Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@:5]1([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH2:78])[CH2:69][C:70]2[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=2)=[CH:55][CH:54]=1.CN1CCOCC1>CN(C=O)C>[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH:78][C:11](=[O:12])[C@@H:10]([N:7]2[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:23][CH:24]([CH3:25])[CH3:26])[C:6]2=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:69][C:70]2[CH:71]=[C:72]([F:77])[CH:73]=[C:74]([F:76])[CH:75]=2)=[CH:55][CH:54]=1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N(Cc2ccc(OC)cc2)C1
Reactant: CC(=O)N[C@]1(CC(C)C)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@@](CC(C)C)(NC(C)=O)C2=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Step 1 (A): To a solution of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 96 mg, 0.266 mmol) in DMF (1.5 ml) was added HATU (121 mg, 0.319 mmol). A solution of (1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation C, 115 mg, 0.266 mmol) in DMF (1.0 ml) was then added, followed by N-methylmorpholine (102 μl, 0.931 mmol). The reaction mixture was stirred at rt for 30 min. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 75-100% ethyl acetate/hexane) gave 114 mg (55%) of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide as a clear, colorless oil:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[F:23])=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:24][C:25]([F:53])([C:49]([F:52])([F:51])[F:50])[C:26]([F:48])([F:47])[C:27]([F:46])([F:45])[O:28][C:29]([F:44])([F:43])[C:30]([F:42])([F:41])[O:31][C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:41])([F:42])[C:29]([F:43])([F:44])[O:28][C:27]([F:45])([F:46])[C:26]([F:47])([F:48])[C:25]([F:24])([F:53])[C:49]([F:52])([F:51])[F:50])([F:40])[F:39])=[CH:18][C:17]=2[F:23])=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2F)nc1
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2F)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-[4-hydroxy-2-fluorophenyl)pyrimidine (1.5 g, 4.7 mmol, prepared from 2-fluoro-4-hydroxybenzamidine hydrobromide and (CH3)2NCH=C(OC8H17)CHO) with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl bromide (3.0 g, 5.4 mmol, Example 3). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (190-210° C. at 0.5 torr), to provide a yield of 2.85 g.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=S)=S.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].O>CCCCCC>[C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][C:2]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)Cl
Solvent: O
Solvent: S=C=S
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Yield: 85 %

Procedure:
Fluorene (30.4764 g, 183.5928 mmol), FeCl3 (0.5 eq., 14.7517 g) and CS2 (300 ml) were introduced to a three-neck 1 liter flask fitted with a mechanical stirrer and hydrogen chloride trap which had been flame-dried and filled with nitrogen, and stirred. t-BuCl (2.5 eq., 50 ml) was dripped into this solution during 10 minutes. The reaction solution was stirred at room temperature for 7 hours, then water was added to quench the reaction. Next, the organic layer was extracted twice with methylene chloride, the extracted organic layer was washed with saturated salt solution, and dried using MgSO4. The dried solution was filtered, and was concentrated under reduced pressure to give a crude product (49.4598 g, brown solid). This crude product was refined by silica gel column chromatography (hexane), and the target product 2,7-di-t-butylfluorene (43.6058 g, 85%, white solid) was thus obtained. For the reaction, no further purification was carried out, but for measurement of analysis data, a sample which had been recrystallized from EtOH was used.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[C:37]([C:44]#[N:45])=[CH:36][N:35]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.C(#N)C>[C:44]([C:37]1[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:39][C:34]([NH:33][C:32]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH2:14][N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]4=[O:22])=[C:4]([CH:3]([O:23][CH3:24])[O:2][CH3:1])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:31])=[N:35][CH:36]=1)#[N:45]
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1

Procedure:
A mixture of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 268 mg, 0.641 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (intermediate 96, 834 mg, 1.122 mmol) and DMAP (7.83 mg, 0.064 mmol) in acetonitrile (2.6 ml) was heated at reflux for 3.5 h. The reaction mixture was evaporated and applied to a 24 g RediSep silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an off-white solid. (UPLC-MS 6) tR 0.92; ESI-MS 538.7 [M+H]+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][N:6]([CH3:25])[CH2:7][CH:8]([CH3:24])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH2:11]>O.Cl>[CH3:25][N:6]([CH3:5])[CH2:7][CH:8]([CH3:24])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][NH:11][C:2]([NH2:3])=[O:1]
Reactant: CC(CN(C)C)C(CN)(c1ccccc1)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(CN(C)C)C(CNC(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 120 g of potassium cyanate in 200 ml of water was added while stirring to a solution of 220 g of N4,N4 -dimethyl-2,2-diphenyl-3-methyl-1,4-butanediamine in 1000 ml of water and 200 ml of concentrated hydrochloric acid at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, filtered, and made basic with 9N sodiumhydroxide. The crystalline product was filtered and washed with water. The product was taken up in 1 liter of methanol and 200 ml water, and then 70 ml of glacial acetic acid were added. The solution was filtered, and 25% ammonium hydroxyde was added dropwise to pH=9. The product was filtered and washed successively with 500 ml methanol, 500 ml water and 500 ml methanol. The product was dried overnight in vacuo at 70° C. Yield: 204 g of pure N-(4-dimethylamino-2,2-diphenyl-3methyl-1-butyl)urea as a white powder, melting at 226°-228° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1sc(C(=O)O)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (3.30 g, 11.54 mmol) in dioxane/H2O (4:1, 100 mL) was added K2CO3 (5.5 g, 40.0 mmol), tetrakistriphenylphosphine Pd(0) (671 mg, 0.58 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (2.66 g, 13.71 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 hours. The reaction mixture was partitioned between H2O and CHCl3. The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl3. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (3.3 g, quant.): LC-MS (ES) m/z=289 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[I:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[I:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(I)cc2)CC1

Procedure:
10.67 g (57.3 mmol) of t-butyl piperazine-1-carboxylate was dissolved in 180 ml of dimethylformamide. 10 ml (57.3 mmol) of diisopropylethylamine and a solution of 17.3 g (57.3 mmol) of 4-iodobenzenesulfonyl chloride in 20 ml of dimethylformamide were added to the solution at 0° C., and the resultant mixture was stirred for 5 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, crude t-butyl 4-(4-iodobenzenesulfonyl)piperazine-1-carboxylate was obtained. This crude product was dissolved in 150 ml of dimethylformamide. 750 mg (3.5 mmol) of palladium (II) acetate, 55 ml (1.39 mol) of methanol and 19 ml (139 mmol) of triethylamine were added to the solution, and the resultant mixture was stirred under heating at 90° C. in the presence of carbon monoxide for 23 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude title compound was obtained. This product was then purified by the silica gel column chromatography.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:15]1([C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:24]O)[CH2:22][OH:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC.C(OC(C)C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:2]2([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:23][CH2:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:24][O:1]2)=[CH:13][CH:12]=1
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OCC(c2ccccc2)(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
42.5 g (0.2 M) of ethyl 2-oxo-2-(4-chlorophenyl)acetate are placed in 400 ml of CH2Cl2 in a 500 ml reactor. 22.8 g (0.1 M) of 2,2-diphenylpropane-1,3-diol and then 14.2 g (0.1 M) of BF3.Et2O are added. The mixture is left to react with stirring for 72 h at room temperature. The reaction mixture is taken up in NaHCO3 solution. The organic phase is washed with saturated NaCl solution. After drying over Na2SO4 and concentration, a very thick oil is obtained. 150 ml of isopropyl ether are added and a white precipitate forms. After filtration, 30 g of product melting at 156-158° C. are obtained (yield: 71%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:25][CH:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)CCCC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCOc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask at which point the solution turned color from yellow to orange. The solution was kept stirring at 0° C. for 30 minutes. 1-Bromo-3,7-dimethyloctane (344.4 μL, 1.66 mmol) in 1 mL of DMF was cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen to warm back to room temperature over 14 hours. The desired product was obtained through preparatory thin layer chromatography using a 7:3 Hexanes:Ethyl acetate solvent system. The purified product was verified by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CD3COCD3): δ 0.95-1.86 (19H), 4.08 (t, 2H), 6.40 (d, 1H, J=9 Hz), 7.17 (m, 2H), 7.27 (s, 1H), 7.92 (d, 1H, J=9 Hz); 13C-NMR (75 Hz, CD3COCD3): δ 19.91, 22.87, 22.97, 25.13, 25.37, 36.60, 37.92, 39.93, 67.54, 111.97, 117.58, 118.47, 120.28, 120.56, 129.10, 144.35, 149.19, 156.44, 160.77. FIRMS (EI) Calcd. for C19H26O3: 302.18820. found: 302.18871.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[Cl:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH2:31][CH2:32][O:28][C:29]4=[O:33])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([Cl:23])[CH:20]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Reactant: O=C1NCCO1
Product: CS(=O)(=O)c1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 84.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]methanone (0.5 g) described in Preparation Example 74 and oxazolidin-2-one (130 mg), the title compound (429 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][NH:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][N:25]([C:4](=[O:6])[C@H:3]([N:7]2[C:16](=[O:17])[C:15]3=[CH:18][NH:19][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[CH2:8]2)[CH:2]([CH3:20])[CH3:1])[CH2:24]1
Reactant: N#CC1(CF)CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC(C#N)(CF)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 31.9 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.293 mmol) under nitrogen. DMF (0.5 mL), 3-(fluoromethyl)azetidine-3-carbonitrile (93 mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (34.5 mg, 25.3%). 1H NMR (400 MHz, DMSO-d6) δ 0.78 (dd, J=6.57, 3.79 Hz, 3 H) 0.97 (dd, J=12.88, 6.32 Hz, 3 H) 2.30-2.41 (m, 1 H) 3.99 (dd, J=9.98, 4.42 Hz, 1 H) 4.22 (d, J=9.35 Hz, 2 H) 4.36 (s, 1 H) 4.62-4.71 (m, 1 H) 4.76-4.88 (m, 2 H) 4.87-5.03 (m, 1 H) 5.02-5.09 (m, 1 H) 7.09 (t, J=4.80 Hz, 1 H) 7.88 (dd, J=5.56, 2.27 Hz, 1 H) 8.27 (t, J=5.31 Hz, 1 H) 12.25 (d, J=8.84 Hz, 1 H). [M+H] calc'd for C19H20FN5O2, 370; found, 370.5.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:37]([O:36][C:34](=[O:35])[O:23][C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:1])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=2)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Oc1nc2c(N)nc(OCCOC)nc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxy-ethoxy)-9H-purin-8-ol, 29 (11.75 mg, 0.027 mmol, prepared according to the procedure described by Kurimota, et al., Bioorg. Med. Chem., 12, 1091-109 (2004) was suspended in CH2Cl2 (0.6 mL) and cooled to 0° C. DIEA (11.96 μL, 0.068 mmol) and ethyl chloroformate (3.86 mg, 0.036 mmol, added as a 10% by volume solution in dichloromethane) were then added to the suspension. The reaction mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature for 15 minutes. TLC of the reaction mixture shows that starting material remained. The reaction mixture was heated to 35° C., DMAP (cat.), methanol (60 μL portions) was added to dissolve 29, and additional aliquots of ethyl chloroformate (3.86 mg, 0.036 mmol, added as a 10% by volume solution in dichloromethane) were added until the reactions was complete. The crude mixture was purified by flash chromatography using a 0 to 100% gradient of ethyl acetate in hexane. The desired peaks were collected and concentrated in-vacuo to yield 8.5 mg (80%) of compound 51 as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=Hz, 2H), 7.27 (m, 3H), 4.98 (s, 2H), 4.46 (m, 4H), 3.74 (m, 2H), 3.42 (s, 2H), 1.46 (t, 3H); MS [M+H]+m/z 388.3.
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>C1COCC1.C(Cl)Cl>[C:1]([NH:20][CH:21]([CH2:22][OH:23])[CH2:24][O:25][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([C:29]2[O:28][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=2)=[CH:38][CH:39]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC(COCc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-trityl-1,3-dihydroxy-2-propanamine (3.7 g; 11 mmol) is dissolved in THF (22 ml) and cooled to 0° C. NaH (0.44 g; 11 mmol; 60% in oil) is added and the reaction is warmed to room temperature and allowed to stir for 2 hours. 4-(benzoxazol-2-yl)benzylbromide (1.6 g; 5.5 mmol) is added and the reaction allowed to stir for 15 hours.. The reaction is diluted with CH2Cl2 and washed with H2O 2×, dried (Na2SO4), concentrated and purified by column chromatography with basic alumina and eluted with 2% MeOH/98% CH2Cl2 to obtain N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-hydroxy-2-propanamine as a white solid which is used directly in Step E.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[NH:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2.[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27]Br)=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]>CN(C=O)C>[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27][N:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:7])=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: Cc1nc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(C)nc3cccnc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
Cesium carbonate (294 mg, 0.902 mmol) was added to 2-methylimidazo[4,5-b]pyridine (60 mg, 0.451 mmol) in DMF (2 mL) at room temperature under nitrogen. After stirring at 50° C. for 15 min, a solution of 4-(1-carbomethoxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-dipropylbenzyl bromide (from Step C) (27 1 mg, 0.585 mmol) in DMF (2 mL) was added and the mixture stirred at 50° C. for 12 h. After cooling to room temperature, the mixture was poured onto ice/water and extracted with ethyl acetate (4 times). The combined organic phase was washed with water twice, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The crude product (a mixture of regioisomers) was purified by flash chromatography on silica-gel (3,4,5% methanol/methylene chloride) to provide the title compound (87 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].[CH2:22]1[CH2:27][O:26][CH:25]=[CH:24][CH2:23]1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:25]2[CH2:24][CH2:23][CH2:22][CH2:27][O:26]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole (5.0 g, 14.2 mmol) in THF (50 mL) is added DHP (2.4 g, 28.5 mmol) and CH3SO3H (1.0 g, 10.4 mmol). The resulting mixture is stirred at RT for 1 hour. Then EtOAc and aqueous NaHCO3 solutions are added. The organic phase is separated, dried over anhydrous MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (5:1) to give the desired product (5.5 g, 89.0% yield). MS (m/z): 436.0 (M+H).