Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][C:15]3([CH3:21])[CH3:20])[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][C:15]4([CH3:21])[CH3:20])[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCOCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCOCC3(C)C)n(C)c2n1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A mixture of 2-chloro-8-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (44 mg, 0.11 mmol), 2-ethylbenzimidazole (18 mg, 0.12 mmol), Pd2(dba)3 (5.2 mg, 5 mol %), Xphos (5.3 mg, 10 mol %) and Cs2CO3 (54 mg, 0.17 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 24 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 535 (33 mg, 59%) as a pale beige solid. LCMS: (Method I): RT 2.52 min; [M+H]+ 505.2. 1H NMR (400 MHz, CHCl3-d): δ 8.02-7.97 (m, 1H), 7.77-7.72 (m, 1 H), 7.29-7.22 (m, 2 H), 4.52-4.14 (m, 4 H), 3.86 (t, J=4.8 Hz, 4 H), 3.80 (s, 3 H), 3.79-3.67 (m, 2 H), 3.35 (q, J=7.5 Hz, 2 H), 3.34-3.23 (m, 2 H), 3.05-2.92 (m, 2 H), 2.92-2.80 (m, 2 H), 2.77-2.54 (m, 2 H), 1.44 (t, J=7.5 Hz, 3 H), 0.99 (s, 6 H)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.[OH-].[K+]>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted with stirring in a nitrogen gas stream at 150° C. for 2 hours to obtain 2.5 g of 4-(5-trifluoromethyl-2-pyridyloxy)phenol. The thus-obtained 4-(5-trifluoromethyl-2-pyridyloxy)phenol was dissolved in 20 ml of methyl ethyl ketone, and 1.7 g of anhydrous potassium carbonate was added thereto. The mixture was reacted with stirring under reflux for 1 hour, and the reaction product thusobtained was cooled to 40° C., and 2.5 g of ethyl 4-bromo-2-pentenoate was dropwise added thereto gradually. The mixture was allowed to stir for 30 minutes and then to react under reflux for 7 hours. After completion of the reaction, the reaction product was thrown into 100 ml of water, and an oily matter was extracted with methylene chloride. The extracted phase was washed with water several times, and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a crude product which was subsequently subjected to silica gel column chromatography using toluene as an eluent to obtain 1.5 g of the object product having a refractive index, nD23, of 1.5145. This was found to have a boiling point of 148°-151° C./l mm Hg with some decomposition.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)CCC>C1(C)C=CC=CC=1.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>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccco1
Temperature: 110 °C
Reaction time: 23 h
Yield: 64.2 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (450 mg, 1.32 mmol), 2-(tributylstannyl)furan (0.622 ml, 1.97 mmols) and tetrakis(triphenylphosphine)palladium(0) (153 mg, 0.132 mmoles) in toluene (26 ml) is heated at 110° C. with stirring for 23 h. The mixture was filtered through celite, concentrated and purified by reverse-phase preparative HPLC to yield 280 mg (64%) of the title compound as a light brown solid. It is further purified by triturating with CH2Cl2 to yield a gray solid: mp 158–163° C.; 1H NMR (DMSO-d6): δ 5.04 (2H, s), 6.61 (1H, d, J=3.11 Hz), 6.67–6.69 (2H, m), 6.85 (1H, dd, J=8.47 Hz, J=2.33 Hz), 6.95 (1H, dd, J=8.72 Hz, J=2.27 Hz), 6.99 (1H, d, J=1.98 Hz), 7.77 (1H, d, J=8.77 Hz), 7.82 (1H, d, J=8.53 Hz), 7.85 (1H, d, J=1.32 Hz), 8.24 (1H, s), 9.70 (1H, s), 9.75 (1H, s); MS (ESI) m/z 329 (M−H)−, 331(M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](S)=[N:12][C:11]=2[CH:16]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([Cl:4])=[N:12][C:11]=2[CH:16]=1
Reactant: Sc1nc2cc(Br)ccc2s1
Reactant: O=S(=O)(Cl)Cl
Product: Clc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To sulfuryl dichloride (5 mL) was added 5-bromobenzo[d]thiazole-2-thiol (450 mg, 1.8 mmol) portionwise. The mixture was stirred at rt for 1 hour and heated at 50° C. for 15 min. After cooling to rt, the reaction mixture was slowly poured onto ice (50 g) and the resulting suspension was stirred for 30 min. Solid was collected through filtration and washed with water (10 mL) and dried under high vacuum to afford 5-bromo-2-chlorobenzo[d]thiazole as a pink solid (470 mg, 100%). MS (ESI) m/z 248 (M+H+).
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[Se]=O.FC(F)(F)C(O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)([CH3:32])[CH3:31]>O1CCOCC1.CC(O)=O>[OH:20][C:2]1([C:36]2[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][C:35]=2[O:39][CH3:40])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(O)C2=O
Reactant: COc1cccc(C(C)C)c1
Agent: O=[Se]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(NC(C)=O)ccc([N+](=O)[O-])c2C1=O
Reaction time: 12 h
Yield: 19.7 %

Procedure:
N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (1.50 g, 6.4 mmol) was completely dissolved in anhydrous dioxane (15 ml). This solution was added with selenium oxide (1.56 g, 14.0 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 12 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). A trifluoroacetic acid solution of the resulting product was added with isopropyl-3-methoxy benzene (962 mg, 6.4 mmol) followed by stirring for 12 hours. The resulting product was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (0.52 g, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](OC)=[O:11])=[C:5]([N+:14]([O-])=O)[CH:4]=1)#[N:2]>CC(O)=O.[Fe]>[O:11]=[C:10]1[CH2:9][C:6]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[NH:14]1
Reactant: COC(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)NC(=O)C2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
Methyl (4-cyano-2-nitrophenyl)acetate (128 mg) was dissolved in AcOH (3.0 ml), followed by addition of iron powders (129 mg), and the reaction solution was stirred in an oil bath at 100° C. for 1.5 hours. It was concentrated to remove AcOH, followed by addition of EtOAc. The brown solid was separated by filtration, and the organic layer was washed with a 1M HCl solution and saturated brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=99:1 to 95:5) to obtain to obtain 2-oxoindoline-6-carbonitrile (52.0 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>ClCCCl.[O-]S([O-])(=O)=O.[Cu+2]>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[N:4]=[CH:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1cnc(C=O)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)n1cnc(/C=N/[S@@](=O)C(C)(C)C)c1
Temperature: 65 °C
Yield: 72.8 %

Procedure:
To CuSO4 (24.28 g, 152 mmol) and tert-butyl 4-formyl-1H-imidazole-1-carboxylate (19.9 g, 101 mmol) in DCE (100 mL) was added (S)-2-methylpropane-2-sulfinamide (13.52 g, 112 mmol). The reaction was heated to 65° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The pad was rinsed with DCM (200 mL) and the filtrated was concentrated. The residue was then run through a pad of silica gel with heptane/EtOAc (3:1) as eluent. The filtrate was concentrated to give crude (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (22 g). LCMS (B) m/z 300.2 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:35]=[CH:34][C:27]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])=[CH:26][CH:25]=2)=[N:21][CH:22]=1>ClCCl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:30](=[O:31])[CH:29]([O:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:36])([F:37])[F:15])=[CH:22][N:21]=2)=[CH:35][CH:34]=1)[CH3:33]
Reactant: NCC1OCCO1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)NCC1OCCO1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1,3-Dioxolan-2 ylmethylamine (4 grams; 0.04 mol), triethylamine (5 ml) and dichloromethane (150 ml) were placed in a 3-necked glass reaction flask equipped with stirrer, thermometer and reflux condenser and cooled to 5° C. 2[4-(5-Trifluoromethyl-2-pyridinyloxy)-phenoxy]propanoic acid chloride (9 grams; 0.027 mol) in dichloromethane (30 ml) was added in a five minute time period. The reaction mixture was stirred for 1 hour at 5° C.-20° C., washed with water, passed through phase separating paper and concentrated to a dark gum (10.5 grams). The product was chromatographed through Florisil clay (100 ml), using hexane-ethyl acetate solvent mixtures. The desired product was isolated as a yellow gum (3.0 grams) and had the following elemental analysis:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].O>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCOCC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOCC1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of tetrahydro-4H-pyran-4-ol (408 mg, 102 mmol) and pyridine (632 mg, 19.1 mmol) in 15 mL of CH2Cl2 was added p-nitrophenyl chloroformate (968 mg, 102 mmol). The mixture was stirred at rt for 30 h. Water was added and the organic layer was separated, and washed with 5% aq. citric acid. The organic layer was treated with an aq. solution of ammonia (NH4OH/H2O: ¼ v/v) for 15 min. The organic layer was separated, washed with aq. sodium bicarbonate and brine. After the solvent was removed, the desire product was isolated as a solid. 1H NMR (CD3Cl, 400 MHz) δ 1.80 (m, 2H), 2.00 (m, 2H), 3.52 (m, 2H), 3.92 (m, 2H), 4.88 (m, 1H), 7.32 (d, J=7 Hz, 2H), 8.21 (d, J=7 Hz, 2H).
Reaction SMILES: COC1C=CC(CC2C=CC=C(OC)C=2)=C(C2C=CC(O)=CC=2)C=1.Cl.ClCCN1CCCCC1.C[O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65]C)[CH:60]=2)=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]3)=[CH:45][CH:44]=2)[CH:42]=1>>[OH:65][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[CH2:58][C:40]1[C:41]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]3)=[CH:47][CH:48]=2)=[CH:42][C:37]([OH:36])=[CH:38][CH:39]=1
Reactant: COc1cccc(Cc2ccc(OC)cc2-c2ccc(OCCN3CCCCC3)cc2)c1
Agent: COc1cccc(Cc2ccc(OC)cc2-c2ccc(O)cc2)c1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1cccc(Cc2ccc(O)cc2-c2ccc(OCCN3CCCCC3)cc2)c1
Yield: 47.4 %

Procedure:
Synthesized from 5′-methoxy-2′-(3-methoxybenzyl)biphenyl-4-ol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-[5′-methoxy-2′-(3-methoxybenzyl)biphenyl-4-yloxy]ethyl}piperidine (158 mg) was used according to an analogous synthetic method to Example 779 to provide the title compound (70 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38].C(N(C(C)C)C(C)C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].C(=O)(O)[O-].[Na+]>ClCCCl>[F:30][CH:29]([F:31])[C:21]1[N:20]([C:18]2[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:15]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([N:4]4[CH2:5][CH2:6][C@H:2]([NH:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:3]4=[O:38])[CH2:8][CH2:9]3)[CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), N-ethyl-N-isopropylpropan-2-amine (73 μL), and 1,2-dichloroethane (750 μL) was added methanesulfonyl chloride (17 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}methanesulfonamide (82 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]([OH:30])=O)[N:18]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28](=[O:30])[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:18]=2)[CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)O)ncc2[N+](=O)[O-])CC1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid (120 mg, 0.28 mmol) in DMF (1.5 mL) were added pyrrolidine (48 μL, 0.57 mmol), TBTU (141 mg, 0.43 mmol), and diisopropylethylamine (99 μL, 0.57 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and washed with water (×2) and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluant to afford 19 mg of (4-{[5-nitro-2-(2-oxo-2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a light brown solid.
Reaction SMILES: C([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(O)(=O)C.NN>CN(C)C=O>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 61.1 %

Procedure:
10 g (25.6 mmoles) of α-D-glucose pentaacetate and 2 g (21.7 mmoles) of hydrazine acetate in N,N-dimethylformamide were together stirred at 50° C. for 45 minutes. The reaction solution was extracted with ethyl acetate, and washed with a saturated aqueous sodium chloride solution. After working up in a conventional manner, purification by silica gel column chromatography (eluent; ether: n-hexane =2:1 to 3:1) gave 5.45 g of 2,3,4,6-tetra-O-acetyl-α-D-glucose.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([O:12][CH:13]3[CH2:16][CH:15]([NH:17]C(=O)OC(C)(C)C)[CH2:14]3)=[N:9][C:8]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[N:7][C:6]=2[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:4]=1)#[N:2].Cl>C(Cl)Cl>[NH2:17][CH:15]1[CH2:14][CH:13]([O:12][C:10]2[C:11]3[C:3]([C:1]#[N:2])=[CH:4][N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]=3[N:7]=[C:8]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[N:9]=2)[CH2:16]1
Reactant: Cn1cc(Nc2nc(OC3CC(NC(=O)OC(C)(C)C)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Agent: Cl
Solvent: ClCCl
Product: Cn1cc(Nc2nc(OC3CC(N)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl {3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (cis:trans (1:1), 470 mg, 0.85 mmol) in DCM (20 mL) was added HCl (0.85 mL of 4 M in 1,4-dioxane, 3.4 mmol). After 20 hrs, the volatiles were removed and the reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4 and evaporated to give the title compound (380 mg, 99% yield) as a 1:1 cis:trans isomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (d, J=12.59 Hz, 1H) 8.10 (s, 1H) 7.96 (br. s., 1H) 7.55 (s, 1H) 5.53 (br. s., 2H) 3.82 (s, 3H) 3.61-3.73 (m, 1H) 3.52-3.60 (m, 4H) 3.04 (br. s., 1H) 2.71-2.85 (m, 1H) 2.15-2.40 (m, 2H) 1.76-1.92 (m, 1H) 0.76-0.91 (m, 1H) −0.12 (br. s., 9H). m/z (APCI+) for C21H30N8O2Si 455.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (10.8 g, 40.60 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (10 g, 118.88 mmol, 2.93 equiv) and TsOH (780 mg, 4.53 mmol, 0.11 equiv) in THF (100 mL) was stirred for 2 h at 60° C. The reaction mixture was cooled to room temperature and quenched by the addition of 100 mL of saturated sodium bicarbonate solution. The resulting solution was extracted with 2×80 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:20) to give 13 g (91%) of ethyl 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 5.40-5.38 (m, 1H), 4.34-4.29 (m, 2H), 4.08-4.05 (m, 1H), 3.73-3.70 (m, 1H), 2.07-1.98 (m, 3H), 1.69-1.62 (m, 3H), 1.39-1.32 (m, 3H) ppm. LCMS (method C, ESI): RT=1.53 min, m/z=351.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([Br:27])[CH:15]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45]O)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45][N:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]=2)=[CH:15][C:16]=1[Br:27])[C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br
Yield: 90 %

Procedure:
4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with 5% either in methylene chloride afforded the title compound (90%) as a thick yellow oil: Rf =0.75 (CHCl3 --CH3OH 20:1); LRMS (m/z, relative intensity) 683 (M+,18).