Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24](C4C=CC=CC=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc2cccnc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of NEt(iPr)2 (520 μL, 386 mg, 2.99 mmol), DMAP (12 mg, 0.098 mmol), and C-(3-chloropyrazin-2-yl)-C-quinolin-7-ylmethylamine (compound of Formula IV where Q1=quinolin-7-yl) (608 mg, 1.97 mmol) in dry CH2Cl2 (10 mL), cooled by ice/water, was added cyclobutanecarbonyl chloride (250 μL, 260 mg, 2.19 mmol), then the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2.5 h. Water was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with dilute HCl (pH 2), water, saturated NaHCO3 solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-21)→1:3 (22-44)→EtOAc (45-56)], yielding the title compound as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.81-1.91 (m, 1H), 1.91-2.03 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.87 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 353.1/355.0 (100/39) [MH+].
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].[OH-].[Li+]>>[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][O:20][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC1COCCO1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC2COCCO2)nc1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 58% yield starting from ethyl 6-chloronicotinate and 1,4-dioxan-2-ylmethanol. The reduction was performed using 3 equiv of lithium hydroxide. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.14 (dd, 1 H), 6.93 (d, 1 H), 4.28-4.32 (m, 2 H), 3.84-3.92 (m, 1 H), 3.72-3.83 (m, 2 H), 3.56-3.69 (m, 2 H), 3.44-3.55 (m, 1 H), 3.35-3.42 (m, 1 H); S (ESI) m/z 240[M+H+], m/z 238[M−H+];
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:27]1([CH2:33][NH:34][C:16]2[O:17][C:13]3[CH:12]=[C:11]([CH2:10][N:7]4[C:6]5[CH:23]=[C:24]([O:25][CH3:26])[C:3]([O:2][CH3:1])=[CH:4][C:5]=5[N:9]=[CH:8]4)[CH:22]=[CH:21][C:14]=3[N:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCCC1
Reactant: COc1cc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(NCC5CCCCC5)oc4c3)c2cc1OC
Temperature: 90 °C
Yield: 29.4 %

Procedure:
A stirred mixture of 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (60 mg, 0.162 mmol), cyclohexylmethylamine (36 mg, 0.323 mmol), and DIEA (63 mg, 0.485 mmol) in anhydrous DMA (2 mL) was heated at 90° C. for 15 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine (20 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 7.37 (s, 1H), 7.11-7.24 (m, 4H), 5.42 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.11 (t, J=6.2 Hz, 2H), 1.50-1.79 (m, 7H), 1.07-1.26 (m, 2H), 0.81-1.00 (m, 2H). LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([F:25])=[CH:20][N:19]=1.O>CO>[C:11]([C:9]([NH:8][C:6]1[C:5]([O:15][CH3:16])=[CH:4][CH:3]=[C:2]([NH:1][C:20]2[C:21]([F:25])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[N:7]=1)=[O:10])([CH3:13])([CH3:12])[CH3:14]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)nc1NC(=O)C(C)(C)C
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(Cl)ncc2F)nc1NC(=O)C(C)(C)C

Procedure:
A homogeneous mixture of 6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35) (1.5 g, 6.72 mmol) and 2,4-dichloro-5-fluoropyrimidine (53) (1.68 g, 10 mmol) in methanol:water (20 mL, each) was stirred at 60° C. for 48 hours. The reaction mixture upon dilution with water (100 mL) gave a solid, which was isolated by filtration to obtain N4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine. LCMS: purity: 89%; MS (m/z): 354 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[NH:6][C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1.[H][H].I[CH3:17]>CN(C)C=O>[CH3:17][N:9]1[C:8]([C:10]#[N:11])=[C:7]([C:12]#[N:13])[N:6]=[C:5]1[O:4][CH3:3]
Reactant: [H][H]
Reactant: CI
Reactant: COc1nc(C#N)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(C#N)c(C#N)n1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
Sodium hydride g; 60% in an oil dispersion) was added in small portions to a stirred solution of the above-identified 2-methoxy-4,5-imidazoledicarbonitrile (3.25 g; 0.022 mol) in dimethylformamide (25 mL). Hydrogen gas was evolved. The mixture was cooled, iodomethane (3.2 g) was slowly added and the mixture was stirred overnight. The mixture was poured into ice-water and extracted with chloroform. The combined chloroform extract was washed with water, dried (magnesium sulfate) and concentrated to dryness in vacuo. The residue was chromatographed (silica gel eluted with dichloromethanehexanes) and the product was crystallized from dichloromethane-hexanes to give 1.6 g (45%) of 1-methyl-2-methoxy-4,5-imidazoledicarbonitrile (top 65°-66 ° C.).
Reaction SMILES: I[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.CCN(CCOC1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl.C(#N)C.[C:39]([O:43][CH3:44])(=[O:42])[CH:40]=[CH2:41]>[Zn].O>[CH3:13][O:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[CH2:41][C:40]([C:39]([O:43][CH3:44])=[O:42])=[CH:4]2
Reactant: C=CC(=O)OC
Reactant: COc1cc(I)c(C=O)cc1OC
Agent: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Temperature: 80 °C
Yield: 21.3 %

Procedure:
2-Iodo-4,5-dimethoxybenzaldehyde (292 mg, 1.0 mmol), CoCl2 (dppe) complex (26.4 mg, 0.05 mmol), dppe (19.9 mg, 0.05 mmol) and zinc power (179.8 mg, 2.75 mmol) were placed in a vial, which was sealed with a septum and flushed several times with nitrogen. Acetonitrile (3 mL) and methyl acrylate (172 mg, 2.0 mmol) were then sequentially added and the mixture was heated at 80° C. overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic extracts were concentrated under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 8:1 (v:v) as eluent to give methyl 5,6-dimethoxy-1H-indene-2-carboxylate (50 mg, 21%). LC-MS (ES-API); rt 7.89 min; m/z calculated for C13H14O4 [M+H]+ 235.1, found 235.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:22][CH2:23][C:24]([CH2:30][F:31])([CH:28]=[CH2:29])[C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](/[CH:29]=[CH:28]/[C:24]([CH2:30][F:31])([CH2:23][F:22])[C:25]([OH:27])=[O:26])=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Reactant: C=CC(CF)(CF)C(=O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C(CF)(CF)C(=O)O)cc2n1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (105 mg, 0.3 mmol), 2,2-bis-fluoromethyl-but-3-enoic acid (50 mg, 0.33 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.13 mL, 0.9 mmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol) as a yellow gum. LCMS (m/z) 421.1 [M+H], Tr=2.27 min. A solution of crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.13 mL, 0.75 mmol), 4-(dimethylamino)-pyridine (73 mg, 0.6 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in anhydrous dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 2:1 to 0:1 to afford the partially purified title compound (26 mg, 10%) as a yellow gum. LCMS (m/z) 834.3, 836.2 [M+H], Tr=3.39 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C[CH2:31][O:30][CH2:29][CH2:28]1.ClC(OCC(C)C)=[O:35]>C1COCC1.C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:31][O:30][C:29](=[O:35])[CH2:28][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Similarly to a method reported in J. Med. Chem., 1988, 31, 2199, to a stirred solution of (S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid (J. Org. Chem., 1992, 57, 379; 1 g, 2.93 mmol) in THF (10 mL) at 0° is added N-methylmorpholine (0.35 mL, 3.18 mmol), followed by isobutyl chloroformate (0.39 mL, 3.0 mmol). The suspension is stirred for 1 hour, then filtered. The precipitate is washed with dry ether (5 mL). A saturated solution of diazomethane in ether is added at 0° until persistence of a yellow color. After stirring for 1 hour at 0° and 1 hour at room temperature, the solution is concentrated in vacuo to yeild the intermediate diazoketone as a beige solid (m.p. 128°-129°). The solid is suspended in methanol (10 mL). A solution of silver benzoate (150 mg, 0.65 mmol) in triethylamine (3 mL) is added dropwise. The dark solution is stirred at room temperature for 30 minutes, then filtered through Celite. The filtrate is concentrated under reduced pressure and the residue is redissolved in ethyl acetate (20 mL). The organic layer is washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and 1N hydrochloric acid (10 mL) before being dried over anhydrous sodium sulfate and filtered. After evaporation of the solvent in vacuo, the residue is purified by flash-chromatography on silica gel, eluting with 25% ethyl acetate in hexane. (S)-3-t-Butoxycarbonylamino-4-(biphenyl-4-yl)-butyric acid methyl ester is obtained as a solid, m.p. 86°-87°.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH:35][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(CC(SC(C)=O)C(=O)O)cc1
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(OC)cc1)SC(C)=O
Yield: 50 %

Procedure:
Condensation of 2-acetylthio-3-(para-methoxyphenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 4:6.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=1)=[O:7].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[ClH:1].[ClH:1].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=2)=[O:7])[CH2:30][CH2:29]1
Reactant: COc1ccc(C(=O)CCCCCl)cc1S(N)(=O)=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCCCC(=O)c2ccc(OC)c(S(N)(=O)=O)c2)CC1
Product: Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 123.2 %

Procedure:
A mixture of 2.6 g of 5-(5-chlorovaleryl)-2-methoxy-benzenesulfonamide, 1.8 g of 1-(2-methoxyphenyl)piperazine, 1 g of sodium carbonate and 20 ml of dimethyl sulfoxide was stirred at 90° C. for 3 hours. After the reaction was finished, water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue was dissolved in acetone followed by adding concentrated hydrochloric acid in required amount to produce crystals. The thus-produced crystals were recrystallized from methanol to obtain 2.8 g of the titled compound (yield: 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@@:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH:27]3[CH2:32][CH2:31][CH:30]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[C:18]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].N1C=NN=N1.[O:44]1CCCC1.C(N(CC)[P:52]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:38])[NH:7][C@@:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH:27]3[CH2:28][CH2:29][CH:30]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)[CH2:31][CH2:32]3)[C:18]=2[C:22]([F:24])([F:25])[F:23])[CH:13]=1)([CH3:11])[CH2:9][O:10][P:52]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:44])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Yield: 82.4 %

Procedure:
To a solution of {(R)-1-[6-(4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester (11 mg, 0.000020 mol) and 1H-tetrazole (14 mg, 0.00020 mol) in tetrahydrofuran (3 mL, 0.04 mol) was added di-tert-butyl N,N-Diethylphosphoramidite (28 μL, 0.00010 mol) at RT. The reaction was then quenched with 10% NaS2O3 in saturated sodium bicarbonate, extracted with EtOAc, washed with saturated sodium chloride and then dried with Na2SO4. The drying agent was filtered and the organic layer was concentrated under vacuum, yielding the crude product. The crude was taken up in DCM and purified using silica gel chromatography (24 g column), 0-100% ethyl acetate in hexanes) to give 12 mg of the desired compound as a white solid (77%). ESI-MS: 728 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=8.18-8.08 (m, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.63-7.42 (m, 2H), 7.22 (dd, J=5.0, 9.0 Hz, 1H), 4.32-4.11 (m, 1H), 3.98-3.80 (m, 2H), 2.18-1.98 (m, 2H), 1.92-0.71 (m, 46H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][I:20]>CC(C)=O>[I-:20].[CH2:1]([N+:8]1([CH3:19])[CH2:9][C:10]2[C:15](=[CH:14][C:13]([OH:17])=[C:12]([OH:18])[CH:11]=2)[CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Oc1cc2c(cc1O)CN(Cc1ccccc1)C2
Solvent: CC(C)=O
Product: C[N+]1(Cc2ccccc2)Cc2cc(O)c(O)cc2C1
Product: [I-]
Reaction time: 4 h

Procedure:
590 mg (2.44 mmol) of N-benzyl-5,6-dihydroxyisoindoline was dissolved in 10 ml of acetone, and 0.16 ml (2.5 mmol) of methyl iodide was added thereto at room temperature. The mixture was left to stand for 4 hours, and the precipitated crystals were collected by filtration and washed with 10 ml of acetone to obtain 733 mg of the above identified compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23].Cl>O.COC(C)(C)C.O1CCOCC1>[F:21][C:20]1[CH:15]=[C:16]([F:23])[CH:17]=[C:18]([F:22])[C:19]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Temperature: 40 °C
Yield: 43.4 %

Procedure:
Into a mixture of 4.8 g of sodium hydride (60% in oil) and 100 ml of 1,4-dioxane, 19.2 g of diethyl malonate were added dropwise at room temperature, and then 17.2 g of cuprous bromide and 21.1 g of 1-bromo-2,4,6-trifluorobenzene were subsequently added thereto at 40° C. and refluxed for 26 hours under heating. To the reaction mixture, conc. hydrochloric acid was added under ice-cooling, and then tert-butyl methyl ether and water were added. The organic layer was separated, washed with aqueous sodium hydroxide solution, dil. hydrochloric acid and water subsequently, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 12.6 g of diethyl (2,4,6-trifluorophenyl)malonate.
Reaction SMILES: [N:1](CC1C=CC=CC=1)=[N+:2]=[N-:3].[C:11]([C:13]1[N:17]2[C:18]3[C:23]([N:24]=[C:25]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[C:16]2=[N:15][CH:14]=1)=[CH:22][C:21]([C:31]([F:34])([F:33])[F:32])=[CH:20][CH:19]=3)#[CH:12].O=[C:36]1O[C@H:41]([C@H:43]([CH2:45]O)O)[C:39]([O-])=[C:37]1O.[Na+]>C(O)(C)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:36]1([N:1]2[CH:12]=[C:11]([C:13]3[N:17]4[C:18]5[C:23]([N:24]=[C:25]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[C:16]4=[N:15][CH:14]=3)=[CH:22][C:21]([C:31]([F:32])([F:33])[F:34])=[CH:20][CH:19]=5)[N:3]=[N:2]2)[CH:45]=[CH:43][CH:41]=[CH:39][CH:37]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3cn(-c4ccccc4)nn3)cnc12
Reaction time: 18 h
Yield: 7 %

Procedure:
To a solution of (azidomethyl)benzene (16 mg, 0.12 mmol) in t-butyl alcohol (0.12 mL) and water (0.12 mL), under argon, was added 3-{[1-ethynyl-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 30 (40 mg, 0.12 mmol), copper sulfate (0.2 mg, 0.0012 mmol) and a freshly prepared 1M aqueous solution of sodium ascorbate (0.012 mL, 0.012 mmol). After 18 h at room temperature, a white precipitate was formed. Water was added to the reaction mixture then cooled with an ice bath. The precipitate was filtered, washed with cold water and then dried under vacuum. The crude product was purified by preparative TLC (silica gel, ethyl acetate) to afford the title compound (4 mg, 7%) as a white solid.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([CH2:8][NH2:9])[CH2:5][O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[S:14](N)([NH2:17])(=[O:16])=[O:15].C(Cl)(Cl)Cl>O1CCOCC1>[O:1]1[CH2:7][CH:6]([CH2:8][NH:9][S:14]([NH2:17])(=[O:16])=[O:15])[CH2:5][O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: NCC1COc2ccccc2OC1
Reactant: NS(N)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1COc2ccccc2OC1

Procedure:
((3,4-Dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfamide (3.11 g, 32.4 mmol) were combined in dry dioxane (60 ml) and heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated under vacuum and purified by chromatography (2% to 8% acetone in dichloromethane) to yield the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:51])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:15][CH:16]=3)=[C:9]([Br:51])[N:8]([C@@H:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a cooled solution of (R)-tert-butyl 3-(4-amino-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (81) (506 mg, 0.856 mmol) in DCM (20 mL) was added NBS (167 mg, 0.942 mmol). The resulting mixture was stirred at 0° C. for 2 hr. The reaction was quenched with water and extracted with DCM (20 mL×2). The combined organic layer was dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 15% MeOH in DCM, with 0.5% TEA) to provide (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (82) (344 mg, 60%). LC-MS (ESI): m/z (M/M+2) 668.8/670.8