Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)[N:6]=1.I[CH3:28].[O:29]1CCC[CH2:30]1>C(OCC)(=O)C>[NH2:20][C:18]1[N:19]=[C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])=[N:6]2)[N:15]=[C:16]2[C:17]=1[N:21]([CH3:28])[C:30](=[O:29])[NH:22]2
Reactant: C1CCOC1
Reactant: CI
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1N
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c2nc(-n3nc(Cc4ccccc4F)c4ncccc43)nc(N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.392 mmol) of 2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine (example 2A) were initially charged in tetrahydrofuran (11.1 ml) and the suspension was cooled to 0° C. Subsequently, 0.43 ml of a 1M solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran was added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 24.4 μl (0.392 mmol) of iodomethane were added dropwise and the reaction mixture was stirred at RT overnight. The reaction mixture was again cooled to 0° C. and a further 12.2 μl (0.196 mmol) of iodomethane (dissolved in 1.0 ml of tetrahydrofuran) were added. Thereafter, the mixture was stirred at 0° C. for 1 h and then heated to reflux overnight. The reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was chromatographed on silica gel (eluent: dichloromethane/methanol 40:1) and the product fractions were concentrated. This gave 15.6 mg (10% of theory) of the title compound in solid form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:9][CH2:10][C:11]([CH3:13])=[CH2:12])[CH2:6]C=C)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH:13]=[C:11]([CH3:12])[CH2:10][O:9]1)=[O:14])[CH3:2]
Reactant: C=CCC(OCC(=C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1CC=C(C)CO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
To a refluxing stirred solution of 2-(2-methyl-allyloxy)-pent-4-enoic acid ethyl ester (396 mg, 2.0 mmol) in CH2Cl2 (100 mL, 0.02 M solution) was added drop wise a solution of the tricyclohexylphosphine (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(benzylidine)ruthenium (IV)dichloride (85 mg, 0.1 mmol) in CH2Cl2 (3.0 mL). After 50 min, the reaction mixture was cooled to room temperature, concentrated and purified on silica gel bond elute using EtOAc/hexane (1:20) as an eluent furnished 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (320 mg, 92% yield) as a brown oil.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15](C)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[CH3:25]C(C)=O>>[CH3:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:19]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3cccc(C)c3)cs2)c(C)s1
Yield: 76 %

Procedure:
48 mg (0.194 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-1-phenylpropan-1-one (0.223 mmol; 48 mg) was added and the solution was allowed to reflux for 5 h. The solution was allowed to cool and the reaction mixture was concentrated and dissolved in 50 mL of CH2Cl2. The organic layer was washed with 50 mL of 1N HCl (aq.), dried over sodium sulfate and concentrated. The crude product was purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 53 mg (76% yield) of methyl 4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][OH:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Cl.Cl[C:23]([N:25]1[CH:30]([CH3:31])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]1[CH3:39])=[O:24]>>[CH3:39][C@H:26]1[CH2:27][NH:28][CH2:29][C@@H:30]([CH3:31])[N:25]1[C:23]([O:5][CH2:4][C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([F:12])[CH:14]=2)=[CH:7][C:6]=1[F:11])=[O:24]
Reactant: Fc1ccc(CCl)cc1F
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1C(=O)Cl
Reactant: OCc1c(F)cc(O)cc1F
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1c(F)cc(OCc2ccc(F)c(F)c2)cc1F

Procedure:
2,6-Difluoro-4-(3,4-difluorobenzyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 3,4-difluorobenzyl chloride and 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Example 54 and 121 to give the product as a yellow oil: δH (400 MHz; d6-DMSO) 1.13 (6H, d, J 7.0 Hz), 2.60 (2H, dd, J 12.0, 4.5 Hz), 2.66 (2H, d, J 12.0 Hz), 3.77–3.85 (2H, m), 5.04 (2H, s), 5.13 (2H, s), 6.84–6.92 (2H, m), 7.29–7.35 (1H, m), 7.48 (1H, dt, J 11.0, 8.5 Hz) and 7.55 (1H, ddd, J 11.5, 7.5, 2.5 Hz); HPLC (XTERRA, 50–80%, 220 nm) 99.5% (6.17 min).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])N)=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17].N([O-])=O.[Na+]>C(OCC)(=O)C>[Cl:1][C@@H:9]([CH2:8][C:7]1[CH:14]=[CH:15][C:4]([O:3][CH3:2])=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: Cl
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](Cl)C(=O)O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To suspension solution of O-methyl-3-nitro-L-tyrosine.hydrochloride(4.93 g) in 6N aqueous hydrochloric acidwas added under ice-cooling, sodium nitrite (1.97 g) and was stirredat the same temperature for 1 and 1/2 hour and further at roomtemperature for 3 hours. The resultant suspension solution wasextracted with ethyl acetate (50 ml×3). After the ethyl acetate layerwas washed with saturated brine, dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo to give (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionicacid (4.46 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:14][NH2:15].C[O-].[Na+].[C:19](=[O:26])(OCC)OCC>CO>[NH2:14][N:15]1[CH2:12][C@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:11][C:19]1=[O:26]
Reactant: CCOC(=O)OCC
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: NN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NN1C[C@H](COCc2ccccc2)OC1=O
Temperature: 95 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
(R)-2-(Benzyloxymethyl)oxirane (2.5 g, 15.23 mmol) was added dropwise to hydrazine mono-hydrate (4.67 g, 91 mmol), previously heated at 95° C., under vigorous stirring. The mixture was refluxed for 30 min. The excess of hydrazine hydrate was evaporated under vacuum for 3 h, at 53° C. and then at r.t., under vigorous magnetic stirring, for 18 h. A sticky colourless oil was obtained. The crude was dissolved in dry MeOH (5 mL) and a solution of sodium methoxide 0.5M in methanol (4.6 mL, 2.284 mmol), then diethyl carbonate (2.16 g, 18.27 mmol) were added dropwise. The mixture was refluxed for 6 h. The solvent was evaporated and the crude purified by flash silica-gel chromatography (DCM/MeOH=75:1) affording the title compound as a yellow oil that solidified on standing into a white solid (2.232 g, 10.04 mmol). Yield=66%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:21])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12

Procedure:
The synthesis route used to prepare analogues is described in Scheme 3. (2-ethoxycarbonylmethyl-phenyl)-acetic acid ethyl ester 2 (71%) was obtained by hydrolysis of 1, 2-phenylenediacetonitrile 1 with concentrated H2SO4. Compound 2 with sodium ethoxide in ethanol gave compound 3 (61%), which further reacted with guanidine in the presence of potassium t-butoxide under 150° C. in a microwave reaction to give compound 4 (34%). To access target compounds, first, compound 4 was tried to turn the 4-oxo to 4-chloro, which traditionally is adopted in synthesizing 4-anilino substituted analogues. However, because of the lower aromaticity of the ring, the chlorination did not run well under known reaction conditions. Compound 4 was decomposed when refluxed with POCl3. Thus, the 4-oxo was converted to 4-sulfonate, which is a good leaving group for SNi reaction. Compound 5 was obtained when treating compound 4 with the 4-nitrobenzensulfonyl chloride (36%). The target compound 6 with different substitution on the phenyl ring was obtained when refluxing compound 5 with corresponding aniline for 12-18 h.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([O-:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30]([CH3:41])=[CH:29][CH:28]=1)([OH:21])=[O:20].[CH3:42][N+:43]([CH2:46][C:47]([OH:49])=[O:48])([CH3:45])[CH3:44]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](/[CH:41]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[CH:29][CH:28]=1)([OH:21])=[O:20].[CH3:42][N+:43]([CH2:46][C:47]([OH:49])=[O:48])([CH3:45])[CH3:44]
Reactant: Cc1cc[n+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc12
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Agent: C[N+](C)(C)CC(=O)O
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)c4ccc(S(=O)(=O)O)cc34)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-6-sulfonato-chinolinium betaine are converted according to the general directions given above. Column chromatography: SiO2 (RP 18), eluent: methanol/water.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:27]=O)[CH:24]=[CH:25][CH:26]=1.C(O)=O>CO.O>[C:9]1([S:15]([CH:27]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)NC(c1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A quantity of 4.49 g (38.29 mmol) of tert-butyl carbamate and 12.57 g (76.57 mmol) of sodium benzenesulphinate were introduced in 110 ml of methanol/water 1:2 and admixed in succession with 10 g (57.43 mmol) of 3-(trifluoromethyl)benzenecarbaldehyde and 2.87 ml (76.09 mmol) of formic acid. The mixture was stirred at RT for 30 h. The precipitated product was isolated by filtration, washed in succession with water and diethyl ether and sucked dry. Further drying in an HV gave 11.2 g (47% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][NH:15][CH3:16].[CH2:17]=O>C(O)C>[CH3:14][N:15]([CH2:17][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH3:16]
Reactant: CNC
Reactant: C=O
Reactant: COc1ccc2cccnc2c1O
Solvent: CCO
Product: COc1cc(CN(C)C)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a cold (0°) solution of 8-hydroxy-7-methoxyquinoline (0.92 g, 5.25 mmol) and 26% aqueous dimethylamine (3.0 g, 17 mmol) in 10 mL of ethanol was added dropwise 37% aqueous formaldehyde (0.77 g, 9.5 mmol). After stirring at room temperature for 1 hr, the mixture was refluxed for 30 min, cooled and evaporated to dryness. The residue was diluted with water, extracted with ether and dried (MgSO4). Evaporation gave 5-dimethylaminomethyl-8-hydroxy-7-methoxyquinoline as an oil (0.85 g, 69%); structure confirmed by NMR. This oil (0.85 g, 3.6 mmol) was heated under nitrogen with 2,4-diamino-6-methylthiopyrimidine (0.57 g, 3.6 mmol) in ethylene glycol (5 mL) at 140°-165° for 45 min, then cooled. The solid that separated was collected, and washed with ethanol and ether to give 2,4-diamino-5-(8-hydroxy-7-methoxy-5-quinolylmethyl)-6-methylthiopyrimidine as a tan solid (0.47 g, 37%), structure confirmed by NMR and mass spectroscopy. A portion of this solid (0.38 g, 1.1 mmol) was used in the procedure of Example 11B to give the title compound (mp 245°-250° dec). Anal. Calcd for C17H19N5SO2.0.5H2O: C, 55.72; H, 5.50; N, 19.11; S, 8.75. Found: C, 55.71; H, 5.51; N, 19.11; S, 8.74.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl.[CH3:41][N:42]([CH2:44][C:45](Cl)=[O:46])[CH3:43]>CO.ClCCl>[CH3:41][N:42]([CH3:43])[CH2:44][C:45]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:46]
Reactant: CN(C)CC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in methanol (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by dimethylaminoacetyl chloride hydrochloride (43.4 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide filtered and purified by preparative HPLC yielding 2-(dimethylamino)-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (27.3 mg, 20.39%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[N+]([O-])(O)=O.[NH2:16][NH:17][C:18](N)=N.[OH-].[Na+]>C(O)C>[NH2:5][C:4]1[C:3]([C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:1])=[CH:18][NH:17][N:16]=1
Reactant: N=C(N)NN
Reactant: N#CCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Nc1n[nH]cc1C(=O)c1ccccc1

Procedure:
A reaction mixture comprising 73.36 g of α-(dimethylamino)methylene]-β-oxo-2-benzenepropanenitrile, 63.45 g of aminoguanidine nitrate, 500 ml of ethanol and 36.6 ml of 10N sodium hydroxide was refluxed for 10 hours and then cooled. The resulting precipitate was collected and washed with water, giving 17.1 g of the desired product, mp 177°-179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[I:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[I:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(I)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(I)c1
Temperature: -80 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Iron powder (12.5 g, 224 mmol) was added to a suspension of 2-benzyloxy-5-nitroiodobenzene (10 g, 28 mmol) in water (300 ml) and acetic acid (75 ml) and the mixture was stirred at −80° C. for 12 hours. The mixture was allowed to cool to room temperature and filtered through Hyflo™, washing with 4:1 water:acetic acid and ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic extract was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (9 g, 99% yield). 1H NMR (360 MHz, CDCl3) δ 7.49-7.47 (2H, m), 7.40-7.28 (3H, m), 7.19 (1H, d, J 2.4 Hz), 6.70 (1H, d, J 8.6 Hz), 6.62 (1H, dd, J 2.4, 8.6 Hz), 5.04 (2H, s). MS (ES+) m/z 326 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C(O)(=O)C>[Fe].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:17])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(C(F)(F)F)cs2)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(N)c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
The product from Step D (3.1 g, 0.011 mol) was suspended in a mixture of glacial acetic acid (15 mL) and water (5 mL). The mixture was heated on a steam bath to a temperature of 65° C. Iron powder (1.9 g, 0.035 mol) was then added in small portions (exothermic). Care was taken during the addition to ensure that the temperature did not exceed 75° C. Once the iron had been added, heating at 75° C. was continued for another 10 min. The reaction mixture was hot-filtered onto 30 g cracked ice. After the ice melted, the aqueous mixture was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated sodium bicarbonate and brine (30 mL each). The dried (MgSO4) solution was concentrated to furnish 1.4 g (53% yield) of the title compound as a white solid melting at 100°-103° C. 1H NMR (400 MHz, CDCl3) δ 7.62 (s,1H), 7.39 (s,1H), 7.03-7.05 (m,1H), 6.69-6.71 (m,1H), 5.82 (br s,2H), 2.28 (s,3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:26][C:27]2[C:31]3=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=[C:30]3[S:29][CH:28]=2)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:26][C:27]1[C:31]2=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=[C:30]2[S:29][CH:28]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccc(Cl)nc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccc(Cl)nc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 118.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((5-chlorothieno[3,2-b]pyridin-3-yl)methyl)((S)-1,1-diethoxypropan-2-yl)amino)-1-oxopropan-2-ylcarbamate (Compound III-7) 512 mg (0.66 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 429 mg (119%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:14]1([CH:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:21][N:22]([CH2:35][CH2:36][CH2:37]O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=2[Cl:34])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OC1C=C(C=CC=1)CC1N(COCC)N=NN=1.BrCCCO>C(OCC)C>[ClH:34].[Cl:34][C:25]1[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:22]([CH2:21][CH:20]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH2:37][O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:12]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(N2CCOCC2)n1
Agent: CCOCn1nnnc1Cc1cccc(O)c1
Agent: OCCCBr
Solvent: CCOCC
Product: Cl
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCOCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Yield: 32 %

Procedure:
Following the procedure of Example 6(d), except 6-morpholin-4-yl-pyridin-2-ol and N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine were used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole and 3-bromo-propanol in step 6(d), the title compound was synthesized as the free base. The tertiaryamine was then dissolved in diethyl ether and acidified with 1.0 M HC/diethyl ether to give 90 mg (32% yield) of the title compound as a white solid. MS (ESI) 610.2 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]2[S:34][C:28]3=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=[C:27]3[CH:26]=2)(=[O:24])=[O:23])[C:16]1=[O:35].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][N:21]([S:22]([C:25]1[S:34][C:28]2=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=[C:27]2[CH:26]=1)(=[O:24])=[O:23])[CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:7][CH:2]=2)[C:16]1=[O:35]
Reactant: O=C1C(NS(=O)(=O)c2cc3ccc(Cl)nc3s2)CCCN1c1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN(C1CCCN(c2ccc(-n3ccccc3=O)cc2)C1=O)S(=O)(=O)c1cc2ccc(Cl)nc2s1

Procedure:
The compound of Example 3 was treated with methyl bromoacetate in the presence of potassium carbonate using the procedure described for the preparation of compound 9, Part A. Purification by flash chromatography provided the title compound. MS(ESI+) (M+H)+. 1HNMR (CDCl3) δ 8.08 (m, 1H); 7.89 (s, 1H); 7.48 (m, 1H); 7.39 (m, 2H); 7.31 (m, 4H); 6.78 (m, 1H); 6.36 (m, 1H); 4.72 (m, 1H); 4.27 (m, aH); 3.83 (m, 1H); 3.78 (s, 3H); 3.74 (m, 1H); 3.66 (m, 1H); 2.60 (m, 1H); 2.16 (m, 3H). MS m/z 586.9 (M+H)+. HRMS calcd for C26H24N4O6S2Cl: 587.0826. Found: 587.0813.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0115 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 88%).