Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:54])[C:7]([O:10]/[N:11]=[C:12](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][C:26]1[N:27]=[N:28][N:29]([CH2:31][CH2:32][NH:33]C(OC(C)(C)C)=O)[CH:30]=1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][N:29]1[CH:30]=[C:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:54])=[O:5])/[C:41]3[N:42]=[C:43]([NH2:46])[S:44][CH:45]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[N:27]=[N:28]1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cc1cn(CCN)nn1)c1csc(N)n1)C(=O)O
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection, using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-oxoazetidine-1-sulfonic acid (7.22 mg, 9.00 μmol), DCM (200 μl) and TFA (50 μl, 649 μmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (1.2 mg, 24%). LCMS: Rt=0.487 min, m/z=546.2 (M+1). Method 2m_acidic.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:18]=[N+:19]=[N-:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 95 °C
Yield: 78 %

Procedure:
The compound (3R)-1-benzyl-3-[(methylsulfonyl) oxy]pyrrolidine (1.3 g, 5.8 mM) was dissolved in dimethylformamide (25.0 ml) and sodium azide (1.5 g, 23.3 mM) was added to it. The reaction mixture was maintained at 90-100° C. for about 12 hours followed by cooling at room temperature. The reaction mixture was poured into cold water (150.0 ml) with constant stirring. The organic compound was extracted with ethyl acetate and washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated to give the title compound. Yield=78% (0.9 g, 4.5 m. This material was used as such in the next step.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:44]=[C:45]([CH3:51])[C:46](=[O:50])[N:47]([CH3:49])[N:48]=1>CN(C)C=O>[CH3:49][N:47]1[C:46](=[O:50])[C:45]([CH3:51])=[CH:44][C:43]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)=[N:48]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Cl)nn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (0.31 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) and 6-chloro-2,4-dimethyl-2H-pyridazin-3-one (75 mg) in dimethylformamide (1 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->80:20) to afford the title compound. Yield: 0.10 g (67% of theory). Mass spectrum (ESI+): m/z=476 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O.Cl>CN(C)C=O>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH2:8][CH2:9][CH2:10][C:11]([OH:22])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (9.4 g, 33.7 mmol) in anhydrous dimethyl formamide “DMF” (40 mL) was cooled in an ice bath. Pyridinium dichromate (44 g, 117 mmol) was added in 4 portions of with 15 min intervals. The reaction mixture was allowed to stir overnight at room temperature resulting in a viscous black slurry. The slurry was poured into water (400 mL), acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with, 5% NaHSO4 (100 mL), water (4×300 mL). Subsequently, the organic layer was extracted with 1M NaOH (150, 75, and 50 mL). The combined aqueous layers were cooled with an ice bath and the pH was adjusted to 3 with concentrated HCl. The resulting white suspension was extracted three times with ethyl acetate (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated in vacuo to give N-benzyl-N-(t-butoxy-carbonyl)-4-amino-1-butanoic acid (4.0 g, 40%) as viscous oil. 1H NMR (CDCl3): δ 7.23-7.35 (m, 5H); 4.41 (bs, 2H); 3.29 (bs, 1H); 3.19 (bs, 1H); 2.33 (bs, 2H); 1.82 (bs, 2H); 1.46 (bs, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>CC#N>[C:34]([O:37][CH2:38][C:39](=[O:40])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])(=[O:36])[CH3:35]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, acetoxyacetyl chloride (0.28 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2.5) to give (N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)methyl acetate (0.54 g, 75%) as a white solid: mp 108-110° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 7.87-7.79 (m, 2H), 7.71-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.4 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 4.56 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.47 (m, 2H), 2.11 (s, 3H), 2.08-1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.66, 169.96, 169.72, 167.46, 167.37, 166.36, 138.80, 134.68, 133.01, 132.47, 127.04, 121.87, 62.36, 48.84, 37.46, 30.38, 21.93, 20.49; Anal. Calcd. For C18H17N3O7+0.15H2O: C, 55.43; H, 4.47; N, 10.77. Found: C, 55.43; H, 4.54; N, 10.44.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7](/[CH:10]=[C:11](/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])\[CH3:12])=[CH:8][CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[C:16]([O:15][C:13](/[C:11](/[CH3:12])=[CH:10]/[C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(/C=C(\C)C(=O)OC(C)(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
5-[(1E)-2-(tert-Butoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylic acid methyl ester (1.18 g, 4.19 mmol) obtained in step 1 was dissolved in tetrahydrofuran (5 mL), 1N aqueous lithium hydroxide solution (4.6 mL) was added, and the mixture was stirred overnight. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound (1.06 g).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([C:28]1[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][NH:30][N:29]=1)[CH2:26][CH3:27].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([CH2:4][N:30]2[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28]([CH2:25][CH2:26][CH3:27])=[N:29]2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCCc1n[nH]cc1CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)OCC
Reaction time: 12 h
Yield: 53.5 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a mixture of 4-[(4-chloromethylphenoxy)methyl]-5-methyl-2-phenyloxazole (910 mg), ethyl 3-(3-propyl-1H-pyrazol-4-yl)propionate (500 mg) and N,N-dimethylformamide (10 ml), which was stirred for 12 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionate (620 mg, yield: 53%) was obtained as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[N+:17]([O-])=O)C>[C].[Pd].C(O)C>[F:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][C:10]=1[NH2:14])[NH:17][C:4](=[O:3])[CH:5]=[N:6]2
Reactant: CCOC(=O)CNc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2[nH]c(=O)cnc2cc1F
Yield: 68.8 %

Procedure:
N-(2,4-Dinitro-5-fluorophenyl)glycine ethyl ester (9.32 g), 2% palladium-carbon (50% hydrated) (10 g) and ethanol (200 ml) were charged into an autoclave, and catalytic reduction was carried out at room temperature under an initial pressure of 37 atm. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to give 6-fluoro-7-amino-1,2-dihydroquinoxalin-2-one (4.0 g; yield, 68.0%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([CH:1]2[CH2:3][CH2:2]2)[OH:25])[C:21]([S:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: O=Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of cyclopropylmagnesium bromide (0.5 M, 1.55 ml, 0.78 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-formyl-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (130 mg, 0.22 mmol) in THF (15 ml) and the mixture stirred for 2 hours. The reaction was concentrated under reduced pressure onto silica and the residue purified by flash column chromatography using ethyl acetate 1/1 hexane as eluent to afford 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide as a green foam (74 mg, 54 %). 1H NMR (CDCl3): 8.40 (1H, s, py); 8.18 (1H, d, Ar); 7.51 (3H, m, py and Ar); 7.39 (1H, s, py); 7.34 (1H, d, Ar); 7.06 (2H, d, Ar); 4.50 (1H, d, CHOH); 2.89 (4H, m, 2×CH2N pip); 1.54 (4H, m, 2×CH2 pip); 1.34 (2H, m, CH2 pip); 0.97 (1H, m, CH cprop); 0.39 (4H, m, 2×CH2 cprop).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22]COC)[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)ccc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)c(O)c1
Yield: 77 %

Procedure:
Then, 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone was dissolved in 7.5 ml of methanol, and 7.5 ml of hydrochloride acid/methanol was added to the solution and the mixture was heated and refluxed. After the reaction, the solvent was removed from the reaction mixture by distillation and the obtained residue was dissolved in a small amount of ethyl acetate and crystallized from ether/hexane to obtain 3.5 g (yield=77%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-hydroxy-4-methoxyphenyl)-1-propanone in the form of a colorless transparent rectangular crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[H-].[Na+].Cl[CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:33][C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[C:21](=[O:25])[CH:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cn1cc(CCl)cn1
Reactant: N#Cc1cc(COc2cc[nH]c(=O)c2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)cc2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
To a solution of 2-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyridinyl)oxy]methyl}benzonitrile (60 mg, 0.143 mmol) in N,N-dimethylformamide (2 mL) was added Sodium hydride (40 mg, 1.00 mmol) at rt in one portion. After stirring at rt for 10 min, 4-(chloromethyl)-1-methyl-1H-pyrazole (40 mg, 0.306 mmol) was added. The reaction mixture was heated at 60° C. in the microwave for 30 min, then quenched by addition of methanol, concentrated. Purification via Biotage-C18 system afforded the title product (13.6 mg) as a white solid. LC-MS (ESI): m/z 515 [M+H]+; 3.36 min (ret time).
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([O:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([O:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[C:9]([OH:33])=[O:8])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O

Procedure:
A mixture of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid benzyl ester and 10% Pd/C wet in EtOAc was hydrogenated under H2 balloon for 30 mins. The reaction was filtered off the catalyst and concentrated. The residue was purified by HPLC (15 to 70% ACN—H2O (0.1% TFA)) to give oil: 128 mg. HPLC retention time=1.07 minutes (condition C); MS (m−1)=375.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].CCO>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 65.5 %

Procedure:
To a solution of 5-nitroisoindoline-1,3-dione (2 g, 10.41 mmol) in DMF (10 ml), K2CO3 (1.439 g, 10.41 mmol) and methyl 2-bromoacetate (1.930 ml, 20.82 mmol) were added, and the mixture was reacted under MW irradiation for 2 hr at 140° C. Then the solid K2CO3 was filtered off, the solvent was evaporated and the resulting crude was triturated with EtOH obtaining the title compound as a pale brown solid (1.8 g, 6.82 mmol, 65.5% yield, UPLC-MS purity 90%, MS/ESI+ 265.1 [MH]+) which was used without any additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:10][C:11]=1[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:10][CH2:9][N:8]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccsc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Temperature: 40 °C
Yield: 76 %

Procedure:
A solution of the product from step b) (5.83 g, 18 mmol) was dissolved in EtOH (32.4 ml) and treated with 10% Pd/C (Wet Degussa type, 11.7 g) and heated to 40° C. for 2 days under H2 (1 atm). Next, the Pd/C was removed by filtration through celite, replaced with fresh 10% Pd/C (11.7 g) and the reaction was continued for two more days. The Pd/C was filtered through celite and the EtOH was evaporated in vacuo to provide the subtitle compound (4.5 g, 76%) that was used without further purification. MS calculated for C19H23NO2S+H 330, observed 330.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([OH:24])[C:12](=[NH:23])[NH:13][O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>COCCOCCOC>[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][N:13]=1)[OH:24]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Solvent: COCCOCCOC
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(O)c1noc(-c2ccccc2)n1
Yield: 29.9 %

Procedure:
A solution of (3) (1.5 g, 4.3 mmol) in diglyme was heated at 150° C. in a microwave (Smith Creator, S00219) for 40 minutes. Solvent evaporated under vacuum in Genevac Evaporator at 80° C. for 3 hours to give a brown solid. This was taken in dichloromethyl (40 ml) and treated with trifluoroacetic acid at room temperature for 2 hours. Solvent evaporated to dryness under reduced pressure, crude taken in water, washed with DCM, aqueous layer basified with 1M NaOH solution and extracted with dichloromethyl. Organic layer dried over Na2SO4 to give pale brown solid (300 mg); 1HNMR (CDCl3) 8.14–8.10 (m, 2H), 7.59–7.47 (m, 3H), 4.83 & 4.65 (d, J=5 Hz, 1H), 3.18–3.05 (2m, 1H), 1.71–1.20(m, 2H), 1.05–0.97 (dt, J=7.2 Hz, 3H).
Reaction SMILES: CS(C)=[O:3].C([O-])([O-])=O.[K+].[K+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:27][CH:28]=3)[CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)#[N:12].OO>CO.O>[N:36]1([CH2:35][CH2:34][CH2:33][O:32][C:26]2[CH:25]=[C:24]3[C:29]([CH2:30][CH2:31][N:22]([S:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]([NH2:12])=[O:3])=[CH:14][CH:15]=4)(=[O:20])=[O:21])[CH2:23]3)=[CH:28][CH:27]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Yield: 26 %

Procedure:
A 1.4 mL DMSO mixture of K2CO3 is stirred under N2, 2-(4-cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline (75 mg, 0.17 mmol) is added, 0.2 mL H2O added, followed by 30% H2O2 (1.4 mL, 12 mmol) and reaction is stirred at room temperature for 4 hours. The reaction mixture is diluted with MeOH, filtered, and the solids washed twice with MeOH. The filtrate is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give the product as an off-white solid (26 mg, 26% yld). MS (ES+)458.2(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:10][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)cc1Sc1ccc(Cl)cc1

Procedure:
3-(4-Chlorophenylthio)-4-nitro-benzenesulphonamide (0.50 g, 1.45 mmol), NH4Cl (0.16 g; 2.90 mmol) and Fe powder (0.40 g; 7.25 mmol) were suspended in EtOH (10 ml)/water (5 ml) and refluxed for 30 minutes. The solution was filtered, evaporated down and the residue was taken up in CH2Cl2. It was washed with water, dried over MgSO4 and evaporated down. The residue was used again in its crude form. Yield: 0.43 g=94% 13C (100 MHz, CDCl3)d 152.17, 136.12, 133.59, 132.24, 130.75, 129.86, 129.38, 128.37, 114.69, 114.09