Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.C([CH:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36][N:35]1[C:49]([OH:51])=[O:50])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH2:37][CH2:36][N:35]([C:49]([O:51][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:50])[CH2:34][CH:39]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:20]([C:26]([F:28])([F:27])[F:29])([C:22]([F:23])([F:24])[F:25])[OH:21])[CH2:11]1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)C1C=C(B2OC(C)(C)C(C)(C)O2)CCN1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 85 °C
Reaction time: 16 h
Yield: 144 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 1.00 mmol) prepared in Step 5 of Preparation 24, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-carboxylic acid (370.0 mg, 1.20 mmol), potassium carbonate (690.0 mg, 4.98 mmol), and Pd(dppf)Cl2 (73.0 mg, 0.10 mmol) were added to a mixed solvent of 1,4-dioxane (15.0 mL) and distilled water (4.0 mL). The reaction mixture was stirred at 85° C. for 16 hours. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 435.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1.[CH2:20]([NH2:22])[CH3:21].S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>O1CCCC1>[CH2:20]([NH:22][CH:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1)[CH3:21]
Reactant: CCN
Reactant: CC(=O)CN1CCc2c(c(=O)oc3ccccc23)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC(C)CN1CCc2c(c(=O)oc3ccccc23)C1
Temperature: 40 °C
Yield: 51.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (18.2 g, 0.071 moles), ethylamine (10 ml, 0.153 moles), anhydrous calcium sulfate (15 g), and glacial acetic acid (1 ml) in tetrahydrofuran (450 ml) is shaken at 40° C. in a pressure vessel. After 18 hours the mixture is cooled and filtered. The filtrate is hydrogenated at 25° C. and 50 psi in the presence of 10% platinum or carbon until hydrogen uptake ceases. The catalyst is removed by filtration, and the filtrate is evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave the product (10.5 g), mp 104°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)CC2

Procedure:
33.5 g (0.2065 mol) of 6-methoxy-2,3-dihydro-1H-indenone is added in portions to a solution of 3.8 g (0.1 mol) of lithium aluminium hydride in 700 ml of dry ether and 50 ml of dry tetrahydrofuran, under an inert atmosphere with cooling. (H.0. House et al. J. Org. Chem. 35 647-51, 1970 and J. Org. Chem. 42, 2155-60, 1977).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2.[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25](I)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]4)[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Reactant: CN1CCc2cccc(N)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1nn(C)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A suspension of 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (23.06 mg, 0.13 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol, Ex. 2.02), palladium(II) acetate (1.469 mg, 6.54 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7.57 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) in dioxane (1 ml) was stirred at 80° C. overnight under nitrogen. The same reactants were dissolved in DMA (1 mL) and sealed into a microwave tube. Argon was bubbled through the reaction mixture then the reaction was heated to 150° C. over a period of 30 minutes in a microwave reactor. The crudes were combined, poured onto a silica gel column and purified by flash chromatography eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. Trituration with a few drops of MeCN gave a solid which was taken up into Et2O, collected by filtration and dried to afford the title compound (19 mg, 33.7%) as a white solid. 1H NMR spectrum (500 MHz, CDCl3): 2.16 (s, 3H), 2.90-2.99 (m, 2H), 3.14 (s, 3H), 3.51-3.58 (m, 2H), 3.79 (s, 3H), 5.94 (s, 1H), 6.42 (s, 1H), 6.90 (d, 1H), 7.20 (dd, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 8.26 (s, 1H), 11.13 (s, 1H); Mass spectrum: ESI+ MH+ 431.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(F)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) was reacted with (3-fluorophenyl)magnesium bromide (14 mL, 6.97 mmol, 0.5 M in THF, 2.5 equiv) according to General Procedure 3. The resulting endo-olefin (methyl 4-(3-fluorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound: 150 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.35 (m, 1H), 2.73-3.01 (m, 3H), 3.84 (s, 3H) 4.22 (t, J=7.13 Hz, 1H), 6.65 (d, J=1.46 Hz, 1H), 6.86-6.93 (m, 2H) 7.00 (d, J=7.66 Hz, 1H), 7.19-7.30 (m, 1H) 9.07-9.28 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][CH:12]([NH:16][CH3:17])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]>O.C(O)C>[N+:3]([C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][CH:12]([NH:16][CH3:17])[CH2:13][CH:14]([OH:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: CNC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC1CCc2ccc([N+](=O)[O-])cc2C(O)C1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of 125 g of sodium borohydride in 625 ml of water at 10° C. was added to a solution of 125 g of the product of Step C in 2 liters of ethanol kept at 25°-30° C. and the mixture was stirred for one hour and let stand for 12 hours. The mixture was concentrated to 0.5 liters and 0.5 liters of water was added thereto. The mixture was extracted 4 times with 250 ml of methylene chloride and the combined organic extracts were extracted 3 times with 200 ml of 2 N hydrochloric acid. The aqueous acid phase was washed with 200 ml of methylene chloride and made alkaline with excess ammonium hydroxide at 10° C. The mixture was extracted 5 times with 200 ml of methylene chloride and the combined organic phases was dried over sodium sulfate and evaporated to dryness to obtain 103 g of raw product. The latter was added to 1.5 liters of a 2-1 ether-ethyl acetate mixture and 10 g of activated carbon was added thereto. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 95 g of 3-nitro-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-ol in the form of a brown resin.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[C:22]([Br:35])[CH:21]=1>>[Br:35][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1Br
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1Br
Yield: 47 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-thiophen-2-yl-pyrimidine-4-ylamino)-butan-1-ol (425 mg, 1.5 mmol) with (RS)—S-(4-amino-2-bromphenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (404 mg, 1.3 mmol) according to procedure 5b, the desired product is obtained in 47% yield (340 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:11]
Reactant: Cc1cc(C)c(C(C(=O)O)c2ccccc2)c(C)c1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3c(C)cc(C)cc3C)CC2)c1

Procedure:
Example 14 was prepared from mesityl(phenyl) acetic acid and N-{3-[1-(3-aminopropyl) 4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 9: ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]([NH2:18])=[N:16][C:9]2[N:10]=[C:11](SC)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:22])(=O)=O.CCOCC>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:17]([NH2:18])=[N:16][C:9]2[N:10]=[C:11]([Cl:22])[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc2cnc(SC)nc2nc1N
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc2cnc(Cl)nc2nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a suspension of the product of Example 128 in 50 mL of chloroform is slowly added sulfuryl chloride, followed by 2 drops of ethanol. The reaction is stirred at room temperature for 16 hours, poured into ether, and the solid collected to give 0.50 g (98%) of the product.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Cl.Cl.N[C@@H]1CCN(S(C2C=C3C(=CC=2)C=NC=C3)(=O)=O)C1.[C:36]([O:40][C:41]([NH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41]([NH:43][C@H:44]1[CH2:48][CH2:47][N:46]([S:2]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[N:10][CH:9]=[CH:8]3)(=[O:4])=[O:3])[CH2:45]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Agent: Cl
Agent: N[C@@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Temperature: 25 °C

Procedure:
A dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) was added with stirring at room temperature to a solution containing 423 mg of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine dissolved in 20 mL of dichloromethane further supplemented with 0.5 mL of triethylamine, and reacted for 6 hour. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:2) to obtain 560 mg of the compound of interest as a colorless oil (65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1

Procedure:
tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamate was synthesized according to the procedure for General Method 1, outlined above, starting with 2.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 4.0 mmol of piperidin-4-yl-carbamic acid tert-butyl ester. LC/MS [9.47 min; 541 (M+1)]
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[N:23]=[C:22]3[CH3:30])=[CH:17][CH:16]=2)=[N:5][C:6]2[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:7]=2[N:8]=1.[C:31](OC)(=[O:34])[C:32]#[CH:33]>C(O)CCC>[CH3:13][C:11]1[C:10]([CH3:14])=[CH:9][C:7]2[N:8]3[CH:33]=[CH:32][C:31](=[O:34])[N:1]=[C:2]3[CH2:3][C:4]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[N:23]=[C:22]4[CH3:30])=[CH:19][CH:20]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(N)=N2
Reactant: C#CC(=O)OC
Solvent: CCCCO
Product: Cc1cc2c(cc1C)-n1ccc(=O)nc1CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Yield: 10.3 %

Procedure:
A solution of 2-amino-7,8-dimethyl-4-[4-(2-methylimidazo-[4,5-c]pyrid-1-yl)phenyl]-3H-[1,5]benzodiazepine (Example 44) (395 mg, 1.0 mmol) and methyl propiolate (168 mg, 2.0 mmol) in n-butanol (4 ml) was heated at reflux for 16 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate:methanol: diethylamine=100:10:5). Fractions containing product were concentrated, and the residue was treated with dichloromethane, leaving some insoluble tarry material. The dichloromethane solution was decanted, concentrated, and the resulting brown solid triturated with hexane to give the title compound (46 mg, 10%), m.p. 192°-194° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]3[CH:36]=[N:35][C:34]([CH3:37])=[N:33]3)=[C:26]([F:38])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:38][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[N:32]1[CH:36]=[N:35][C:34]([CH3:37])=[N:33]1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)cc(F)c1-n1cnc(C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OC(F)(F)F)cc2)cc(F)c1-n1cnc(C)n1
Yield: 45.6 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (753 mg, 1.36 mmol), sodium iodide (1.02 g, 6.80 mmol), and diisopropylethylamine (1.19 mL, 6.80 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 321 mg (44% yield) of the titled compound as a white solid. LC-MS (M+H)+ 518.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (s, 1 H), 7.20 (s, 4 H), 6.90-6.96 (m, 2 H), 6.73 (s, 1 H), 4.17-4.34 (m, 3 H), 3.72 (s, 3 H), 2.47 (s, 3 H), 2.13-2.26 (m, 1 H), 2.05-2.13 (m, 1 H), 1.92-2.04 (m, 2 H), 1.82-1.92 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:23]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCn1c(=O)ccc2cc(Br)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromoquinolin-2(1H)-one (430 mg, 1.91 mmol) in tetrahydrofuran (8 ml) was added sodium bis(trimethylsilyl)amide (2.1 ml, 2.08 mmol). After 15 minutes, 4-(boc-amino)butyl bromide (403 mg, 1.6 mmol) was added. The solution was stirred for 15 hours, concentrated and purified by flash chromatography to provide the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].CS(Cl)(=O)=O.CCN(CC)CC.S([O-])(=O)(=O)C>C(Cl)Cl.COCCOC>[C:9]([N@@:8]1[CH2:2][CH:3]1[C:4]([O:6][CH3:7])=[O:5])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)C1C[N@]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
(S. Kato et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; J. Smrt et al., Experientia 1957, 15, 291). Crude (R)-methyl 3-hydroxy-2-(N-tritylamino)propanoate (45.20 g, 0.13 mol) was dissolved in CH2Cl2 (300 mL) and cooled to 0° C. under Ar. Methanesulfonyl chloride (10.64 mL, 0.14 mol) was added to the cooled solution, followed by the dropwise addition of Et3N (26.14 mL, 0.19 mol). The resulting solution was allowed to stir at 0° C. (30 min) and then successively washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). After drying (Na2SO4) and evaporation of the solvent, the crude mesylate (53.30 g, 0.12 mol) was dissolved in DME (300 mL) and Et3N (33.73 mL, 0.24 mol) was added. The reaction mixture was stirred at 80° C. (48 h) and then evaporated in vacuo. The residue was dissolved in EtOAc (300 mL) and washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was recrystallized (EtOH) to yield 30.81 g (74%) of desired product as a transparent crystal: mp 127-128° C. (Kato, S. et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; mp 129-131° C.); [α]20D +94.7° (c 1.5, CHCl3) (Smrt, J. et al., Experientia 1957, 15, 291; [α]20D +95 (c 1, CHCl3)); Rf=0.45 (1/5 EtOAc/hexanes); 1H NMR (CDCl3) δ 1.41 (dd, J=1.7, 6.4 Hz, NCHH′CH), 1.89 (dd, J=2.8, 6.4 Hz, CHH′CHN), 2.26 (dd, J=1.7, 2.8 Hz, NCHH′CH), 3.76 (s, OCH3), 7.20-7.31 (m, 9 PhH), 7.48-7.52 (m, 6 PhH); 13C NMR (CDCl3) δ 28.8 (NCH2CH), 31.8 (CH2CHN), 52.2 (OCH3), 74.5 (NCPh3), 127.1, 127.8, 129.4, 143.7 (3 C6H5), 172.0 (C(O)).
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]3[C:21](=[O:36])[N:22]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH2:23][C:10]3=[CH:9]2)=CC=1>C(O)(C(F)(F)F)=O>[N:15]1([C:12]2[C:13](=[O:14])[NH:8][CH:9]=[C:10]3[CH2:23][N:22]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[C:21](=[O:36])[C:11]=23)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COc1ccc(Cn2cc3c(c(N4CCOCC4)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
5-(4-Methoxy-benzyl)-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (30 mg, 0.059 mmol, see Example 14) was dissolved in TFA (30 ml), stirred and heated to about 100° C. for about 12 h. LC-MS analysis indicated complete conversion. The crude material was purified via preparative thin-layer chromatography (MeOH/DCM=10:90) to give the title compound (17 mg, 0.043 mmol, 73.4% yield).