Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)=[CH:5][CH:4]=1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 1(b), 208 mg of 2-{2-[4-(4-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran were treated with 1 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 223 mg (yield 93%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CCCP(=O)=O>C1COCC1>[CH2:11]([N:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6]/[C:7]/1=[N:15]\[C:19](=[O:20])[C:18]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:17]=1[F:16])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCn1ccc(C(C)(C)C)cc1=N
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCn1ccc(C(C)(C)C)c/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Yield: 44.2 %

Procedure:
A mixture of Example 92A (315 mg, 1.3 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (324 mg, 1.56 mmol), Et3N (543 μL, 3.89 mmol) and propylphosphonic anhydride (927 μL, 1.56 mmol) in THF (15 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with NaHCO3 and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 10-100% EtOAc/hexanes gradient) to afford 228 mg (44%) of the title compound. MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Cl:15][CH2:16][CH2:17][CH2:18]I.O>C1COCC1.[Cu]I>[Cl:15][CH2:16][CH2:17][CH2:18][C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1
Reactant: ClCCCI
Reactant: c1ccc2sccc2c1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: ClCCCc1cc2ccccc2s1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
n-BuLi in heptanes (0.75 ml, 1.2 mmol, 1.6M) was added drop wise to benzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at −5° C. under argon. The reaction mixture was stirred at −5° C. for 15 min, then 1-chloro-3-iodopropane (151 μl, 1.2 mmol) and copper (I) iodide (19 mg, 0.1 mmol) were added. The reaction was stirred at −5° C. for 1 h, then at room temperature for 0.5 h. Water (5 ml) was added, the product was extracted with diethyl ether (2×10 ml) and the organic layer was dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0–2% ethyl acetate in heptanes) to give 2-(3-chloro-propyl)-benzo[b]thiophene (93 mg, 44%). 1H NMR (CDCl3): δ 2.22 (tt, 2H), 3.10 (dt, 2H), 3.61 (t, 2H), 7.06 (m, 1H), 7.30 (m, 2H), 7.69 (m, 1H), 7.78 (m, 1H). 2-(3-Chloro-propyl)-benzo[b]thiophene (53 mg, 0.25 mmol), 4-butylpiperidine (36 mg, 0.25 mmol), sodium iodide (75 mg, 0.5 mmol) and sodium carbonate (53 mg, 0.5 mmol) in acetonitrile (2 ml) were shaken at 80° C. for 18 h, then the reaction was cooled to room temperature. Water (5 ml) was added and the product was extracted with ethyl acetate (2×10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0–15% ethyl acetate in heptanes+0.1% Et3N) to yield the title compound 54. Yield 29 mg (37%). The hydrochloride salt was formed by addition of HCl (4M in dioxane) and recrystallised from methanol-diethyl ether to give a white precipitate that was filtered and dried. 1H NMR (CD3OD): δ 0.91 (t, 3H), 1.32 (m, 6H), 1.39 (m, 2H), 1.55 (m, 1H), 1.96 (br. d, 2H), 2.19 (tt, 2H), 2.93 (m, 2H), 3.04 (t, 2H), 3.14 (m, 2H), 3.53 (m, 2H), 7.14 (br. s, 1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.[NH4+].[Cl-]>C(Cl)Cl>[C:16]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][CH2:10][O:9][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([NH2:1])[CH:7]=[C:6]([Cl:8])[N:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cc(Cl)nc(OCCO)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-amino-6-chloro-3-nitro-pyridin-2-yloxy)-ethanol (4.40 g, 18.8 mmol, prepared as described in the previous step) and tert-butyl-chloro-dimethyl-silane (3.12 g, 20.7 mmol) in DCM (50 mL) was added imidazole (1.80 g, 26.4 mmol). After stirring at room temperature for 2 h, the resulting mixture was treated with saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (3×50 mL), brine (50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0:100-20:80 EtOAc/hexane) to yield 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-chloro-3-nitro-pyridin-4-ylamine as a light yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 6.35 (s, 1H), 6.17 (br. s., 2H), 4.49 (t, J=5.1 Hz, 2H), 3.96 (t, J=5.1 Hz, 2H), 0.88 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylate (450 mg, 1.04 mmol) in dichloromethane (4.5 ml) was admixed at 0° C. with trifluoroacetic acid (0.46 ml, 6.0 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was washed with water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was filtered through silica gel, the filtercake was rinsed with ethyl acetate and methanol, and the filtrate was concentrated.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].C12(O)CC3CC(CC(O)(C3)C1)C2.C(Cl)(=O)C=C>>[OH:13][C:1]12[CH2:10][C:5]3([O:11][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: C=C(C)C(=O)Cl
Agent: C=CC(=O)Cl
Agent: OC12CC3CC(C1)CC(O)(C3)C2
Product: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
The title compound was prepared in the same manner as in Production Example 6, except that 1,3,5-adamantanetriol and methacrylic chloride were used instead of 1,3-adamantanediol and acrylic chloride, respectively.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C(=N\OC(=O)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 24.7 %

Procedure:
2-(2-Triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid (10 g) was suspended in 140 ml of anhydrous dichloromethane, and 6.7 ml of triethylamine was added to this suspension under ice cooling with stirring. To the resulting solution was added a solution of benzoyl chloride (3.2 g) in dichloromethane (20 ml). The mixture was stirred at room temperature for one hour, the insoluble matters were filtered off, and the filtrate was washed twice with 20ml 1N hydrochloric acid and 30 ml of saturated sodium chloride solution each and dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure, and the brown viscous residue (12 g) was purified by silica gel column chromatography using chloroform containing 10 to 15% methanol as eluent, giving 3 g of the objective compound as light brown crystals.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][CH2:50][NH:51][CH:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:37]1([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35][NH:34][C:30]2[N:29]=[C:28]([CH2:49][CH2:50][NH:51][CH:52]([CH2:53][CH3:54])[CH2:55][CH3:56])[N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:10]2[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.1 %

Procedure:
N-(2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}ethyl)-N-(1-ethylpropyl)amine (250 mg, 0.31 mmol) (preparation 19) was dissolved in dry tetrahydrofuran (1 ml), a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 ml, 1 mmol) added and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue purified by column chromatography eluting with a gradient system of dichloromethane:methanol:ammonia (94:6:0.6) changing to dichloromethane:methanol:ammonia (90:10:1) to give the crude product as a foam. This was dissolved in ethyl acetate (15 ml) and the solution washed sequentially with dilute aqueous sodium hydroxide solution, brine and water, then dried with anhydrous sodium sulfate. The solvent removed under reduced pressure to give the title compound as a powder (100 mg). MS: 575 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[CH:10](=O)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[CH:10](=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9])[CH3:11]
Reactant: CC=O
Reactant: N#CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC=C(C#N)c1cccnc1
Temperature: 20 °C
Reaction time: 30 h

Procedure:
A mixture of 57 g of 3-pyridineacetonitrile, 23.3 g of acetaldehyde and 0.5 g of cesium carbonate were dissolved in 1 liter of ethanol. The solution was stirred at 20° C. for 30 hours, then partitioned between 2 liters of water and 1 liter of ether. The aqueous phase was extracted with three 1 liter portions of ether and then 500 ml of ethyl acetate. All organic layers were combined, dried and the solvent removed at reduced pressure giving an orange oil. This oil was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1), giving a pale yellow oil which was crystallized from methylene chloride-hexane, giving α-ethylidene 3-pyridineacetonitrile as white needles, mp 46°-47° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2].[OH-:27].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)(=[O:27])[NH2:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C(N)=O)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1 N HCl and then concentrated. HPLC purification gave product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=2 Hz, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.46 (dd, J=9.6, 2.4 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.24 (s, 3H), 2.09 (dd, J=15.2, 9.6 Hz, 1H). 3 protons assumed to be exchanged with solvents. MS (ESI) m/z=341 [M−H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][C:16]1[O:20][N:19]=[CH:18][CH:17]=1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9]([O:14][CH2:15][C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccno1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccno1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A 631 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 310 mg (3.13 mmol) of 5-hydroxymethyisoxazole and 0.344 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 4 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 2% ethyl acetate in methylene chloride. The solvent was removed and the product dried to afford 0.473 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:4].S(Cl)([Cl:30])=O>>[Cl:30][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:27]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
One gram of 1,20-eicosanedicarboxylic acid monomethyl ester is dissolved in 5 ml of thionyl chloride. After stirring at room temperature for 12 hours, excess thionyl chloride is distilled off under reduced pressure to give crude crystals of methyl 21-chloroformylheneicosanoate. This product is submitted to the following step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:7][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=2[CH3:28])=[O:20])[CH2:11][CH2:10]1)#[N:38]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of the above aniline (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added cyclopropanecarbonyl chloride (14 μL, 0.15 mmol) and the solution was stirred at room temperature for 16 hours to afford COMPOUND 154 as a white solid (56 mg, 96%) following work-up and purification. 1H NMR (CDCl3) δ 0.74-0.79 (m, 2H), 0.98-1.15 (m, 7H), 1.43 (m, 1H), 1.56 (m, 1H), 1.74-1.79 (m, 3H), 2.19 (m, 1H), 2.50 (s, 6H), 2.58 (m, 1H), 2.75-2.87 (m, 3H), 3.32 (m, 1H), 3.57 (m, 1H), 3.82 (m, 1H), 3.89 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.26 (m, 3H), 7.39-7.44 (m, 1H), 7.49-7.53 (m, 3H), 8.64 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 7.64, 13.36, 15.44, 21.95, 29.04, 30.17, 30.77, 39.86, 43.64, 48.46, 51.94, 56.68, 60.10, 112.48, 114.66, 118.98, 121.61, 129.27, 129.43, 130.06, 130.58, 130.84, 131.12, 141.85, 144.86, 157.51, 163.09, 166.38, 171.62. ES-MS m/z 580 (M+H). Anal. Calcd. for C34H41N7O2.0.45CH2Cl2: C, 66.96; H, 6.83; N, 15.87. Found. C, 66.99; H, 7.02; N, 15.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(S(OC)(=O)=O)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12]
Reactant: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Agent: COS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a cold (−20° C.) solution of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M in THF) was added over a period of 40 minutes with the temperature of the reaction maintained at −20° C. After the addition was complete, the reaction mixture was stirred at −20° C. for one hour. Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100° C. for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane. Collection and concentration of appropriate fractions provide the title compound as oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([O:8][C:5]2[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)nc2)C1
Temperature: 90 °C
Yield: 29.5 %

Procedure:
In a 250 mL round bottom flask, added 6-Bromo-pyridin-3-ol (4.69 g, 26.95 mmol) and 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (7.63g, 26.95 mmol) and Cs2CO3 (12.26 g, 37.73 mmol) in DMF (10 mL) with stirring under argon. The reaction was heated at 90° C. overnight. Reaction was then poured onto water (200 mL). The crude product was extracted with EtOAc (3×50 mL). The organic extraction was concentrated and purified by flash chromatography with 10% EtOAc in Hexanes to afford product 2.62 g (yield 30%) of 3-(6-Bromo-pyridin-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide as a yellow solid (50 mg, 38%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (94 mg) and 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (120 mg) in DMF (3.0 mL) was added potassium carbonate (67 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (102 mg) as a colorless oil.