Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)(=O)C(Cl)=O.O[C:23]1[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C:23]2[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([OH:52])=[O:51])[C:29](=[O:48])[C:30]3[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:12])=[CH:14][CH:15]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CC(C)CCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(OCCC(C)C)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(isopentyloxy)benzoic acid (37 mg, 0.178 mmol) in DCM (0.5 mL) was added DMF (1 drop) and oxalyl chloride (0.016 mL, 0.190 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (60 mg, 0.119 mmol) and TEA (0.050 mL, 0.357 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 41.2 mg (54%) of 2-(N-(4-((4-(isopentyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 46. LCMS-ESI (m/z) calculated for C37H38N2O8: 638; found 637 [M−H]−, tR=8.44 min (Method 4). 1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 10.24 (s, 1H), 8.13-8.02 (m, 2H), 7.69-7.62 (d, J=8.4 Hz, 2H), 7.48-7.28 (m, 4H), 7.26-7.19 (dt, J=6.7, 1.9 Hz, 4H), 7.16-7.08 (m, 2H), 6.93-6.83 (m, 2H), 4.72-4.54 (d, J=31.5 Hz, 2H), 4.16-4.08 (t, J=6.6 Hz, 2H), 4.05-3.86 (d, J=27.0 Hz, 2H), 3.71 (s, 3H), 3.57 (s, 2H), 1.88-1.75 (dp, J=13.3, 6.7 Hz, 1H), 1.72-1.62 (q, J=6.7 Hz, 2H), 0.97-0.86 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=2)[NH:4][CH:3]=1.[C:18](O)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:14][C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: CC/C=C/C(=O)O
Reactant: Cc1c[nH]c2ncc(-c3cccc(N)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C/C(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.7 %

Procedure:
A solution of 24 (50 mg, 0.2242 mmol) and trans-2-pentenoic acid 25 (24.6 mg, 0.246 eq) in DMF was added EDC.HCl (33 mg, 0.2706 mmol) and HOBt (36.5 mg, 0.2706 mmol). DIPEA (57.9 mg, 0.448 eq) was added to the reaction, stirred 12 h at RT and check the TLC for completion of the reaction and quench the reaction mixture with dilute water. The organic layer was treated with ethyl acetate (25 mL) and was washed with brine solution (25 mL) and dried over sodium sulphate, filtered and concentrated to get the crude product. The resulting oil was purified through silica gel chromatography using a gradient of 4% Ethyl acetate:hexane to afford 8 mg of Compound 26. MS-ES+305.1 1H NMR (400 MHz, DMSO-D6-d6): 11.45 (s, 1H), 10.08 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H), 7.61 (m, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 5.62 (m, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([NH:26][CH:23]([CH3:25])[CH3:24])([NH:26][CH:23]([CH3:25])[CH3:24])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Reactant: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(NC(C)C)NC(C)C)C(=O)SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (10.5 g.; 0.027 mol.) dissolved in 100 ml. of diethyl ether was added to a solution containing isopropylamine (6.7 g.; 0.11 mol.) in 50 ml. of diethyl ether. The reaction mixture was stirred for 2 hours at 25° C., then filtered. The filtrate was washed with 5% sodium bicarbonate, then water. The ether layer was separated, dried over sodium sulfate and concentrated in vacuo. To remove remaining traces of solvent, the residue was concentrated at 25° C. and 0.05 mm. and yielded ethyl-N-[(benzylthio)carbonyl]-N-[bis(isopropylamino)phosphinylmethyl]-glycinate (7.0 g.) as crystals having a melting point of 69°-72° C. and the following analysis:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 141.7 %

Procedure:
Trifluoroacetic acid (1.7 ml, 2.6 mmol) was added dropwise to a solution of 5-(tert-butoxycarbonylaminomethyl)-3-phenylisoxazole (Method 43; 473 mg, 1.73 mmol) in DCM (8 ml) cooled in an ice bath. The mixture was warmed to ambient temperature and stirred for 18 hours and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (427 mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, 1H), 7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H).
Reaction SMILES: CN(C1C2[C:10]([N:14]([CH3:16])C)=[CH:11][CH:12]=[CH:13][C:8]=2C=CC=1)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[C:28]([O:31]CC)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:21]([O:20][C:18]([N:14]1[CH2:10][CH2:11][CH:12]=[C:13]([CH2:8][O:31][C:28](=[O:30])[CH3:29])[CH2:16]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(C)=O
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)OCC1=CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
This material is dissolved in 200 mL of methylene chloride. Proton sponge (2.5 mmol) is added in a single portion and the reaction mixture cooled to 0° C. Benzyl chloroformate (53 mmol) is added dropwise via addition funnel and the reaction mixture allowed to warm to room temperature. Stirring is continued for 2 hours at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL) and washed with 1N hydrochloric acid (3×100 mL), water and brine. The organic layer is worked up to provide N-Benzyloxycarbonyl-3-acetoxymethyl-1,2,5,6-tetrahydropyridine. 1H NMR (CDCl3) δ7.40-7.25 (m, 5H), 5.90 (s, 1H), 5.14 (s, 2H), 4.47 (s, 2H), 3.95 (s, 2H), 3.54 (t, J=9.6Hz, 2H), 2.23-2.13 (m, 2H), 2.04 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C@@H:28]([C:30]1[CH:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=1)[OH:29])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO.O>[C:1]([O:5][C:6]([N:8]([CH2:27][C@H:28]([OH:29])[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)cc2)cc1)C[C@H](O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)cc2)cc1)C[C@H](O)c1cccnc1
Yield: 96.5 %

Procedure:
4′-[3-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylic acid (100 mg), ammonium formate (50 mg) and palladium on carbon powder (30 mg) in methanol (5 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform-methanol) over silica gel to give 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylic acid (90 mg) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[N:47]([S:48]([CH3:51])(=[O:49])=[O:50])[C:52](=[O:54])[CH3:53])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:30])([F:31])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:33])[F:34])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1nn(C)c2c(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)cccc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 35 (20 mg, 0.027 mmol) in methylene chloride (2 mL) was added acetic anhydride (0.03 mL, 0.27 mmol), triethylamine (0.04 mL, 0.027 mmol), and the reaction mixture was stirred for one hour at room temperature. The solution was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title compound 38A: 1H NMR (400 MHz, methanol-d4) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.18 (m, 1H), 7.09 (d, 1H), 6.76 (tt, 1H), 6.46 (d, 1H), 6.42-6.21 (m, 2H), 4.85-4.52 (m, 3H), 3.50 (m, 6H), 3.12 (m, 1H), 3.00-2.80 (m, 1H), 2.59-2.31 (m, 2H), 1.86 (s, 3H), 1.41 (m, 1H), 1.04 (m, 1H). MS (m/z): 778.95 [M+H]+ and 11 mg of compound 38B. MS (m/z) 820.83 [M+H]+.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccc(Cl)cc2Cl)n1
Reaction time: 1.5 h

Procedure:
A suspension of 7.97 g. of 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred under nitrogen as 4.61 g. of ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 8.99 g. of 2,4-dichlorobenzyl chloride in 30 ml. of dry dimethylformamide is added during ca. 10 minutes. Stirring is continued for 5 hours and then 25 ml. of glacial acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred throughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution and filtered. The crude product is dissolved in 5 liters of boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 500 ml. and chilled. The crystalline solid is collected and again recrystallized from methanol to afford 6.33 g. of the title compound, m.p. 249°-250° C., NMR (dDMSO and D2O): δ 5.58 (singlet, N--CH2 --C6H3Cl2), 6.68 (doublet, J=8 Hz, 5H), 7.10 (doublet, J=3 Hz, 9H), 7.52 (doublet, J=3 Hz, 8H), 7.68 (doublet, J=8 Hz, 6H) p.p.m.; λmax95%EtOH 258 mμ (26,000) and 315 mμ (8,500).
Reaction SMILES: [C:1]([O:9][C@H](CC1C=C(C)C2C(=CN(COCC[Si](C)(C)C)N=2)C=1)C(OC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxopropan-2-yl benzoate (14.2 g, 30.3 mmol) in tetrahydrofuran (80 mL) and methanol (80 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (5.09 g, 121 mmol) in water (80 mL). The reaction was stirred at 0° C. for 1 h. The ice bath was removed and stirring continued at room temperature for 2 h. The reaction was concentrated, dissolved in water (5 mL), cooled to 0° C., and treated with 1M hydrochloric acid until mildly acidic. A non-solid ppt formed. The suspension was extracted with ethyl acetate (3×), which were washed with brine, dried over magnesium sulfate, and concentrated to give the crude hydroxy acid as an oil with white solid forming in it (probably residual benzoic acid) which was used without purification. Mass spec.: 349.34 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:18])=[C:6]([Cl:17])[C:7]2[O:11][CH:10](/[C:12](=[N:14]\[OH:15])/[OH:13])[CH2:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].O1CC[CH2:21][CH2:20]1.S(=O)(=O)(O)O>C(O)C>[C:1]([C:4]1[C:5]([OH:18])=[C:6]([Cl:17])[C:7]2[O:11][CH:10](/[C:12](=[N:14]\[OH:15])/[O:13][CH2:20][CH3:21])[CH2:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)c1cc2c(c(Cl)c1O)OC(/C(O)=N\O)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCO/C(=N/O)C1Cc2cc(C(C)=O)c(O)c(Cl)c2O1
Yield: 76.1 %

Procedure:
The acid 4a was esterified by stirring in a solution of tetrahydrofuran, ethanol, and concentrated sulfuric acid (39:60:1) for 16 hours at room temperature. The resulting solution was evaporated and the residue dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. Recrystallization from ethyl acetate/hexane furnished 76.1% of white crystals, m.p. 154°-155° C. Anal. (C13H14ClNO5) C,H,N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15]C=CC=3)N=2)=[CH:6][CH:5]=1.C(Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:31]C1C=C(O)C=CC=1C(O)=O>>[CH2:1]([O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:14][CH:15]=2)=[CH:8][C:9]=1[F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1F
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting two equivalents of benzyl bromide and 2-Fluoro-4-hydroxy-benzoic acid provided the title compound. MS: (M+H m/z=337.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:20][CH3:21])(=O)=O>CC(=O)CC.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:20][CH3:21])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOc1cc(Br)cc(Br)c1
Temperature: 90 °C

Procedure:
A dispersion of 3,5-dibromophenol (0.398 g, 1.6 mmol) and potassium carbonate (0.437 g, 3.2 mmol) in 2-butanone (4 mL) was treated with diethyl sulfate (0.246 g, 1.6 mmol) and the reaction mixture heated at 90° C. for 15 hours. The resulting thick suspension was cooled to room temperature, diluted with dichloromethane and extracted with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The title compound was obtained as a light brown oil (0.38 g, 86% of theory) which was used in the next step without further purification.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15]N=CC=1)[NH2:6].FC(F)(F)C1C=C([N+]([O-])=O)C=CC=1SC1C=C[N:31]=[CH:30][CH:29]=1.C(O)(=O)C.[OH-].[Na+]>CCOCC.O.[Fe]>[N:31]1[CH:30]=[CH:29][CH:15]=[CH:16][C:11]=1[S:10][C:9]1[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1

Procedure:
3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3-trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for 4 h. The mixture was diluted with Et2O (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50% hexane) Rf 0.10; 1H-NMR (DMSO-d6) δ 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz, 2H). A13c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][CH:6]=[CH:7][CH2:8]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.[Cu]I.[Pd](Cl)Cl>[ClH:5].[CH3:30][C:29]([CH3:32])([CH3:31])[C:33]#[C:34]/[CH:3]=[CH:2]/[CH2:1][NH:4][CH2:6][CH2:7][CH3:8]
Reactant: ClC=CCCl
Reactant: CCCN
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCNC/C=C/C#CC(C)(C)C
Product: Cl
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 100 ml (1.21 mol) of n-propylamine in 170 ml of tetrahydrofuran was added 18.2 ml (0.198 mol) of 1,3-dichloropropene (E/Z=9/1) under ice cooling. The solution was stirred for 2 hours, and 1.90 g (0.01 mol) of copper (I) iodide, 709 mg (4.0 mmol) of palladium chloride, 2.10 g (8.0 mmol) of triphenyiphosphine and 29.3 ml (0.238 mol) of tert-butylacetylene were added to the solution under ice cooling. The mixture was stirred for 20 hours at room temperature, and extracted with a mixture of 100 ml of ethyl acetate and 100 ml of water. The organic layer was washed with 100 ml of water. The aqueous layers were combined and extracted with 20 ml of ethyl acetate. A mixture of 200 ml of water and 6N hydrochloric acid was then added to the combined organic layers to adjust to pH 2. The aqueous layer was separated. The organic layer was extracted with 50 ml and 20 ml of water. The aqueous layers were combined, and washed with a mixture of 50 ml of ethyl acetate and 20 ml of n-hexane. The aqueous layer was treated with 200 ml of dichloromethane and then adjusted to pH 9 with 6N sodium hydroxide aqueous solution. The organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. The combined organic layers were washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and treated with 17% isopropylalcohol solution of hydrogen chloride. The solvent and excess hydrogen chloride were distilled off under reduced pressure to crystallize. The crystalline residue was suspended with a mixture of 30 ml of ethyl acetate and 50 ml of n-hexane. The crystals were collected by filtration and then dried under reduced pressure to obtain 25.0 g (yield: 59%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[NH:14]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:15]([C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[CH2:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:14][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reaction time: 13 h
Yield: 101.9 %

Procedure:
N,N-Diisopropylethylamine (81 μL, 0.463 mmol) and subsequently bromoacetonitrile (147 μL, 2.103 mmol) were added to a solution of Boc-Lys(Z)-OH (Compound tk44) (160 mg, 0.421 mmol) in acetonitrile (0.6 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 13 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk45) (180 mg, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:14]([OH:16])=[O:15])=[CH:11][S:12][CH:13]=2)=[CH:4][CH:3]=1.[C:17](=O)([O-])O.[Na+].IC.CN(C)C=O>O>[CH3:17][O:15][C:14]([C:10]1[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][S:12][CH:11]=1)=[O:16]
Reactant: O=C(O)c1cscc1Sc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cscc1Sc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 4-(4-chlorophenylsulfanyl)thiophene-3-carboxylic acid (1.0 g), sodium hydrogen carbonate (1.6 g), iodomethane (2.3 mL) and N,N-dimethylformamide (10 mL) was stirred was stirred at 40° C. for 5 hours. The mixture was cooled to room temperature, diluted with water (100 mL) and the aqueous phase extracted with ethyl acetate. The combined organic extract was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (1.0 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH2:15])=[O:14])(=O)C.[CH3:19]N.CO>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH:15][CH3:19])=[O:14]
Reactant: CN
Reactant: CON=C(C(N)=O)c1ccccc1COC(C)=O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-methoxyiminoacetamide (194 mg, E/Z≠79/21), methanol (3.0 ml) and a 40% methylamine/methanol solution (1.0 ml) was stirred at 40° C. for 3 hours. After the mixture was ice-cooled, the solvent was evaporated under reduced pressure to obtain the crude product (203 mg, E/Z≠91/9) of the title compound.