperature with stirring overnight. The reaction was quenched by slowly adding saturated aqueous Na2SO4 (5 mL). The slurry was filtered through a pad of Celite. The Celite pad was rinsed with EtOAc and the solution was dried in vacuo to yield (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.77 g, 12 mmol) as a clear oil. [M+H] calc'd for C11H21NO4, 232; found, 232.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].CN(C(ON1N=[N:39][C:34]2[CH:35]=[CH:36]C=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NC1(C#N)CC1.Cl.C(OC(C)(C)C)=O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]([C:13](=[O:15])[NH:39][C:34]1([C:33]#[N:38])[CH2:36][CH2:35]1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)(C)OC=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-3-(4-(allyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (5 g, 15.6 mmol, Eq: 1.00) was dissolved in DMF (30 ml). HATU (11.8 g, 31.1 mmol, Eq: 2.00), Hunig's Base (4.02 g, 5.43 ml, 31.1 mmol, Eq: 2.00) and 1-amino-1-cyclopropanecarbonitrile hydrochloride (2.21 g, 18.7 mmol, Eq: 1.20) were added to the above suspension and stirred at 25° C. for 24 h. The reaction mixture was poured into 0.1M HCl (250 mL) and extracted with AcOEt (3×75 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was dissolved in CH2Cl2 (10 mL), 2 minutes later it began to precipitate. The suspension was filtered. The filtered solution was purified by flash chromatography (silica gel, 80 g, 0% to 90% AcOEt in heptane) to yield a light yellow solid (3.0 g; 50%). m/z=286.1 [M+H-Boc]+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13]/[C:14](=[C:19](\[CH:24]([CH3:26])[CH3:25])/[C:20]([O:22][CH3:23])=[O:21])/[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:18][O:17][C:15](=[O:16])/[C:14](/[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=1)=[C:19](/[CH:24]([CH3:25])[CH3:26])\[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)/C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of dimethyl 2-[4-(t-butyldimethylsilyloxy)benzyl]-3-isopropylmaleate (823 mg, 2.02 mmol) in tetrahydrofuran (13 mL) was added a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.1 mL, 2.1 mmol) at room temperature, and the mixture was left standing at room temperature for 1 h. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 592 mg of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester as a solid (quantitative).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH2:7][C:6]1=[O:20])(=[O:3])[CH3:2].CC([O-])=O.[Na+]>CC(C)=O>[C:1]([O:4][C:5]1[C:6](=[O:20])[CH2:7][O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:10]=1[OH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OCC(=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1OCC(=O)C(OC(C)=O)=C1O
Reaction time: 3 h
Yield: 83.3 %

Procedure:
[Litt=S. Andersen et al. J. Carbohydrate Chemistry, 17 (1998) 1027-1035, P. Jarglis and F. W. Lichtenthaler. Angew. Chem. 94 (1982) 140-141 with a benzoylated analog]. To a solution of 3,4,6-tri-O-acetyl-1,5-anhydro-D-fructose (3) (2.21 g, 7.67 mmol) in dry acetone (77 mL), anhydrous NaOAc (2.2 g) was added and the reaction mixture was stirred for 3 h. The salts were filtered off and washed with acetone. The filtrate was concentrated and purified by column chromatography (30 g silica, eluted with hexane-EtOAc. 2:1) to give 4 as a syrup (1.56 g, 89%): 1H NMR (CDCl3 at 7.27, 300 MHz) δ 2.12 (s, 3H, OCOCH3), 2.26 (s, 3H, OCOCH3), 4.24 (dd, J=4.0 and 12.0, 1H, H-6), 4.25 (dd, J=2.0 and 16.5, 1H. H-1), 4.42 (dd, J=6.0 and 12.0, 1H, H-6′), 4.46 (d, J=16.5, 1H, H-1′), 4.80 (dddd, J=2.0, 2.0, 4.0 and 6.0, 1H, H-5), 6.59 (d, J=2.0, 1H, H-4). 13C NMR (CDCl3 at 77.0, 50.3 MHz) δ 20.3-20.7 (2×OCOCH3), 64.4 (C-6), 71.4 (C-1), 72.6 (C-5), 132.8 (C-4), 143.8 (C-3), 168.1-170.7 (2×OCOCH3), 187.7 (C-2)
Reaction SMILES: [CH:1]([N:3]([CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)=[O:2].[Cl:36][C:37]1[C:38]2[CH:48]=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[CH:48]=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42]([N:19]([CH2:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH:1]=[O:2])[CH3:35])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH2:22][CH2:21]1)=[O:43]
Reactant: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 52 (325 mg, 0.64 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (171 mg, 0.74 mmol) using Method D to give the title compound.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O.CC#N>[Cl:11][C:4]1[CH:3]=[C:2]([I:21])[CH:9]=[C:8]([F:10])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)cc(N)cc1Cl
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(F)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a cooled (0° C.) solution of 4-amino-2-chloro-6-fluorobenzonitrile (3.55 g, 20.8 mmol), sulfuric acid (3.33 ml, 62.4 mmol), water (30 ml) and MeCN (100 ml) was added slowly a solution of sodium nitrite (1.58 g, 22.9 mmol) in water (10 ml). A solution of potassium iodide (6.91 g, 41.6 mmol) in water (10 ml) was added slowly while maintaining temperature of the reaction mixture below 10° C. After being stirred at RT for 2 h, the reaction was quenched by adding water (100 ml) and concentrating the mixture to about half of the original volume. The mixture was extracted with DCM (3×150 ml), and combined organic fractions were dried over Na2SO4 and evaporated to yield 4.77 g, (81%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 8.06 (dd, 1H), 8.08 (m, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([O:26][CH3:27])[C:23]([F:25])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[F:25][C:23]1[C:22]([O:26][CH3:27])=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:28]
Reactant: COc1cc2c(cc1F)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspended mixture of 1′-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.49 g, 1.09 mmol), triethylsilane (0.23 g, 2.0 mmol) and trifluoroacetic acid (0.57 g, 5.0 mmol) was refluxed under nitrogen for 5 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The oily residue was sonicated with hexanes (10 mL) for 10 min and a solid product was filtered off to afford 6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.29 g, 92%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.37-6.91 (m, 4H), 6.74 (d, J=11.0 Hz, 1H), 6.39 (d, J=8.3 Hz, 1H), 4.82 (ABq, 2H), 3.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ180.0, 155.2, 154.9, 154.7, 151.9, 142.9, 142.7, 140.2, 132.1, 129.2, 124.1, 123.6, 122.7, 122.7, 110.4, 109.0, 108.9, 100.0, 99.7, 80.5, 58.8, 57.2; MS (ES+) m/z 285.8 (M+1).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][NH:5][CH2:4]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: C1CCNC1
Product: C1CCN(CC2CNCCO2)C1

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and pyrrolidine, the reaction is similarly carried out as Reference example 2 to give 2-(1-pyrrolidinylmethyl)morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][C@H:29]([C:31]([O-:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@@H](C)C(=O)[O-])cn(C)c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@@H](C)C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a stirred solution of N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-L-alaninate (D81) (160 mg) in THF (2 mL) was added NaOH (2 M, 2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was acidified with HCl (2 M) to pH 6-7. The resulting solid was separated and suspended in methanol (2 mL) with stirring, HCl (2 M) was added until the solid dissolved completely. The solution was freeze dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-L-alanine (E60) (130 mg, HCl salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.50 (3H, d), 3.70 (3H, s), 3.92 (1H, q), 4.36 (2H, s), 4.88 (1H, m), 7.28 (1H, t), 7.45 (1H, d), 7.51 (1H, d), 7.62 (1H, s), 8.04 (1H, d), 8.13 (1H, d), 8.20 (1H, d). MS (ES): C24H26ClN4O4 requires 468; found 380.2 (M—C3H6NO2+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nc(CO)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(COS(C)(=O)=O)cs1
Reaction time: 1 h

Procedure:
A solution of 1.2 mmol of 4-(hydroxymethyl)-2-isopropylthiazole and 1.3 mmol of diisopropylethylamine in 20 ml of dichloromethane was cooled to -20° C. and treated dropwise with 1.3 mmol of methanesulfonyl chloride. The resulting mixture was stirred for 1 h, quenched with aqueous citric acid, separated, dried over Na2SO4, and concentrated in vacuo to provide the desired compound.
Reaction SMILES: [OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(OCC)(=O)C>[OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:36]2[CH:37]=[CH:38][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCC[Si]1(O)CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCCC[Si]1(O)CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To 5-(1-hydroxysilinan-1-yl)pentanoic acid (130 mg, 0.601 mmol) in ethyl acetate (5 mL), N,N′-dicyclohexylcarbodiimide (186 mg, 0.901 mmol) was added. The reaction was stirred under nitrogen at ambient temperature for 30 minutes. After this time, 4-nitrophenol (100 mg, 0.719 mmol) was added, and the reaction was stirred for 16 hours at ambient temperature. After this time, the reaction was filtered to remove any solids, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexanes to 1:3 ethyl acetate/hexanes to afford 4-nitrophenyl 5-(1-hydroxysilinan-1-yl)pentanoate (106 mg, 52%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.26 (dt, J=9.0, 2.5 Hz, 2H), 7.27 (dt, J=9.0, 2.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.84-1.78 (m, 2H), 1.76-1.67 (m, 4H), 1.56-1.44 (m, 4H), 1.40-1.33 (m, 1H), 0.75-0.63 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:16]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[N:10]([C:16]3[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: O=S1(=O)CC(c2ccc(F)cc2)CN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CC(c3ccc(F)cc3)CS2(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
18.00 g of 4-(4-fluorophenyl)isothiazolidine 1,1-dioxide, 20.59 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017) and 81.75 g of Cs2CO3 were stirred in 500 ml of anhydrous DMF at RT for 5 hours. Then a further 2.00 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate were added, and the mixture was stirred at RT for 1 hour and left to stand at RT for 15 hours. The reaction mixture was poured into 1800 ml of water and stirred at RT for 1 hour, and the product was filtered off with suction. The product was then dissolved in 1 l of EA, and the solution was mixed with MgSO4 and activated carbon and stirred at RT for 15 minutes. It was then filtered and the solvent was removed in vacuo. 35.00 g of a colorless foam were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccc(Cl)cc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccc(Cl)cc21
Yield: 15.4 %

Procedure:
A solution of 6-chloro-N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (143.0 mg, 0.4 mmol), piperazine (694.0 mg, 8.00 mmol) and N,N-diisopropylethylamine (0.52 mL, 4.00 mmol) in acetonitrile (5 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (5% methanol in dichloromethane) to yield 26.0 mg (15% yield) of desired product. 1H NMR (400 MHz, CD3OD): δ 7.64 (d, 1H) 7.25 (d, 1H), 7.15 (dd, 1H), 6.81 (d, 1H), 6.45 (d, 1H), 6.35 (dd, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 4.26 (m, 2H), 3.31 (m, 4H), 3.03 (m, 4H), 2.98 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC(COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>CCOCC.C([O-])([O-])=O.[Na+].[Na+].O>[CH2:30]([O:29][C:27]([CH:26]1[C:11](=[O:14])[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:13][CH2:12]1)=[O:28])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a 0° C. solution of 1-BOC-4-piperidone (20 g, 0.10 mol) in Et2O (200 mL) was added BF3.Et2O (14 mL, 0.11 mol) followed by drop-wise addition of ethyl diazoacetate (13.7 mL, 0.11 mol) over 1 h. After addition was complete, the mixture was stirred at 0° C. for 1 h. The mixture was diluted with 30% aq. Na2CO3 and water at 0° C. and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue (FCC) afforded the title compound (25.6 g, 98%). 1H NMR (CDCl3): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J=7.8 Hz, 9H), 1.31-1.24 (m, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(#N)C.O>[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1)[CH2:31][CH2:30]2
Reactant: C1CN2CCC(CC2)N1
Reactant: CNS(=O)(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 96 °C
Yield: 80.6 %

Procedure:
To a solution of 5-fluoro-N-methyl-2-nitrobenzenesulfonamide (Intermediate 16A) (1.0 g, 4.27 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.77 g, 12.81 mmol) followed by 1,4-diazabicyclo[3.2.2]nonane 2,2,2-trifluoroacetate (1.17 g, 4.27 mmol). The resulting suspension was heated to reflux at 96° C. overnight. The reaction mixture was diluted in water (50 mL) and split between two 20 g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzenesulfonamide (1.17 g, 3.44 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:32])([CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([CH3:40])[CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)c2ccccc2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)c2ccccc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-phenylpropan-2-yl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.