Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.CN.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([NH:34][CH3:33])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with methylamine, HATU and DIPEA in THF to give 330 as a colorless solid after reverse phase HPLC. MS: (ESI+) 453.0
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:10]([O:17][C:18]1[CH:43]=[CH:42][CH:41]=[CH:40][C:19]=1[CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:10]([O:17][C:18]1[CH:43]=[CH:42][CH:41]=[CH:40][C:19]=1[CH:20]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C(=Cc1ccccc1OCc1ccccc1)c1ccccc1
Yield: 75.7 %

Procedure:
5.09 g of benzaldehyde and 26.1 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved in 100 ml of acetonitrile, with heating. 8.04 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were then added dropwise to the solution at 80° C., whilst stirring, and the resulting mixture was stirred at the same temperature for 40 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure, and 100 ml of a 2:1 by volume mixture of hexane and ethyl acetate were added to the resulting residue, and the mixture was agitated. Insoluble materials were filtered off, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 30:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 10.4 g (yield 76%) of 2-benzyloxystilbene.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH:34]C(OC(C)(C)C)=O)=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
TFA (1 ml, 12.98 mmol) was added to a flask of benzyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (70 mg, 0.127 mmol) in dichloromethane (1 ml) at room temperature and the reaction was allowed to stir for 1 hour. The reaction was quenched by the addition of saturated sodium bicarbonate until bubbling stopped. The aqueous layer was extracted (2×) with EtOAc. The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was then purified by reverse phase HPLC to provide the desired product. 1H NMR (DMSO-d6) δ: (10.36s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.3 Hz, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.08-7.41 (m, 1H), 5.12 (s, 2H), 5.02 (s, 2H), 4.26 (d, J=6.3 Hz, 2H) MS: cal'd 453 (MH+), exp 453 (MH+). The in vitro HDAC1 IC50 of this compound is 32 nM. The IC50 of this compound in HCT-116 cells is 590 nM. Percent Cyp inhibitions at 10 μM are 7, 25 and 24%, for Cyp3A4, 2C9, and 2D6, respectively. The inflection point for MK-499 binding is 12.2 μM.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([C:11]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:14][NH:15]2)[CH:9]=[CH2:10].O>C(O)=O>[CH2:8]([C:11]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:14][N:15]2[CH:1]=[O:3])[CH:9]=[CH2:10]
Reactant: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2C=O
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Formic acid (3.3 g, 71.7 mmol) and acetic anhydride (7.32 g, 71.7 mmol) was mixed under ice-cooling and the mixture was stirred for 10 minutes. To the mixture was added a solution of N-[2-(4-allyl-2,3-dihydro-5-hydroxyindol-3-yl)ethyl]propionamide in formic acid (10 mL). The mixture was stirred for 1 hour under ice-cooling and poured into water. The product was extracted with 10% methanol/ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, brine and water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to afford the title compound (yield 2.0 g, 46% from N-[2-(4-allyl-5-hydroxyindol-3-yl)ethyl]propionamide).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
Methyl 4-fluoro-3-nitrobenzoate Compound 3a (1.0 g, 5.02 mmol) (prepared as described in Nicolaou, et al., Bioorg. Med. Chem., 1998, 1185), 1-[bis(4-fluorophenyl)methyl]piperazine Compound 3b (1.59 g, 5.52 mmol) and potassium carbonate (0.76 g, 5.52 mmol) were dissolved in N,N-Dimethylformamide (15 mL) and heated to about 80° C. for about 5 h then cooled to rt. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL) and water (2×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester Compound 3c (2.4 g) as a yellow foam. MS m/z 468 (M+H). A mixture of the nitro substituted methyl ester Compound 3c (2.4 g, 5.13 mmol) and tin (II) chloride dihydrate (11.60 g, 51.34 mmol) was stirred in DMF (50 mL) for about 1 h. The reaction was diluted with ethyl acetate (100 mL), washed with brine (2×100 mL) and water (3×150 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 3-amino-4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-benzoic acid methyl ester Compound 3d (1.88 g) as a yellow foam. MS m/z 438 (M+H). A mixture of the amino substituted methyl ester Compound 3d (1.88 g, 4.30 mmol) and phenyl isocyanate Compound 3e (0.51 g, 4.30 mmol) was stirred in diethyl ether (50 mL) for about 18 h. The precipitate was collected by filtration, then washed with ether and hexane to provide Compound 11 (1.80 g) as an off-white solid. MS m/z 559 (M+H). A solution of Compound 11 (0.45 g, 0.81 mmol) and LiAlH4 in THF (1.0 M, 1 mL, 1.0 mmol) in THF (10 mL) was stirred for about 18 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give Compound 10 (0.31 g) as a white solid. MS m/z 529 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSCCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 61 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%)(0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane. The product fractions are combined and recrystallized from ethyl acetate-methanol-hexanes to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:29]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)ccc(F)c3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=427.98.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([CH3:11])[CH2:9][OH:10])[CH:7]=1.C(N(CC)CC)C.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)([CH3:11])[CH2:9][O:10][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1

Procedure:
A solution of (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol (6.95 g, 18.9 mmol) in dichloromethane (170 ml) was treated at room temperature with triethylamine (5.78 ml, 41.5 mmol), 4-dimethylaminopyridine (1.15 g, 9.43 mmol), and tert-butyldimethylchlorosilane (1.15 g, 37.7 mmol). After 16 hours at room temperature the reaction mixture was consecutively extracted with saturated sodium hydrogen carbonate solution (100 ml), water (100 ml), and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using heptane as the eluent, [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (intermediate C8A) was obtained as a colourless oil (8.0 g, 88% of theory). MS (ISP): m/z=482.2, 484.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C(Cl)Cl>[Si:24]([O:13][CH2:12][CH:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([I:1])=[CH:3]1)[CH3:14])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)n1cc(I)c2cnccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
To a solution of 2-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)propan-1-ol (Preparation 56, 11.5 g, 38.1 mmol) and imidazole (6.48 g, 95.2 mmol) in DCM (300 mL) was added a solution of TBDMSCl (6.95 g, 45.7 mmol) in DCM (50 mL) dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. To the reaction was added water (500 mL) and DCM (200 mL), the organic layer collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (15 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:4]([C:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[NH:10][CH:11]=2)=[N:5][N:6]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH:38]=[CH:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:4]([C:7]2[CH:8]=[C:9]([C:12]([N:35]3[CH2:39][CH:38]=[CH:37][CH2:36]3)=[O:13])[NH:10][CH:11]=2)=[N:5][N:6]=1
Reactant: C1=CCNC1
Reactant: Nc1nnc(-c2c[nH]c(C(=O)O)c2)n1-c1cccc(Cl)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2c[nH]c(C(=O)N3CC=CC3)c2)n1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 4-[5-amino-4-(2,3-dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-1H-pyrrole-2-carboxylic acid (10 mg, 0.03 mmol) in DMA (1 mL) was added CDI (6 mg, 0.04 mmol). The solution was stirred at RT for 30 min before the addition of 2,5-dihydro-1H-pyrrole (6 mg, 0.09 mmol). The reaction mixture was stirred at RT for another 60 min and purified by Gilson HPLC directly to afford a white solid (7.5 mg, 64%). MS (ES+): m/e=389.2 (M+H); LC: 2.65 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[CH2:23][NH:24][CH2:25][CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:25]([N:24]([CH2:23][CH:19]1[O:20][CH2:21][CH2:22][O:18]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:26]
Reactant: CCNCC1OCCO1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 72 h
Yield: 68.7 %

Procedure:
4-t-Butyl-2,6-dinitrochlorobenzene (1.8 grams; 0.007 mole), N-(1,3-dioxolan-2-yl)methyl ethylamine (1.83 grams; 0.014 mole) and toluene (50 ml) were placed in a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer. The reaction mixture was heated to 90° C. and maintained at this temperature with stirring for 72 hours. Diethyl ether (50 ml) was added to the cooled reaction mixture, which was filtered and evaporated to a volume of 10 cc. The residue was chromatographed on silica to remove unreacted starting material. The product (1.7 grams) was obtained as an oil which solidified on standing (73°-74° C. melting point). The product was analyzed for C16H23N3O6 :
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:61][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To N-(toluene-4-sulfonyl)-L-alanine (2.0 mmoles) in DMF (10 mL) was added BOP (2.1 mmoles) and N-methylmorpholine (4.0 mmoles) and the reaction stirred at room temperature for 45 minutes. L-Phenylalanine benzyl ester (2.0 mmoles) was added and the reaction stirred for 16 hours at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3×50 mL) The combined organic layers were successively washed with 0.2 N HCl (2×50 mL), sat. NaHCO3 (50 mL), and sat. NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a colorless oil (387 mg, 40%). The crude product was purified by silica gel chromatography (50% EtOAc /Hexane, Rf=0.61). The title compound was crystalized from CHCl3/Hexane to yield a white solid, mp=109-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)cc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)cc(Br)c1

Procedure:
A mixture of 5-bromo-3-hydroxytoluene (93 g, 0.5 m) and sodium hydroxide (21 g, 0.5 m) in water (200 ml) is stirred at 10°, treated with dimethyl sulfate (63 g, 0.5 m) over 1 hour, refluxed for 2 hours and cooled. The mixture is diluted with water and extracted with ether. The ether extract is washed, dried with sodium sulfate and concentrated in vacuo to give 5-bromo-3-methoxytoluene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>C(Cl)Cl>[Si:27]([O:11][CH2:10][CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:14])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](NC(CO)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl N-[1-(4-cyanophenyl)-2-hydroxyethyl]-D-alaninate (2 g, 0.0068 mol) in DCM (30 ml) were added imidazole (0.92 g, 0.0136 mol) and tert-Butyldimethylsilylchloride (1.25 g, 0.0082 mol) at RT. The reaction mixture was stirred at RT for 6 h and portioned between DCM and water, separated the layer and concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (80:20) as an eluent to afford (2 g, 74%) of the title compound as brown oil. 1H NMR: (DMSO-d6, 400 MHz) δ 7.80-7.77 (m, 2H), 7.53-7.50 (m, 2H), 4.86-4.85 (t, J=3.9 Hz, 1H), 3.17-3.13 (m, 1H), 2.61-2.55 (m, 1H), 1.95-1.89 (m, 1H), 1.39 (s, 9H), 1.09-1.07 (d, J=7.1 Hz, 3H), 0.80 (s, 9H), 0.04 (s, 3H), −0.12 (s, 3H). LC/MS (Method A): 405.3 (M+H)+. HPLC (Method A) Rt 5.13 min. (Purity: 73.7%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([S:4]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:9])(=[O:6])=[O:5])[CH3:3]>[Pd].O.C(O)C>[CH3:3][C:2]([CH3:19])([S:4]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:9])(=[O:6])=[O:5])[CH3:1]
Reactant: CC(C)(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 99.1 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(1,1-dimethylethylsulphonylaminocarbonyl)-3-nitrobenzene (0.36 g, 1.26 mmol), 10% palladium on carbon (0.1 g, 28% (w/w)) in water (2 ml) and ethanol (25 ml), the title compound (0.32 g, 99%) was afforded as a colourless solid. mp 150° C. (dec.). 1H NMR (360MHz, D6-DMSO) δ 1.30 (9H, s), 4.99 (2H, brs), 6.56-6.63 (1H, m), 6.97 (1H, t, J=7.7 Hz), 7.13-7.25 (2H, m).
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3]1.O.NN.NN>CO>[NH2:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([OH:1])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)C1
Agent: NN
Solvent: O
Solvent: CO
Product: N[C@@H]1CCCC[C@H](O)C1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
2-((1R,3S)-3-Hydroxycycloheptyl)-isoindoline-1,3-dione (1800 mg, 6.94 mmol) was dissolved in methanol (86.80 mL). Hydrazine monohydrate (0.354 mL, 7.29 mmol) was added to the solution and the resulting mixture was stirred overnight at reflux. An additional 0.2 eq (0.067 mL) of hydrazine was added and the mixture was refluxed for a second night. The reaction mixture was concentrated to a volume of a few milliliters and filtered. The solids were rinsed with 50 mL each of DCM and chloroform and the resulting filtrate concentrated under reduced pressure to afford the title compound (174 mg, 1.347 mmol, 19.40% yield) as an oil that was used without further purification. MS (ESI) m/z 130.2 [M+H]+.