Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26]Cl)=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][I:30])=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCCl)cc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCI)cc1

Procedure:
Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)benzoate was converted to iodide by the method described in Example A-I-1, step e to give the title compound (1.16 g) practically pure. Rf (2%MeOH/CHCl3) 0.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:21]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19]C)=[O:17].Cl.O1CCOCC1>CO>[NH2:21][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CCOC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of ethyl 6-(2,6-dimethoxyphenyl)-6-(1,1-dimethylethylsulfinamido)hexanoate (5.360 g; 13.41 mmol) in MeOH (100 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (6.7 ml; 26.80 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h50. The obtained yellow solution was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate as a yellow oil. LC-MS (conditions B): tR=0.62 min.; [M+H]+: 282.10 g/mol.
Reaction SMILES: [K].[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([OH:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].I[CH3:31]>CN(C)C=O>[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([O:27][CH3:31])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18]
Reactant: CI
Reactant: N#Cc1cc(O)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1-n1ccc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reaction time: 2 h

Procedure:
The potassium salt of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-hydroxybenzonitrile (from Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrous dimethylformamide under nitrogen. Iodomethane (93 mg, 0.66 mmol) was added, and stirring continued for 2 hr. The mixture was diluted to 50 ml with ice-cold water, and the white precipitate collected by filtration. The precipitate was washed thrice with water, sucked dry under a blanket of nitrogen, and dried further in vacuo overnight (242 mg, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, J=9.90, 2.39 Hz, 1H), 7.17 (dt, J=8.75, 2.47 Hz, 1H), 6.75 (d, J=7.97 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ −109.24 (quintet, J=7.85 Hz, 1F), −113.54 (quartet, J=9.83 Hz, 1F), −118.33 (d, J=7.77 Hz, 1F). LC/MS tr=5.40 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 421 (M+H). ES-HRMS m/z 421.0522 (M+H calcd for C20H13ClF3N2O3 requires 421.0561).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34]1([CH:37]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH2:38][OH:39])[CH2:36][CH2:35]1.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53](O)=[O:54]>O1CCCC1>[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53]([O:39][CH2:38][CH:37]([CH:34]1[CH2:36][CH2:35]1)[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)=[O:54]
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)OCC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A stirred solution of 11.7 grams (0.045 mole) of triphenylphosphine in 75 mL of dry tetrahydrofuran was cooled to 0° C., and 9.0 grams (0.045 mole) of diisopropyl azodicarboxylate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. Successively, 4.4 grams (0.022 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol (prepared in Example 1, Step B) and 3.4 grams (0.045 mole) of thiolacetic acid were then added. The exothermic reaction caused the reaction mixture temperature to rise to 39° C. After cooling to ambient temperature the reaction mixture was stirred for 16 hours. The reaction mixture was then concentrated under reduced pressure to a residual oil. The oil was subjected to chromatography on silica gel using methylene chloride:heptane (1:4) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.6 grams of 2-cyclopropyl-2-(4-chlorophenyl)ethyl thiolacetate as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([O:17][C:18](=[O:20])[CH3:19])[CH2:14]2)=[CH:9][CH:8]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([O:17][C:18](=[O:20])[CH3:19])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)CC(OC(C)=O)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC(=O)OC1CCc2ccc(O)cc2C1
Temperature: -78 °C

Procedure:
BCl3 (1 M in DCM, 56 mL) is added to a mixture of acetic acid 7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl ester (4.94 g, 22.5 mmol) and Bu4NI (10.8 g, 29.2 mmol) in DCM (112 mL) at −78° C. The mixture is stirred at −78° C. and then warmed to room temperature over 1 h. The mixture is partitioned between EtOAc and ice-cold brine. The organic layer is dried over MgSO4, concentrated and chromatographed to afford acetic acid 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl ester as a yellow oil, which upon standing at room temperature becomes a solid: 1H NMR (CDCl3) δ 6.96 (d, J=8.0 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.55 (s, 1H), 5.18 (m, 1H), 5.00 (m, 1H), 3.05 (dd, J=16.0, 8.0 Hz, 1H), 2.90-2.72 (m, 3H), 2.06 (s, 3H), 2.06-1.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=4[S:29][N:28]=3)=[O:26])=[CH:20][C:19]=2[C:37]([F:40])([F:39])[F:38])[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][C:34]([O:36][C:6]5[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=5)=[CH:35][C:30]=4[S:29][N:28]=3)=[O:26])=[CH:20][C:19]=2[C:37]([F:40])([F:38])[F:39])[CH2:13][CH2:12]1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(O)ccc34)cc2C(F)(F)F)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(Oc5cc(Cl)nc(N)n5)ccc34)cc2C(F)(F)F)CC1

Procedure:
Prepared as described in step 6.3 from 401 mg (2.45 mMol) 2-amino-4,6-dichloropyrimidine, 785 mg (1.74 mMol) 6-hydroxy-benzo[d]isothiazole-3-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide and 1.5 g (7.1 mMol) K3PO4 in 45 ml NMP: MS: [M+1]+=578/580; HPLC: tRet=14.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:15]([O:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccnc1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
152.6 g of potassium carbonate and 15.3 g of cesium carbonate are added to a solution of 122 g of 3-hydroxy-2-iodopyridine and 65.7 ml of benzyl bromide in 1.5 l of dimethylformamide, and the suspension is stirred under argon atmosphere for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with dichloromethane, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with hexane/10-20% ethyl acetate. 146.3 g of 3-benzyloxy-2-iodopyridine is obtained as oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[C:11]2=[O:26])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])[C:11]2=[O:26])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(N2CC(=O)N(c3ccc(C(C)C)cc3)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1ccc(N2C(=O)CN(c3cccc(C(=O)O)c3)C2=O)cc1
Yield: 72.9 %

Procedure:
A solution of methyl 3-[1-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-3-yl]-benzoate (0.30 g, 0.85 mmol) in pyridine (2 mL) was treated with anhydrous lithium iodide (1.5 g, 11.2 mmol), and the resulting mixture was heated to reflux for 4 h. The solution was cooled, evaporated and partitioned between ethyl acetate and 1N aq. HCl. The aqueous layer was extracted with more ethyl acetate, and the extracts were washed with satd. aq. brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title product as a solid (0.21 g, 0.62 mmol, 73%), m.p. 249-252° C. 1H NMR (d6-DMSO, 300 MHz): d 13.09 (1H, br), 8.29 (1H, t, J=2 Hz), 7.82 (1H, d, J=8 Hz), 7.72 (1H, d, J=8 Hz), 7.56 (1H, t, J=8 Hz), 7.38 (2H, d, J=8 Hz), 7.31 (2H, d, J=8 Hz), 4.62 (2H, s), 2.96 (1H, m, J=7 Hz), 1.22 (6H, d, J=7 Hz). Mass spectrum (ES+): m/z 340 (18), 339 (100). Elemental analysis: calculated for C19H18N2O4 C 67.45, H 5.32, N 8.28; observed C 67.26, H 5.10, N 8.12.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[Li]CCCC.CN(C)[CH:21]=[O:22]>O1CCCC1.CCOCC>[CH:11]1([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH:21]=[O:22])[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(C2CC2)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc(C(=O)O)ccc1C1CC1
Temperature: -78 °C
Yield: 76.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3, 500 mg, 2.07 mmol) in tetrahydrofuran/Et2O (1:1, 20 mL). The solution was cooled to −78° C. then n-BuLi (2.5 M in THF) (1.8 mL, 4.5 mmol) was added drop-wise with stirring. The resulting solution was stirred for an additional 30 min at −78° C., then N,N-dimethylformamide (0.49 mL, 6.3 mmol) was added drop-wise over 10 min. The mixture was stirred for 2 h at −78° C., then quenched with water (100 mL). The pH of the solution was adjusted to 3-4 with aqueous HCl (6 M), then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as the eluent to yield 0.3 g (76%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.OC1C=CC([N:16]2[C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[NH:17]2)=CC=1>>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][C:1]=1[N:16]1[C:20](=[O:21])[N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:28])[NH:17]1
Reactant: Cc1ccc(O)cc1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Product: Cc1ccc(O)c(-n2[nH]c(=O)n(-c3ccccc3)c2=O)c1

Procedure:
Compound 32 was prepared from p-cresol in the same manner of compound 27, and was obtained as white solids (60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C=1>>[O:18]=[C:9]1[C@@H:10]2[C@@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1
Reactant: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)[C@H]3CCCC[C@H]3C2=O)cc1)c1ccccc1
Yield: 77.4 %

Procedure:
The title compound (293 mg, 77% yield, white crystals) was prepared from cis-2-(4-hydroxy-phenyl)hexahydroisoindole-1,3-dione (245 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=379 (M+1); Rt=4.08 min.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1>C(#N)C>[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[C:18]([N+:7]([O-:8])=[O:6])=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1
Reactant: O=[N+]=O
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nn(C(=N)N)c(C)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2 g of nitronium tetrafluoroborate were added little by little to a suspension of 2.01 g of 3,5-dimethyl-1H-pyrazole-1-carboxamidine nitrate in 150 ml of absolute acetonitrile, with cooling with ice in argon atmosphere, and the reaction mixture was stirred for 30 minutes with cooling with ice. The solvent was removed by distillation under reduced pressure, and the residue was washed with chloroform to obtain 2.43 g of 3,5-dimethyl-4-nitro-1H-pyrazole-1-carboxamidine nitrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:21]#[N:22])[C:10]1=[O:20])[CH:26]=[CH2:25]
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.00 g, 3.40 mmol) in 20 mL of N,N-dimethylformamide at 0° C. was added sodium hydride (163 mg of 60% dispersion in mineral oil, 4.08 mmol). After 30 minutes, allyl iodide was added (0.342 mL, 3.74 mmol), and the reaction was stirred for 2 hours. The reaction was quenched with water and partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was subjected to flash chomatography through SiO2 (5-60% EtOAc/hexane) to provide the first eluting product as the titled compound. 1H NMR, difference nOe, and HMQC NMR spectral data for the product were consistent with the titled compound. ESI+MS: 335.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:8][O:9][C:10](=O)[C:11]([N:21]1[C:29]2[C:24](=[C:25]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:34]([O:33][C:31]([NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[N:22][N:21]2[C:11]([C:10]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(N)=NOC(=O)C(CC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NC(=O)OC(C)(C)C)cccc32)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B above (0.18 g, 0.33 mmol) in pyridine (9.0 mL) was added phosphorus oxychloride (0.25 g, 1.65 mmol). The mixture was heated at 70° C. for 7 hours, and stirred at 35° C. overnight, then concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO3, water and brine. The organic layer was separated and dried over Na2SO4. The crude product was purified on a silica gel column using a gradient of 0-50% ethyl acetate in hexanes to give the title compound as light brown solid. LC/MS m/z=526.1[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:25])[NH:51][S:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)(=[O:50])=[O:49])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)c4ccccc4)c3)cc12
Yield: 67.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and benzenesulfonamide (43 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the suspension was stirred at r.t. overnight, over which time the solids dissolved. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated to give 32 mg (67% yield) of the title compound as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1H) 8.52 (q, J=4.48 Hz, 1H) 8.24 (s, 1H) 7.97-8.06 (m, 4H) 7.90-7.97 (m, 2H) 7.85 (d, J=7.94 Hz, 1H) 7.74-7.81 (m, 2H) 7.66-7.73 (m, 1H) 7.63 (t, J=7.63 Hz, 2H) 7.58 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87 (d, J=4.58 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.77 min, (ES+) m/z (MH+)=529. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=15.70 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=14.90 min, purity=99%.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=O)=[CH:18][CH:17]=1.O>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=[CH:5][C:3]#[N:4])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=CC#N)CC2
Reaction time: 15 h
Yield: 52.5 %

Procedure:
To a solution of 60% sodium hydride (2.71 g, 67.9 mmol) in THF (150 ml) was added dropwise, under ice-cooling, diethyl cyanomethylphosphonate (11.5 g, 64.8 mmol). The mixture was stirred for 15 hours, to which was then added dropwise a solution of 6-methoxy-1-indanone (10.0 g, 61.7 mmol) in THF (30 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, and the organic layer was subjected to extraction with ethyl acetate. The extract solution was washed with brine and water, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=8:2). Recrystallization of the product-from ethyl acetate/hexane afforded the above-titled compound (6.00 g, yield 53%).
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:9]([NH:11][C:12]([C@@H:14]1[CH2:18][C@H:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][NH:15]1)=[O:13])[CH3:10].[Cl-].[Na+]>CN(C)C=O>[CH2:9]([NH:11][C:12]([C@@H:14]1[CH2:18][C@H:17]([S:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:16][N:15]1[CH2:1][CH3:2])=[O:13])[CH3:10]
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
301 μl of ethyl iodide and 314 mg of sodium bicarbonate were added, whilst ice-cooling, to a solution of 1.00 g of (2S, 4S)-2-ethylcarbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 8 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (eluted with ethyl acetate) to afford 982 mg of the title compound as colorless crystals, melting at 60°-61° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].[CH:23]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32]2[CH:41]=[C:40](O)[C:39]3[C:34](=[CH:35][C:36]([O:43][CH3:44])=[CH:37][CH:38]=3)[N:33]=2)[N:31]=1)([CH3:25])[CH3:24]>CS(C)=O.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH:14]([O:16][C:40]2[C:39]3[C:34](=[CH:35][C:36]([O:43][CH3:44])=[CH:37][CH:38]=3)[N:33]=[C:32]([C:30]3[N:31]=[C:27]([NH:26][CH:23]([CH3:25])[CH3:24])[S:28][CH:29]=3)[CH:41]=2)[CH2:13][CH:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a stirred solution of N-Boc-trans-4-hydroxy-L-proline (221 mg, 0.96 mmol) in DMSO was added potassium tert-butoxide (320 mg, 2.9 mmol). After 1 h compound 12 (319 mg, 0.96 mmol) was added and the mixture was stirred at 70° C. for 72 hours. The mixture was diluted with water and extracted with ethyl acetate. The product was used without further purification. Yield 429 mg, 85%.