Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: O=C(O)c1cccnc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 3-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E10 (113 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.0 (1H, s), 8.70 (1H, d), 8.50 (1H, d), 8.17 (2H, m), 7.50 (1H, m), 7.17 (1H, d), 6.62 (1H, d), 4.70 (2H, dt), 4.17 (1H, m), 3.22 (2H, dt), 1.95 (2H, m), 1.55 (2H, m), MS(ES+) 323 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Si]([O:15][CH2:16][C:17]([CH3:59])([CH3:58])[CH2:18][N:19]1[CH:28]=[C:27]([S:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:43]3[CH:48]=[C:47]([C:49](=[O:54])[NH:50][CH:51]4[CH2:53][CH2:52]4)[CH:46]=[C:45]([F:55])[C:44]=3[CH3:56])[CH:25]=2)[C:20]1=[O:57])(C(C)(C)C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:51]1([NH:50][C:49](=[O:54])[C:47]2[CH:48]=[C:43]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:57])[N:19]([CH2:18][C:17]([CH3:58])([CH3:59])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:4])[C:44]([CH3:56])=[C:45]([F:55])[CH:46]=2)[CH2:53][CH2:52]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 59a, 0.06 g) in DCM (2 mL), and the reaction was stirred at room temperature for 30 min. Toluene (10 mL) was added and the volatiles were removed under reduced pressure (repeated 3×). The residue was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.1% aqueous NH3 in acetonitrile), and after solvent removal and trituration with diethyl ether gave the title compound (0.01 g).
Reaction SMILES: [NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@@H:29]2[CH2:47][CH2:48][CH2:49][N:28]2[C:26](=[O:27])[C@@H:21]([CH2:22][C:23](=[O:25])[OH:24])[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C)=O)[CH:5]=1.[CH3:50][NH2:51].CO>>[NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:35])[CH3:36])[NH:32][C:30](=[O:31])[C@@H:29]2[CH2:47][CH2:48][CH2:49][N:28]2[C:26](=[O:27])[C@@H:21]([CH2:22][C:23](=[O:25])[OH:24])[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([NH:51][CH3:50])=[O:16])[CH:5]=1
Reactant: CN
Reactant: COC(=O)Cn1cc(C[C@H]2NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC(=O)O)NC2=O)c2ccccc21
Solvent: CO
Product: CNC(=O)Cn1cc(C[C@H]2NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC(=O)O)NC2=O)c2ccccc21

Procedure:
cyclo(-DTrp(CH2COOCH3)-DAsp-Pro-DVal-Leu-) prepared in Example 90 was allowed to react with 40% methylamine/methanol as the same procedure described in Example 91 to give the title compound.
Reaction SMILES: C[Si](C)(C)C#C[CH:5]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:17][OH:18])[CH:11]=2)[S:6]1.[CH2:21]1COC[CH2:22]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:21]([CH:17]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[S:6][CH2:5][CH2:14][C:13]2([CH3:15])[CH3:16])[OH:18])#[CH:22]
Reactant: CC1(C)CC(C#C[Si](C)(C)C)Sc2ccc(CO)cc21
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Reaction time: 1 h

Procedure:
5.9 g (19.4 mmol) of α-trimethylsilylethynyl-4,4-dimethyl-6-thiochromanmethanol and 50 ml of THF were introduced into a round-bottomed flask and 21.3 ml (23.3 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) were added dropwise. Stirring was carried out at room temperature for 1 hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (1/4). After evaporating the solvents, 3.9 g (87%) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol were recovered in the form of a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2cccc(C=C(C#N)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2cccc(CC(C#N)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reaction time: 72 h

Procedure:
A solution of the nitrile from Step 2 (400 mg, 0.88 mmol) in THF/EtOH (1:1, 10 mL) containing Pd/C (10%, 40 mg) was stirred under H2 (1 atm) for 3 days. Filtration on celite, evaporation, stirring vigorously in ether for 1 h then filtration afforded the 3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionitrile compound as a white powder.
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14](O)[C:13]=2[C:23](=O)[CH3:24])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>C(OCC)C>[C:26]([O:29][C:14]1[C:13]2[C:23]([CH3:24])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:12]=2[C:17]([Cl:18])=[CH:16][C:15]=1[CH2:19][CH2:20][CH3:21])(=[O:28])[CH3:27]
Reactant: CCCc1cc(Cl)c(OC(C(=O)O)c2ccccc2)c(C(C)=O)c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetic acid (Step b)(3.4 g, 9.3 mmol), anhydrous sodium acetate (6.8 g, 82 mmol) and acetic anhydride (50 mL) was refluxed for 1 hour. The mixture was cooled, diluted with diethyl ether and the salts filtered off. The filtrate was concentrated and the residue chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound, m.p. 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[N:7][C:6]=2[N:8]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN1CCN(CCCCN)CC1
Product: CN1CCN(CCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1

Procedure:
Following the procedure of Example 20, 2.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidine from Example 1 was reacted with 15 mL of 1-(4-aminobutyl)-4-methyl-piperazine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=[O:44])[CH:41]=[CH:42][C:35]1=2>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:43]([C:40]1[CH:41]=[CH:42][C:35]3[O:34][CH:38]=[CH:37][C:36]=3[CH:39]=1)=[O:44])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc2occc2c1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc4occc4c3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 2-(4) to give benzo[b]furan-5-yl 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 626/628 (M+H). 1H-NMR (DMSO-d6) δ 1.74 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.03 (s, 3H), 4.10-4.11 (m, 2H), 4.30 (dt, J=9.9, 4.2 Hz, 1H), 5.27 (t, J=9.9 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.74 (t, J=9.3 Hz, 1H), 6.34 (d, J=9.0 Hz, 1H), 7.06 (d, J=1.3 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.85 (dd, J=8.6, 1.7 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 8.13 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[Br-]>CS(C)=O.O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Clc1ccccc1CBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (8.0 g) in 75 ml of dimethyl sulfoxide was added pulverized potassium hydroxide (6.2 g). This was stirred for 0.5 hour at ambient temperature. To this solution was added 2-chlorobenzyl bromide (9.4 g). After 1 hour, an additional 1 ml of the bromide was added. This was stirred for an additional hour. At this time, 200 ml of water was added, and the precipitate was filtered and washed with water. The solid was taken up in dichloromethane and dried over anhydrous magnesium sulfate. The compound was purified via flash chromatography to yield 6.75 g of solid, mp 150°-161° C. A portion of this was recrystallized from methanol to give analytically pure needles, mp 162°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1Br.BrCC.[Mg].C[O:16][B:17](OC)[O:18]C.Cl>CCOCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: Clc1cc(Cl)c(Cl)c(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: OB(O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2,3,5-trichlorobromobenzene (8.60 g, 0.033 mole) in dry ether (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) was added dropwise to a suspension of magnesium turnings (2.809, 0.12 mole) in dry ether (21.50 ml) at room temperature. The mixture was refluxed for 0.50 hr and cooled to room temperature. The mixture was then added dropwise under nitrogen to a solution of trimethylborate (5.16 ml, 5.16 g, 0.05 mole) in dry ether (8.60 ml) maintaining the temperature below −60° C. This was warmed to room temperature overnight, then cooled in an ice-bath and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2×20 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 4.57 g (61%), M.p. 257-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:27])=[C:14]([C:24]([O-])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:27])=[C:14]([C:24]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH:20]([CH3:21])[CH3:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CC(C)Cn1c(=O)c(C(=O)[O-])c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(C)C)c1=O
Yield: 79 %

Procedure:
A solution of 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-methylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.05 mmol) in 2-methoxyethylamine (1 mL) was heated with a microwave at 140° C. for 20 minutes. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC to give the title compound (17 mg, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.35 (br, 1 H), 8.54 (s, 1 H), 7.25 (s, 1 H), 7.15 (dd, J=8.5, 5.4 Hz, 2 H), 7.03 (t, J=8.5 Hz, 2 H), 4.12 (s, 2 H), 3.97 (br, 2 H), 3.63 (m, 2 H), 3.57 (m, 2 H), 3.39 (s, 3 H), 1.95 (m, 1 H), 0.87 (d, J=6.8 Hz, 6 H); HRMS m/z calcd for C23H27N3O4 (M+H)+ 428.1986, found 428.1977.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH2:22])[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Benzyl bromide (0.111 mL, 0.934 mmol) was added to a flask charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.330 g, 0.778 mmol), DMF (3 mL) and potassium carbonate (0.429 g, 3.11 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with methanol (2 mL). Product was purified by reverse phase HPLC to give Compound 179, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (97 mg, 0.19 mmol, 24%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.08 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.57 (d, J=9.6 Hz, 2H), 7.38-7.30 (m, 4H), 7.26-7.16 (m, 3H), 7.03-6.93 (m, 4H), 5.24-5.21 (m, 2H), 4.53-4.48 (m, 1H), 3.85-3.79 (m, 1H), 3.75 (s, 2H), 3.51-3.45 (m, 2H), 3.17 (d, J=6.0 Hz, 1H), 2.15-2.00 (m, 2H). MS (EI) for C28H27FN6O3. found 515.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH3:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: Cc1ccc(CO)cc1
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OCc1ccc(C)cc1
Yield: 106.7 %

Procedure:
66.5 g of ethoxycarbonyl isothiocyanate were added dropwise to a solution of 61 g of p-methylbenzyl alcohol in 500 ml of tetrahydrofuran and 2 ml of triethylamine and the mixture was refluxed for 24 hours. The mixture was concentrated to dryness to obtain 135 g of raw p-methylbenzyl N-carbethoxy -thiocarbamate.
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][C:13](=[O:21])[CH2:14]2)[CH2:9]1)=[O:7].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:19][C:18]([CH:17]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][C:13](=[O:21])[CH2:14]2)[CH2:9][N:8]1[C:6]([O:5][CH3:4])=[O:7])=[O:20])[CH3:2]
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Reactant: CCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme X, Step A, the compound of structure (i) is esterified by reaction with a compound of formula Et-Br (where Et represents an ethyl group) to provide the intermediate of compound (i-b). For example 2-methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCl. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide ethyl-2-methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate, the compound of structure (i-b). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (i-b).
Reaction SMILES: C[As]([NH:4][C@@H:5]([CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:15][SH:16])=[O:12])[C:6]([OH:8])=[O:7])C.[CH3:24][As:25](N(SSN([As](C)C)[C@H](C(O)=O)CCC(=O)N)[C@H](C(O)=O)CCC(=O)N)[CH3:26].C[As]([As](C)C)C>ClCCl>[CH3:24][As:25]([CH3:26])[S:16][CH2:15][C@@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[NH:13][C:11](=[O:12])[CH2:10][CH2:9][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: C[As](C)N(SSN([C@@H](CCC(N)=O)C(=O)O)[As](C)C)[C@@H](CCC(N)=O)C(=O)O
Reactant: C[As](C)N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: C[As](C)[As](C)C
Solvent: ClCCl
Product: C[As](C)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylarsinoglutathione is made using an adapted of Chen (Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the contents of which are hereby incorporated by reference in their entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved in dichloromethane under nitrogen. Tetramethyldiarsine is added dropwise to the solution and the reaction is stirred overnight at room temperature under nitrogen and then exposed to air for 1 h. The mixture is then evaporated to dryness and the residue is washed with water and dried to give a crude solid that is recrystallized from methanol to give S-dimethylarsinoglutathione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)#[N:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:14]=[C:13]([C:11]#[N:12])[CH:18]=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(C#N)ccc1F)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 43.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.1 mmol), 5-cyano-2-fluorophenylboronic acid (CombiBlocks; 1.00 g, 6.84 mmol), copper(II) acetate (1.1 g, 6.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 60° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 10-50% ethyl acetate/hexanes, to give N′-(5-cyano-2-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (700 mg, 44%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCBr
Reactant: CNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCCN(C)c1ccccc1
Temperature: 110 °C
Reaction time: 22 h
Yield: 84.1 %

Procedure:
A mixture of N-methylaniline (16 g) and ethyl 5-bromovalerate (30.2 g) was stirred at 110° C. for 22 hours. Then the mixture was made alkaline with an aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to obtain ethyl 5-(N-methylanilino)valerate (28.6 g).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[O-].[Na+].[CH2:18](I)[CH3:19]>C1COCC1.CO>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH2:18][CH3:19]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.94 g BocSer in 66 mL THF was added a solution of 1.47 g NaOMe in 2.6 mL MeOH, followed by 11.7 g EtI. After 15 minutes, more NaOMe (0.49 g) and EtI (2 mL) were added and the reaction was stirred at RT overnight. More NaOMe and EtI were added and the reaction was stirred for an additional 6 hours. The mixture was concentrated in vacuo, dissolved in 25 mL H2O and washed 2×25 mL ether. The aqueous phase was acidified with concentrated HCl and extracted 4×25 mL CH2Cl2. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to 0.34 g crude product which carried on. NMR (300 MHz, CDCl3), delta 1.19 (t, J=7 Hz, 3H), 1.46 (s, 9H), 3.53 (q, J=7 Hz, 2H), 4.43 (m, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:35]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[N:36][O:37][N:38]=2)=[N:31][N:30]=1>>[F:43][C:41]([F:42])([F:44])[C:40]([NH:39][C:35]1[C:34]([C:32]2[S:33][C:29]([NH:28][C:25](=[O:26])[CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH2:13][CH2:12]4)[CH:19]=3)=[N:30][N:31]=2)=[N:38][O:37][N:36]=1)=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)O)c2)CC1
Reactant: Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)Nc3nnc(-c4nonc4NC(=O)C(F)(F)F)s3)c2)CC1

Procedure:
Prepared from 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetic acid and N-(4-(5-amino-1,3,4-thiadiazol-2-yl)-1,2,5-oxadiazol-3-yl)-2,2,2-trifluoroacetamide by methods substantially similar to those described in Example 11, supra. Yield 30 mg.