Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][N:8]([C:7]1[N:6]=[C:5]2[O:13][C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([C:16]([NH:18][CH3:19])=[O:17])[C:4]2=[CH:3][C:2]=1[I:1])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(I)cc12
Temperature: 120 °C

Procedure:
To 5-iodo-N-methyl-6-(methylsulfonamido)-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (crude ˜20%) (400 mg, 0.824 mmol) was added 1,4-dibromobutane (1780 mg, 8.24 mmol) and CESIUM CARBONATE (537 mg, 1.648 mmol) and DMF (4 ml) Heated at 120° C. 30 min. Added water and extracted with EtOAc. Conc. on vac to oil. Added 3 mL ACN and 1 mL water. Filtered with 0.45p filter Purified via HPLC C8 40-80% ACN/H2O (0.1% NH4OH) 40 mL/min over 10 min. to give 6-(N-(4-bromobutyl)methylsulfonamido)-5-iodo-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Nc1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.34 mmol) in THF (20 mL) and water (2 mL) was added sodium hydroxide (54.39 mg, 1.36 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (80 mg, 66%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[O:22])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([C:25]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=2[NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[O:22])=[O:32])=[N:35][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
The mixture of the compound of (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide example 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t. for 5 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S M+=541, (M+2)+=543.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[I:13]I>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([I:13])[C:7]=1[OH:8]
Reactant: II
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(Cl)c(O)c(I)c1

Procedure:
To a solution of 3-chloro-4-hydroxyphenylacetic acid (1.25 g) in glacial acetic acid (20 mL) was added 2.0 g of iodine crystals while stirring. The mixture was stirred in dark at ambient temperature for 2 days. The resulting mixture was diluted with water, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-chloro-5-iodo-4-hydroxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (2 mL) carefully, stirred at reflux for 20 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with water, extracted with dichloromethane. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-chloro-5-iodo-4-hydroxyphenylacetic acid methyl ester (90 mg, 4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[C:16]([Cl:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1>[Cl:25][C:16]1[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=1[S:21]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](=[O:12])(=[O:11])[NH2:13])(=[O:23])=[O:22]
Reactant: Nc1cc(F)c(F)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(F)c(F)cc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
2-Amino-4,5-difluorobenzenesulfonamide (99 mg, 0.48 mmol) and dichlorobenzenesulfonyl chloride (152 mg, 0.62 mmol) were dissolved in anhydrous pyridine (2 mL). The mixture was stirred at ambient temperature under an atmosphere of argon for 24 h. The solvent was evaporated in vacuo, water was added and the product was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. Purification by preparative HPLC gave 107 mg (54% yield) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]3[C:15]=2[NH:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[C:26][C:2]2[S:6][C:5]([C:7]3[N:8]=[C:9]4[CH:14]=[N:13][CH:12]=[CH:11][N:10]4[C:15]=3[NH:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(C#Cc3cccnc3)s2)nc2cnccn12
Temperature: 50 °C
Reaction time: 72 h
Yield: 48.6 %

Procedure:
600 mg (1.48 mmol) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1,1,3,3-tetra-methyl-butyl)-amine were dissolved together with 183 mg (1.77 mmol) of 3-ethynylpyridine, 104 mg (0.15 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 28 mg (0.15 mmol) of copper(I)-iodide in DMF (10 ml). After addition of 2.00 ml (14.78 mmol) of triethylamine, the mixture was stirred at 50° C. for 3 d. The reaction solution was then diluted with EA and combined with a sat. aq. sodium carbonate solution. The phases were separated and the aqueous phase extracted with EA. The combined organic phases were washed 2× with a sat. aq. sodium carbonate solution and dried over sodium sulfate. After filtration and removal of the solvents under a vacuum, column chromatography (EA) was carried out with the group. After crystallisation of the resultant crude product, 310 mg (0.72 mmol, 49% of theoretical) of [2-(5-pyridin-3-ylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.[CH2:11]([O:13][C:14]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[C:15]#[CH:16])[CH3:12]>>[CH2:9]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:16]#[C:15][C:14]([O:17][CH2:18][CH3:19])([O:13][CH2:11][CH3:12])[O:20][CH2:21][CH3:22])[CH:7]=1)[CH3:10]
Reactant: CCOc1cncc(Br)c1
Reactant: C#CC(OCC)(OCC)OCC
Product: CCOc1cncc(C#CC(OCC)(OCC)OCC)c1
Yield: 37 %

Procedure:
The title compound was synthesized from 3-bromo-5-ethoxy-pyridine and 3,3,3-triethoxypropyne using the procedure described in Example 43, step (e), in 37% yield. 1H NMR (CDCl3) δ 8.27 (bs, 1H), 8.24 (bs, 1H), 7.21 (m, 1H), 4.02 (q, 2H, J=7.0 Hz), 3.72 (q, 6H, J=7.0 Hz), 1.39 (t, 3H, J=7.0 Hz), 1.23 (t, 9H, J=7.0 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:20])[CH3:19]
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([OH:65])[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:73](Cl)(=[O:87])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([O:65][C:73](=[O:87])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:44][O:45][C:46]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:39])([CH3:40])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Another batch of IX was prepared as follows: to a solution of VIII (1.60 g, 1.78 mmol), Et3N (0.50 mL, 3.56 mmol) and DMAP (22 mg, 0.178 mmol), in CH2Cl2 (12 mL) was added dropwise myristoyl chloride (0.53 mL, 1.96 mmol) at 0° C. The reaction mixture was allowed to warm up slowly to room temperature. After stirring 24 h at room temperature, the reaction mixture was diluted with CH2Cl2 (50 mL), washed sequentially with 5% aqueous sodium bicarbonate (15 mL), water (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 0.2% MeOH in CHCl3) furnished 17 (1.60 g, 81%) as oily liquid. NMR spectra coordinates are as follows: 1H NMR (CDCl3): δ 7.34-7.05 (m, 35H), 5.05-4.96 (m, 1H), 3.53-3.42 (m, 4H), 3.08 (dd, J=10.0, 3.2 Hz, 1H), 2.99 (dd, J=10.0, 6.0 Hz, 1H), 2.68-2.54 (m, 6H), 2.25 (t, J=8.0 Hz, 2H), 1.64-1.55 (m, 2H), 1.35-1.14 (m, 20H), 0.98 (s, 118H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](OC(C)(C)C)[CH2:27][C:26]3=C=O)=[CH:21][CH:20]=2)[C:15](=C=O)[CH2:14]1)(C)(C)C>C(Cl)Cl>[N:16]1([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]1
Reactant: CC(C)(C)ON1CCN(c2ccc(N3CCN(OC(C)(C)C)CC3=C=O)cc2)C(=C=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)ccc1N1CCNCC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution in methylene chloride (1 ml) of 1,4-bis(4-tert-butoxy-carbonyl-1-piperazinyl)benzene (59 mg; 0.13 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resultant concentrated residue (81 mg) was dissolved in methanol-chloroform (1:2). The solution was applied to a column packed with alumina (3 g), and the column was eluted with methanol-chloroform (1:2). The eluate was concentrated under reduced pressure, thereby obtaining 31 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC1(C)OC[C@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 11 h
Yield: 90.2 %

Procedure:
In N,N-dimethylformamide (400 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (14.53 g, 82.00 mmol) and (4S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (23.10 g, 90.20 mmol). Cesium carbonate (34.7 g, 1.06.6 mmol) was added to the solution and the mixture was stirred at 50° C. for 11 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 22.58 g (90%) of the title compound in the form of a yellow orange oily product.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=CC=C[CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.BrC1C=CC=C(C(C)C)C=1>>[CH:25]([C:1]1[CH:2]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[C:9]([OH:11])=[O:10])[CH:4]=[CH:5][CH:6]=1)([CH3:30])[CH3:26]
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: CC(C)c1cccc(Br)c1
Product: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using 1-bromo-3-isopropylbenzene (Lancaster). Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 374.1 [M+H]+; HPLC: single peak at tR=8.95 min (System 1).
Reaction SMILES: [Cs].[CH3:2][CH:3]([CH3:15])[CH2:4][CH2:5][CH:6]1[N:10]([CH3:11])[S:9](=[O:13])(=[O:12])[NH:8][C:7]1=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1([S:28][CH2:29]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.CN(C=O)C>[C:22]1([S:28][CH2:29][N:8]2[C:7](=[O:14])[CH:6]([CH2:5][CH2:4][CH:3]([CH3:15])[CH3:2])[N:10]([CH3:11])[S:9]2(=[O:13])=[O:12])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 85 °C
Yield: 70.6 %

Procedure:
A mixture of 4-(3-methylbutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 retool) of the 1,1-dioxide in methanol with 5 5.13 g of Cs2CO3 followed by removal of the solvent) and phenylthiomethyl chloride (6.65 g, 41.94 mmol) suspended in DMF was heated at 85° C. for 17 hours. The mixture was cooled, and poured into 300 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3×) and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 g (70.6%) of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C@@H:17]1[O:38][C@H:37]([C:39]([O:41][CH3:42])=[O:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:23]([O:24]CC2C=CC=CC=2)[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C@@H:17]1[O:38][C@H:37]([C:39]([O:41][CH3:42])=[O:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:23]([OH:24])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])=[O:4]
Reactant: COC(=O)CCCCCCCCCCCO[C@@H]1O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCCCCO[C@@H]1O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](O)[C@H]1OC(C)=O

Procedure:
A solution of 11 (30 mg) in 2 mL of methanol was hydrogenated in the presence of 5% Pd/C (10 mg) for 24 hours. The reaction was monitored by TLC. The suspension was filtered and, after complete evaporation of the solvent and chromatography, pure methyl 1-O-(11-methoxycarbonylundecyl)-2, 4-di-O-acetyl-β-D-glucopyranosuronate (12) was obtained. The 1H NMR data confirmed the complete debenzylation.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]#[CH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:14]1C=CC=C[C:15]=1OC#N>CCOCC>[C:6]1([C:12]#[C:13][C:15]#[N:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#COc1ccccn1
Reactant: C#Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#CC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (21.6 mL, 2.5M in hexane) was added dropwise to a solution of phenylacetylene (5 g, 0.05 mol) in dry Et2O (200 mL) maintaining at −78° C. under inert atmosphere. A solution of 2-pyridyl cyanate (7.2 g, 0.06 mol) in dry Et2O (100 mL) was added dropwise keeping the temperature below −60° C. The mixture was stirred for 30 min at −78° C. then warmed to RT. The reaction was diluted with Et2O and quenched with 1N NaOH. The organic layer was washed once with 1N HCl and once with saturated NaHCO3. The solvent was removed under vacuum maintaining the temperature under 30° C. to give 3-phenyl-2-propynenitrile as a colorless crystalline solid.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:29])=[O:28])[CH:22]=3)[CH:17]=2)[O:12]1)(C)C.Cl>O1CCOCC1>[OH:6][C@H:7]([CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:8][NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:29])=[O:28])[CH:22]=3)[CH:17]=2)[O:12]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNC[C@H]1CCc2cc(-c3ccnc(C(N)=O)c3)ccc2O1)COc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)COc2ccccc2)O3)ccn1

Procedure:
4-[(2R)-2-({[(2S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-3-(phenyloxy)propyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinecarboxamide (Example 93, 20 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 30 minutes. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the dihydrochloride salt (8 mg, 43%): MS m/z 434.3 (MH+ of the free base); retention time (LC-MS)=2.02 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:36]([O:35][C:31]1[CH:30]=[C:29]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:21])=[CH:9][CH:10]=2)[CH:34]=[CH:33][N:32]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(NCc1ccc(B(O)O)cc1)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)Oc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1cc(-c2ccc(CNC(=O)c3c(Cl)cccc3Cl)cc2)ccn1

Procedure:
4-[(2,6-Dichloro-benzoylamino)methyl]phenylboronic acid (5 g, 15.4 mmol), potassium carbonate (5 g), and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.56 g, 0.77 mmol) were combined in a round bottom flask. 4-Bromo-2-(t-butoxy)pyridine (3.55 g, 15.4 mmol) was dissolved in 20 mL DMF and added to the flask under stirring. The flask was flushed with nitrogen and 10 mL water was added. The reaction mixture was stirred at 70° C. for two hours. After cooling the mixture was poured into 300 mL ethyl acetate and washed with water and brine. The organic phase was dried with magnesium sulfate and evaporated under vacuum. The crude N-[4-(2-tert-butoxy-pyridin-4-yl)-benzyl]-2,6-dichloro-benzamide was further purified by silica gel chromatography (eluent: hexone/ethyl acetate 1:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:34][CH2:35]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1.8 g, 2.57 mmol) in THF (21 ml) was added MnO2 (4.9 g, 56.5 mmol). After stirring at rt for 20 h, the reaction mixture was filtered through a pad of celite with THF wash (250 mL). The filtrate was concentrated, and the residue was purified via silica gel chromatography (MeOH-DCM, 0-5%) to afford the title compound (1.4 g, 76%). LCMS: Rt=1.04 min, m/z=715.3 (M+H). Method 2m_acidic.